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CURRENT Medical Dx & Tx > Chapter 9. Pulmonary Disorders > Approach to the Patient >


 

PHYSICAL EXAMINATION

Examination of the patient with suspected pulmonary disease includes inspection, palpation, percussion, and auscultation of the chest. An efficient approach begins with observing the pattern of breathing, auscultation of the chest, and inspection for extrapulmonary signs of pulmonary disease. More detailed examination follows from initial findings.

The pattern of breathing refers to the respiratory rate and rhythm, the depth of breathing or tidal volume, and the relative amount of time spent in inspiration and expiration. Normal values are a rate of 12–14 breaths per minute, tidal volumes of 5 mL/kg, and a ratio of inspiratory to expiratory time of approximately 2:3. Tachypnea is an increased rate of breathing and is commonly associated with a decrease in tidal volume. Respiratory rhythm is normally regular, with a sigh (1.5–2 times normal tidal volume) every 90 breaths or so to prevent collapse of alveoli and atelectasis. Alterations in the rhythm of breathing include rapid, shallow breathing, seen in restrictive lung disease and as a precursor to respiratory failure; Kussmaul breathing, rapid large-volume breathing indicating intense stimulation of the respiratory center, seen in metabolic acidosis; and Cheyne-Stokes respiration, a rhythmic waxing and waning of both rate and tidal volumes that includes regular periods of apnea. This last pattern is seen in patients with end-stage left ventricular failure or neurologic disease and in many normal persons at high altitude, especially during sleep.

During normal quiet breathing, the primary muscle of respiration is the diaphragm. Movement of the chest wall is minimal. The use of accessory muscles of respiration, the intercostal and sternocleidomastoid muscles, indicates high work of breathing. At rest, the use of accessory muscles is a sign of significant pulmonary impairment. As the diaphragm contracts, it pushes the abdominal contents down. Hence, the chest and abdominal wall normally expand simultaneously. Expansion of the chest but collapse of the abdomen on inspiration indicates weakness of the diaphragm. The chest normally expands symmetrically. Asymmetric expansion suggests unilateral volume loss, as in atelectasis or pleural effusion, unilateral airway obstruction, asymmetric pulmonary or pleural fibrosis, or splinting from chest pain.

 

Chest percussion identifies dull areas that correspond to lung consolidation or pleural effusion or hyperresonant areas suggesting emphysema or pneumothorax. Percussion has a low sensitivity (10–20% in several studies) compared with chest radiographs to detect abnormalities. Specificity is high (85–99%). Since an insensitive test is a poor screening examination, percussion and palpation are not necessary in every patient. These techniques do serve as important confirmatory tests in specific patients when the prior probability of a finding is increased. For example, in a patient with a suspected tension pneumothorax, the finding of tracheal shift and hyperresonance can be lifesaving, permitting immediate decompression of the affected side.

Auscultation of the chest depends on a reliable and consistent classification of auditory findings. Normal lung sounds heard over the periphery of the lung are called vesicular ; . They have a gentle, rustling quality heard throughout inspiration that fades during expiration. Normal sounds heard over the suprasternal notch are called tracheal or bronchial lung sounds . They are louder, higher-pitched, and have a hollow quality that tends to be louder on expiration. Bronchial lung sounds heard over the periphery of the lung are abnormal and imply consolidation. Globally diminished lung sounds are an important finding predictive of significant airflow obstruction .

Audio

 


A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Audio

 


Recording of normal vesicular lung sounds. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Audio

 


Bronchial breath sounds recorded over an area of consolidation in a person with pneumonia. Note the loud expiratory phase, which helps to clarify these sounds as bronchial. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Audio

 


Recording of breath sounds in a person with emphysema. Note the diminished intensity of breath sounds in emphysema. The obstruction to air flow is more severe in expiration than in inspiration, and expiration is prolonged. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Abnormal lung sounds ("adventitious" breath sounds) may be continuous (> 80 ms in duration) or discontinuous (< 20 ms). Continuous lung sounds are divided into wheezes , which are high-pitched, musical, and have a distinct whistling quality; and , which are lower-pitched, sonorous, and may have a gurgling quality. Wheezes occur in the setting of bronchospasm, mucosal edema, or excessive secretions. In each case, the airway is narrowed to the point where adjacent airway walls flutter as airflow is limited. Rhonchi originate in the larger airways when excessive secretions and abnormal airway collapsibility cause repetitive rupture of fluid films. Rhonchi frequently clear after cough.

Audio

 


Lung sound: sibilant rhonchus, often called "wheezes." (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

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Lung sound: sonorous rhonchus. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Discontinuous lung sounds are called crackles—brief, discrete, nonmusical sounds with a popping quality. Fine crackles are soft, high-pitched, and crisp (< 10 ms in duration) . They are formed by the explosive opening of small airways previously held closed by surface forces and are heard in interstitial diseases or early pulmonary edema. Coarse crackles are louder, lower-pitched, and slightly longer in duration (< 20 ms) and probably result from gas bubbling through fluid . Coarse crackles are heard in pneumonia, obstructive lung disease, and late pulmonary edema.

Audio

 


Discontinuous lung sound: fine rales. Note that, in general, each individual rale is less loud and of shorter duration than the coarse rales. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

 

 


Discontinuous lung sound: coarse rales. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds

Interobserver agreement regarding auscultatory findings is good. The clinical usefulness of these findings is also well established. The presence of wheezes on physical examination is a powerful predictor of obstructive lung disease. The absence of wheezes is not helpful since patients may have significant airflow limitation without wheezing. Such patients will have globally diminished lung sounds as the clinical clue to their obstructive lung disease. Normal lung sounds exclude significant airway obstruction. The timing and character of crackles can reliably distinguish different pulmonary disorders. Fine, late inspiratory crackles suggest pulmonary fibrosis, while early coarse crackles suggest pneumonia or heart failure.

Extrapulmonary signs of intrinsic pulmonary disease include digital clubbing, cyanosis, elevation of central venous pressures, and lower extremity edema.

Digital clubbing (see photograph) refers to structural changes at the base of the nails that include softening of the nail bed and loss of the normal 150-degree angle between the nail and the cuticle. The distal phalanx is convex and enlarged: its thickness is equal to or greater than the thickness of the distal interphalangeal joint. Symmetric clubbing may be a normal variant but more commonly is a sign of underlying disease. Clubbing is seen in patients with chronic infections of the lungs and pleura (lung abscess, empyema, bronchiectasis, cystic fibrosis), malignancies of the lungs and pleura, chronic interstitial lung disease (idiopathic pulmonary fibrosis), and arteriovenous malformations. It does not normally accompany asthma or COPD; when seen in the latter, concomitant lung cancer should be suspected. It is observed less often in small-cell cancer than in other histologic types. Clubbing is not specific to pulmonary disorders; it is also seen in cyanotic congenital heart disease, infective endocarditis, cirrhosis, and inflammatory bowel disease. Hypertrophic pulmonary osteoarthropathy is a syndrome of digital clubbing, chronic proliferative periostitis of the long bones, and synovitis. It is seen in the same conditions as digital clubbing but is particularly common in bronchogenic carcinoma. The cause of clubbing and hypertrophic osteoarthropathy is not known with certainty, but the disorder may reflect platelet clumping and local release of platelet-derived growth factor at the nail bed. Both clubbing and osteoarthropathy may resolve with appropriate treatment of the underlying disease. Cyanosis is a blue or bluish-gray discoloration of the skin and mucous membranes caused by increased amounts (> 5 g/dL) of unsaturated hemoglobin in capillary blood. Since the oxygen saturation at which cyanosis becomes clinically apparent is a function of hemoglobin concentration, anemia may prevent cyanosis from appearing while polycythemia may lead to cyanosis in the setting of mild hypoxemia. Cyanosis is therefore not a reliable indicator of hypoxemia but should prompt direct measurement of arterial PO2 or of hemoglobin saturation.

Fig.

 

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Clubbing of the fingers. (Reproduced, with permission, from Cheitlin MD, Sokolow M, McIlroy MB: Clinical Cardiology, 6th ed. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)

Estimation of central venous pressure (CVP) (see illustration) and assessment of lower extremity edema are indirect measures of pulmonary hypertension, the major cardiovascular complication of chronic lung disease. Estimation of CVP can be done with precision in many patients. Elevated CVP is a pathologic finding associated with impaired ventricular function, pericardial effusion or restriction, valvular heart disease, and chronic obstructive or restrictive lung disease. Peripheral edema is a nonspecific finding that, in the setting of chronic lung disease, suggests right ventricular failure.

Bettencourt PE et al. Clinical utility of chest auscultation in common pulmonary diseases. Am J Respir Crit Care Med. 1994 Nov;150(5 Pt 1):1291–7. [PMID: 7952555]

 

Myers KA et al. Does this patient have clubbing? JAMA. 2001 Jul 18;286(3):341–7. [PMID: 11466101]

 

PULMONARY FUNCTION TESTS

Standard pulmonary function tests measure airflow rates, lung volumes, and the ability of the lung to transfer gas across the alveolar-capillary membrane. Indications for pulmonary function testing include assessment of the type and extent of lung dysfunction; diagnosis of causes of dyspnea and cough; detection of early evidence of lung dysfunction; longitudinal surveillance in occupational settings; follow-up of response to therapy; preoperative assessment; and disability evaluation.

Contraindications to pulmonary function testing include acute severe asthma, respiratory distress, angina aggravated by testing, pneumothorax, ongoing hemoptysis, and active tuberculosis. Many test results are effort-dependent, and some patients may be too impaired to make a maximal effort. Suboptimal effort limits validity and is a common cause of misinterpretation of results. All pulmonary function tests are measured against predicted values derived from large studies of healthy subjects. In general, these predictions vary with age, gender, height and, to a lesser extent, weight and ethnicity.

Spirometry (see box) and measurement of lung volumes allow assessment of the presence and severity of obstructive and restrictive pulmonary dysfunction. Obstructive dysfunction is marked by a reduction in airflow rates judged by a fall in the ratio of FEV1 (forced expiratory volume in the first second) to FVC (forced vital capacity). Causes include asthma, COPD (chronic bronchitis and emphysema), bronchiectasis, bronchiolitis, and upper airway obstruction. Restrictive dysfunction is marked by a reduction in lung volumes with a normal to increased FEV1/FVC ratio. Severity is graded by the reduction in total lung capacity. A reduced FVC suggests pulmonary restriction but is not diagnostic. Causes include decreased lung compliance from infiltrative disorders such as pulmonary fibrosis; reduced muscle strength from phrenic nerve injury, diaphragm dysfunction, or neuromuscular disease; pleural disease, including large pleural effusion or marked pleural thickening; and prior lung resection. The flow-volume loop combines the maximal expiratory and inspiratory flow-volume curves and is especially helpful in determining the site of airway obstruction. (See eFigure 9–1.0: illustration.)

Lung volumes, capacities, and the normal spirogram.

 

The volume of gas in the lungs is divided into volumes and capacities as shown in the bars to the left of the figure below. Lung volumes are primary: they do not overlap each other. Tidal volume (VT) is the amount of gas inhaled and exhaled with each resting breath. Residual volume (RV) is the amount of gas remaining in the lungs at the end of a maximal exhalation. The vital capacity (VC) is the total amount of gas that can be exhaled following a maximal inhalation. The vital capacity and the residual volume together constitute the total lung capacity (TLC), or the total amount of gas in the lungs at the end of a maximal inhalation. The functional residual capacity (FRC) is the amount of gas in the lungs at the end of a resting tidal breath. (IC = inspiratory capacity; IRV= inspiratory reserve volume; ERV = expiratory reserve volume.)

The forced vital capacity (FVC) maneuver begins with an inhalation from FRC to TLC (lasting about 1 second) followed by a forceful exhalation from TLC to RV (lasting about 5 seconds). The amount of gas exhaled during the first second of this maneuver is the forced expiratory volume in the first second (FEV1). Normal subjects expel approximately 80% of the FVC in the first second. The ratio of the FEV1 to the FVC (often referred to as the FEV1%) is diminished in patients with obstructive lung disease. It may be increased in patients with restrictive physiology.

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Modified, with permission, from Comroe JH et al: The Lung: Clinical Physiology and Pulmonary Function Tests, 2nd ed. Year Book Medical Publishers, 1962.

eFigure 9–1.0.

 

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Representative spirograms (upper panel) and expiratory flow-volume curves (lower panel) for normal (A), obstructive (B), and restrictive (C) patterns.

 

Spirometry is adequate for evaluation of most patients with suspected respiratory disease. If airflow obstruction is evident, spirometry may be repeated 10–20 minutes after an inhaled bronchodilator is administered. The absence of improvement in spirometry after inhaled bronchodilator in the pulmonary function laboratory does  preclude a successful clinical response to bronchodilator therapy. Measurements of lung volumes and diffusing capacity are useful in selected patients, but these tests are expensive and should not be ordered routinely with spirometry.

Measurement of the single-breath diffusing capacityLCO), which reflects the ability of the lung to transfer gas across the alveolar/capillary interface, is particularly helpful in evaluation of patients with diffuse infiltrative lung disease or emphysema. The total pulmonary diffusing capacity depends upon the diffusion properties of the alveolar-capillary membrane and the amount of hemoglobin occupying the pulmonary capillaries. The diffusing capacity should therefore be corrected for the blood hemoglobin concentration.*

*Corrected DLCO = Measured DLCO x (1.7 Hb/(10.22+Hb)), where [Hb] is the measured hemoglobin concentration (g/dL).

Elevated DLCO is observed in pulmonary hemorrhage and may be seen in acute congestive heart failure and asthma due to an increase in pulmonary capillary blood volume. Reporting the ratio of measured diffusing capacity to alveolar volume (DLCO/VA) is helpful, because a diminished diffusing capacity may only reflect a reduction in the breath taken during the maneuver. In patients with emphysema, the diffusing capacity is characteristically low, the alveolar volume normal or increased, and the DLCO/VA ratio is low. In patients with diffuse infiltrative lung disease, both the diffusing capacity and the alveolar volume are characteristically reduced, and the DLCO/VA ratio is normal or low.

In patients with AIDS, DLCO is a highly sensitive screening test for the presence of pulmonary disease, especially Pneumocystis jiroveci (formerly P carinii) pneumonia, but it lacks specificity. A normal DLCOPneumocystis pneumonia.

Arterial blood gas analysis is indicated whenever a clinically important acid-base disturbance, hypoxemia, or hypercapnia is suspected. Oximetry provides an inexpensive, noninvasive alternative means of monitoring hemoglobin saturation with oxygen. Oximeters monitor oxygen saturation and not oxygen tension. eFigure 9–1.1: illustration displays the normal relationship between oxygen saturation and partial pressure of oxygen in blood. This relationship is not linear. The clinical accuracy of pulse oximeters is reduced in such conditions as severe anemia (< 5 g/dL hemoglobin), the presence of abnormal hemoglobin moieties (carboxyhemoglobin, methemoglobin, fetal hemoglobin), the presence of intravascular dyes, motion artifact, and lack of pulsatile arterial blood flow (hypotension, hypothermia, cardiac arrest, simultaneous use of a blood pressure cuff, and cardiopulmonary bypass). Co-oximetry, a form of oximetry that uses additional wavelengths of light to identify oxyhemoglobin and deoxyhemoglobin, can identify the more common abnormal hemoglobins. The normal arterial PO2 falls with increasing altitude (eTable 9–1.0).

eTable 9–1.0. The effect of altitude on PO2 in normal adults.

 

Altitude (feet)

Barometric Pressure (mm Hg)

Atmospheric1 PO2 (mm Hg)

 

Tracheal2 PO2 (mm Hg)

 

Arterial3 PO2 (mm Hg)

 

Sea level

760

159

149

99

2000

707

148

138

88

4000

656

137

127

77

6000

609

127

118

 

8000

564

118

108

58

10,000

523

109

100

50

15,000

426

90

80

30

1Dry gas.

2Saturated with water vapor.

3Actual values at altitude will be higher, depending on the degree of adaptation (ventilatory response to hypoxia).

eFigure 9–1.1.

 

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Oxygen-hemoglobin dissociation curve, pH 7.40, temperature 38 °C. (Reproduced, with permission, from Comroe JH Jr et al: , 2nd ed. Year Book Medical Publishers, 1962.)

Nonspecific  may aid the evaluation of suspected asthma, when baseline spirometry is normal, and in unexplained cough. The subject inhales a nebulized solution containing methacholine or histamine. These agents cause bronchial smooth muscle constriction in asthmatic patients at much lower doses than in nonasthmatics. If the FEV1 falls by more than 20% at a dose of 16 mg/mL or less, the test is positive. Bronchial provocation testing is 95% sensitive for the diagnosis of asthma. A negative result therefore makes asthma unlikely. Specificity is lower—about 70%—since false positives may occur in several common conditions, including COPD, congestive heart failure, recent viral respiratory infection, cystic fibrosis, and sarcoidosis.

Evans SE et al. Current practice in pulmonary function testing. Mayo Clin Proc. 2003 Jun;78(6):758–63. [PMID: 12934788]

 

Miller MR et al. ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005 Jul;26(1):153–61. [PMID: 15994402]

 

Cardiopulmonary Exercise Stress Testing

Cardiopulmonary exercise testing is usually performed to evaluate patients with unexplained exertional dyspnea. A bicycle ergometer or treadmill is used. Minute ventilation, expired oxygen and carbon dioxide tension, heart rate, blood pressure, and respiratory rate are monitored. The exercise protocol is determined by the indications for the test and the ability of the patient to exercise. Certain patterns of abnormal oxygen uptake or delivery can be identified and may lead to specific pulmonary or cardiac diagnoses. The test is also used to quantify cardiorespiratory capacity. Complications are rare.

ERS Task Force; Palange P et al. Recommendations on the use of exercise testing in clinical practice. Eur Respir J. 2007 Jan;29(1):185–209. [PMID: 17197484]

 

Milani RV et al. Understanding the basics of cardiopulmonary exercise testing. Mayo Clin Proc. 2006 Dec;81(12):1603–11. [PMID: 17165639]

 

Bronchoscopy

Flexible bronchoscopy (see photograph); (see illustration) is an essential tool in the diagnosis and management of many pulmonary diseases. Bronchoscopy is indicated for evaluation of the airway, diagnosis and staging of bronchogenic carcinoma, evaluation of hemoptysis, and diagnosis of pulmonary infections. It allows transbronchial lung biopsy (see illustration), bronchoalveolar lavage, and removal of retained secretions and foreign bodies from the airway. procedure is contraindicated in severe bronchospasm or a bleeding diathesis. Complications include hemorrhage, fever, and transient hypoxemia. The rate of major complications is less than 1% but increases to about 7% when transbronchial lung biopsy is performed. Deaths are rare. Hospitalization for flexible bronchoscopy is not necessary.

Fig.

 

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A patient undergoing flexible fiberoptic bronchoscopy. (Courtesy of J Stauffer.)

 

Fig.

 

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Normal carina. (Reproduced, with permission, from Stradling P: Diagnostic Bronchoscopy. Churchill Livingstone, 1981.)

 

Fig.

 

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Forceps biopsy of cancer, left main stem bronchus. (Reproduced, with permission, from Stradling P: Diagnostic Bronchoscopy. Churchill Livingstone, 1981.)

Rigid bronchoscopy is performed for massive bleeding, extraction of large obstructing objects (foreign bodies, blood clots, tumor masses, broncholiths), biopsy of tracheal or main stem bronchus tumors and bronchial carcinoids, and facilitation of laser therapy. Unlike flexible bronchoscopy, which can usually be performed with only topical anesthesia and low-dose conscious sedation (an opioid or a benzodiazepine or both), rigid bronchoscopy usually requires general anesthesia.

Advances in techniques including endobronchial laser therapy, electrocautery, tracheobronchial stenting, and endobronchial ultrasound guidance to locate lymph nodes prior to transbronchial needle aspiration biopsy promise to expand diagnostic and therapeutic avenues available to the bronchoscopist significantly. This is an area of rapid technological advancement and emerging clinical research study.

Peikert T et al. Safety, diagnostic yield, and therapeutic implications of flexible bronchoscopy in patients with febrile neutropenia and pulmonary infiltrates. Mayo Clin Proc. 2005 Nov;80(11):1414–20. [PMID: 16295020]

 

Seijo LM et al. Interventional pulmonology. N Engl J Med. 2001 Mar 8;344(10):740–9. [PMID: 11236779]

 

DISORDERS OF THE AIRWAYS: INTRODUCTION

Airway disorders have diverse causes but share certain common pathophysiologic and clinical features. Airflow limitation is characteristic and frequently causes dyspnea and cough. Other symptoms are common and typically disease-specific. Disorders of the airways can be classified as those that involve the upper airways—loosely defined as those above and including the vocal folds—and those that involve the lower airways.

DISORDERS OF THE UPPER AIRWAYS

Upper airway obstruction may occur acutely or present as a chronic condition. Acute upper airway obstruction can be immediately life-threatening and must be relieved promptly to avoid asphyxia. Causes of acute upper airway obstruction include foreign body aspiration, laryngospasm, laryngeal edema from airway burns, angioedema, trauma to the larynx or pharynx, infections (Ludwig angina, pharyngeal or retropharyngeal abscess, acute epiglottis), and acute allergic laryngitis.

Chronic obstruction of the upper airway may be caused by carcinoma of the pharynx or larynx, laryngeal or subglottic stenosis, laryngeal granulomas or webs, or bilateral vocal fold paralysis. Laryngeal or subglottic stenosis may become evident weeks or months following a period of translaryngeal endotracheal intubation. Inspiratory stridor, intercostal retractions on inspiration, a palpable inspiratory thrill over the larynx, and wheezing localized to the neck or trachea on auscultation are characteristic findings. Flow-volume loops may show flow limitations characteristic of obstruction. Soft tissue radiographs of the neck may show supraglottic or infraglottic narrowing. CT and MRI scans can reveal exact sites of obstruction. Flexible endoscopy may be diagnostic, but caution is necessary to avoid exacerbating upper airway edema and precipitating critical airway narrowing.

Vocal fold dysfunction syndrome is a condition characterized by paradoxical vocal fold adduction, resulting in both acute and chronic upper airway obstruction. It can cause dyspnea and wheezing that may present as asthma or exercise-induced asthma; it may be distinguished from asthma by the lack of response to bronchodilator therapy, normal spirometry immediately after an attack, spirometric evidence of upper airway obstruction, a negative bronchial provocation test, or direct visualization of adduction of the vocal folds on both inspiration and expiration. The condition appears to be psychogenic in nature. Bronchodilators are of no therapeutic benefit. Treatment consists of speech therapy, which uses breathing, voice, and neck relaxation exercises to abort the symptoms.

Ernst A et al. Central airway obstruction. Am J Respir Crit Care Med. 2004 Jun 15;169(12):1278–97. [PMID: 15187010]

 

Mikita JA et al. Vocal cord dysfunction. Allergy Asthma Proc. 2006 Jul–Aug;27(4):411–4. [PMID: 16948360]

 

DISORDERS OF THE LOWER AIRWAYS

Tracheal obstruction may be intrathoracic (below the suprasternal notch) or extrathoracic. Fixed tracheal obstruction may be caused by acquired or congenital tracheal stenosis, primary or secondary tracheal neoplasms, extrinsic compression (tumors of the lung, thymus, or thyroid; lymphadenopathy; congenital vascular rings; aneurysms, etc), foreign body aspiration, tracheal granulomas and papillomas, and tracheal trauma.

Acquired tracheal stenosis is usually secondary to previous tracheotomy or endotracheal intubation. Dyspnea, cough, and inability to clear pulmonary secretions occur weeks to months after tracheal decannulation or extubation. Physical findings may be absent until tracheal diameter is reduced 50% or more, when wheezing, a palpable tracheal thrill, and harsh breath sounds may be detected . The diagnosis is usually confirmed by plain films or CT of the trachea. Complications include recurring pulmonary infection and life-threatening respiratory failure. Management is directed toward ensuring adequate ventilation and oxygenation and avoiding manipulative procedures that may increase edema of the tracheal mucosa. Surgical reconstruction, endotracheal stent placement, or laser photoresection may be required.

Audio

 


Recording of a person with tracheal stenosis. Note the high-pitched sound of inspiratory stridor. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Bronchial obstruction may be caused by retained pulmonary secretions, aspiration, foreign bodies, bronchogenic carcinoma, compression by extrinsic masses, and tumors metastatic to the airway. Clinical and radiographic findings vary depending on the location of the obstruction and the degree of airway narrowing. Symptoms include dyspnea, cough, wheezing, and, if infection is present, fever and chills. A history of recurrent pneumonia in the same lobe or segment or slow resolution (> 3 months) of pneumonia on successive radiographs suggests the possibility of bronchial obstruction and the need for bronchoscopy.

Roentgenographic findings include atelectasis (local parenchymal collapse), postobstructive infiltrates, and air trapping caused by unidirectional expiratory obstruction. CT scanning may demonstrate the nature and the exact location of obstruction of the central bronchi. MRI may be superior to CT for delineating the extent of the underlying disease in the hilum, but it is usually reserved for cases in which CT findings are equivocal. Bronchoscopy is the definitive diagnostic study, particularly if tumor or foreign body aspiration is suspected. The finding of bronchial breath sounds on physical examination or an air bronchogram on chest radiograph in an area of atelectasis rules out complete airway obstruction . Bronchoscopy is unlikely to be of therapeutic benefit in this situation.

Audio

 


Recording of a person with atelectasis. It shows slight bronchial breathing and fine inspiratory rales. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Right middle lobe syndrome is recurrent or persistent atelectasis of the right middle lobe. This collapse is related to the relatively long length and narrow diameter of the right middle lobe bronchus and the oval ("fish mouth") opening to the lobe, in the setting of impaired collateral ventilation. Fiberoptic bronchoscopy or CT scan is often necessary to rule out obstructing tumor. Foreign body or other benign causes are common.

Duggan M et al. Pulmonary atelectasis: a pathogenic perioperative entity. Anesthesiology. 2005 Apr;102(4):838–54. [PMID: 15791115]

 

Kwon KY et al. Middle lobe syndrome: a clinicopathological study of 21 patients. Hum Pathol. 1995 Mar;26(3):302–7. [PMID: 7890282]

 

ASTHMA

Essentials of Diagnosis

Episodic or chronic symptoms of airflow obstruction: breathlessness, chest tightness, wheezing, and cough.
Complete or partial reversibility of airflow obstruction, either spontaneously or following bronchodilator therapy.
Symptoms frequently worse at night or in the early morning.
Prolonged expiration and diffuse wheezes on physical examination.
Limitation of airflow on pulmonary function testing or positive bronchoprovocation challenge.

General Considerations

Asthma is a common disease, affecting approximately 5% of the population. It is slightly more common in male children (< 14 years old) and in female adults. A genetic predisposition to asthma is recognized. Prevalence, hospitalizations, and fatal asthma have all increased in the United States over the past 20 years. Each year, approximately 470,000 hospital admissions and 5000 deaths in the United States are attributed to asthma. Hospitalization rates have been highest among blacks and children, and death rates for asthma are consistently highest among blacks aged 15–24 years.

Definition & Pathogenesis

Asthma is a chronic inflammatory disorder of the airways. No single histopathologic feature is pathognomonic but common findings include inflammatory cell infiltration with eosinophils, neutrophils, and lymphocytes (especially T lymphocytes); goblet cell hyperplasia, sometimes with plugging of small airways with thick mucus; collagen deposition beneath the basement membrane; hypertrophy of bronchial smooth muscle; airway edema; mast cell activation; and denudation of airway epithelium. This airway inflammation underlies disease chronicity and contributes to airway hyper-responsiveness, airflow limitation, and respiratory symptoms, including recurrent episodes of wheezing, breathlessness, chest tightness, and cough.

The strongest identifiable predisposing factor for the development of asthma is atopy, but obesity is increasingly recognized as a risk factor. Exposure of sensitive patients to inhaled allergens increases airway inflammation, airway hyper-responsiveness, and symptoms. Symptoms may develop immediately (immediate asthmatic response) or 4–6 hours after allergen exposure (late asthmatic response). Common allergens include house dust mites (often found in pillows, mattresses, upholstered furniture, carpets, and drapes), cockroaches, cat dander, and seasonal pollens. Substantially reducing exposure reduces pathologic findings and clinical symptoms.

Nonspecific precipitants of asthma include exercise, upper respiratory tract infections, rhinitis, sinusitis, postnasal drip, aspiration, gastroesophageal reflux, changes in the weather, and stress. Exposure to environmental tobacco smoke increases asthma symptoms and the need for medications and reduces lung function. Increased air levels of respirable particles, ozone, SO2, and NO2 precipitate asthma symptoms and increase emergency department visits and hospitalizations. Selected individuals may experience asthma symptoms after exposure to aspirin, nonsteroidal anti-inflammatory drugs, or tartrazine dyes. Certain other medications may also precipitate asthma symptoms (see Table 9–21). Occupational asthma is triggered by various agents in the workplace and may occur weeks to years after initial exposure and sensitization. Women may experience catamenial asthma at predictable times during the menstrual cycle. Exercise-induced bronchoconstriction begins during exercise or within 3 minutes after its end, peaks within 10–15 minutes, and then resolves by 60 minutes. This phenomenon is thought to be a consequence of the airways' attempt to warm and humidify an increased volume of expired air during exercise. "Cardiac asthma" is wheezing precipitated by uncompensated congestive heart failure.

Clinical Findings

Symptoms and signs vary widely from patient to patient as well as individually over time. General clinical findings in stable asthma patients are listed in Figure 9–1 and Table 9–1; findings seen during asthma exacerbations are listed in Tables 9–2 and 9–3.

Figure 9–1.

 

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Classifying asthma severity and initiating treatment.

(Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007. www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm)

Table 9–1. Assessing asthma control.

 

 

Classification of Asthma Control

 

Well Controlled

Not Well Controlled

Very Poorly Controlled

Impairment

Symptoms

lesserorequal2 days/week

>2 days/week

Throughout the day

Nighttime awakenings

lesserorequal2x/month

1–3x/week

greaterorequal4x/week

Interference with normal activity

None

Some limitation

 

Short-acting betalower2-agonist use for symptom control (not prevention of EIB)

 

lesserorequal2 days/week

>2 days/week

Several times/day

FEV1 or peak flow

 

>80% predicted/personal best

60–80% predicted/personal best

<60% predicted/personal best

Validated questionnaires

 

 

 

 ATAQ

0

1–2

3–4

 ACQ

lesserorequal0.751

 

greaterorequal1.5

N/A

 

greaterorequal20

16–19

lesserorequal15

Risk

Exacerbations requiring oral system corticosteroids

0–1/year

greaterorequal2/year (see note)

Consider severity and interval since last exacerbation

Progressive loss of lung function

Evaluation requires long-term follow-up care

Treatment-related adverse effects

Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk.

Recommended Action for Treatment (see Figure 9–2 for steps)

Maintain current step
Regular follow-ups every 1–6 months to maintain control.
Consider step down if well controlled for at least 3 months
Step up 1 step and
Reevaluate in 2–6 weeks.
For side effects, consider alternative treatment options.
Consider short course of oral systemic corticosteroids,
Step up 1–2 steps, and
Reevaluate in 2 weeks
For side effects, consider alternative treatment options.

1ACQ values of 0.76–1.4 are indeterminate regarding well-controlled asthma.

 

 

The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs.
The level of control is based on the most severe impairment or risk category. Assess impairment domain by patient's recall of previous 2–4 weeks and by spirometry or peak flow measures. Symptom assessment for longer periods should reflect a global assessment, such as inquiring whether the patient's asthma is better or worse since the last visit.
At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (eg, requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had greaterorequal2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma.
Validated Questionnaires for the impairment domain (the questionnaire did not assess lung function or the risk domain).
ATAQ = Asthma Therapy Assessment Questionnaire©
ACQ = Asthma Control Questionnaire© (user package may be obtained at http://www.qoltech.co.uk or juniper@qoltech.co.uk)
ACT = Asthma Control Test™
Minimal Importance Difference: 1.0 for the ATAQ; 0.5 for the ACQ; not determined for the ACT.
Before step up in therapy:
—Review adherence to medication, inhaler
—If an alternative treatment option was used in a step, discontinue and use the preferred treatment for that step.

Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.

 

 

Note: Patients are instructed to use quick-relief medications if symptoms occur or if PEF drops below 80% predicted or personal best. If PEF is 50–79%, the patient should monitor response to quick relief medications carefully and consider contacting a clinician. If PEF is below 50%, immediate medical care is usually required. In the urgent or emergency care setting, the following parameters describe the severity and likely clinical course of an exacerbation.


 

Initial PEF (or FEV1)

Clinical Course

Mild

Dyspnea only with activity (assess tachypnea in young children)

PEV greaterorequal 70% predicted or personal best

bullsm Usually cared for at home

bullsm Prompt relief with inhaled SABA

bullsm Possible short course of oral systemic corticosteroids

Moderate

Dyspnea interferes with limits of usual activity

PEF 40–69% predicted or personal best

bullsm Usually requires office or ED visit

bullsm Relief from frequent inhaled SABA

bullsm Oral systemic corticosteroids; some symptoms last for 1–2 days after treatment is begun

Severe

Dyspnea at rest; interferes with conversation

PEF < 40% predicted or personal best

bullsm Usually requires ED visit and likely hospitalization

bullsm Partial relief from frequent inhaled SABA

bullsm Oral systemic corticosteroids; some symptoms last for > 3 days after treatment is begun

bullsm Adjunctive therapies are helpful

Subset: Life-threatening

Too dyspneic to speak; perspiring

PEF < 25% predicted or personal best

bullsm Requires ED/hospitalization; possible ICU

bullsm Minimal or no relief from frequent inhaled SABA

bullsm

bullsm Adjunctive therapies are helpful

PEF, peak expiratory flow; FEV1, forced expiratory volume in 1 second; SABA, short-acting betalower2-agonist; ED, emergency department; ICU, intensive care unit.

Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

Table 9–3. Evaluation of asthma exacerbation severity.

 

 

 

Moderate

Severe

Subset: Respiratory Arrest Imminent

Symptoms

Breathlessness

While walking

While at rest (infant—softer, shorter cry, difficulty feeding)

While at rest (infant—stops feeding)

 

 

Can lie down

Prefers sitting

Sits upright

 

Talks in

 

Phrases

Words

 

Alertness

May be agitated

Usually agitated

Usually agitated

Drowsy or confused

Signs

Respiratory rate

Increased

 

Often > 30/minute

 

Guide to rates of breathing in awake children:

Age

Normal Rate

< 2 months

< 60/minute

 

< 50/minute

1–5 years

< 40/minute

6–8 years

< 30/minute

 

Usually not

Commonly

Usually

Paradoxical thoracoabdominal movement

Wheeze

 

Loud; throughout exhalation

Usually loud; throughout inhalation and exhalation

Absence of wheeze

Pulse/minute

< 100

100–200

> 120

Bradycardia

Guide to normal pulse rates in children:

2–12 months

 

1–2 years

< 120/minute

2–8 years

< 110/minute

Pulsus paradoxus

Absent < 10 mm Hg

May be present 10–25 mm Hg

Often present > 25 mm Hg (adult)

Absence suggests respiratory muscle fatigue

20–40 mm Hg (child)

 

PEF

greaterorequal 70%

Approx. 40-69% or response lasts < 2 hours

< 40%

< 25%

Percent predicted or percent personal best

Note: PEF testing may not be needed in very severe attacks

PaO2 (on air)

 

Normal (test not usually necessary)

greaterorequal 60 mm Hg (test not usually necessary)

< 60 mm Hg: possible cyanosis

 

and/or PCO2

 

< 42 mm Hg (test not usually necessary)

< 42 mm Hg (test not usually necessary)

greaterorequal 42 mm Hg: possible respiratory failure

 

SaO2 percent (on air) at sea level

 

> 95% (test not usually necessary)

90-95% (test not usually necessary)

< 90%

 

Hypercapnia (hypoventilation) develops more readily in young children than in adults and adolescents.

PEF, peak expiratory low; SaO2, oxygen saturation.

Notes:

The presence of several parameters, but not necessarily all, indicates the general classification of the exacerbation.
Many of these parameters have not been systematically studied, especially as they correlate with each other. Thus, they serve only as general guides.
The emotional impact of asthma symptoms on the patient and family is variable but must be recognized and addressed and can affect approaches to treatment and follow-up.

Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

SYMPTOMS AND SIGNS

Asthma is characterized by episodic wheezing, difficulty in breathing, chest tightness, and cough. Excess sputum production is common. The frequency of asthma symptoms is highly variable. Some patients have infrequent, brief attacks of asthma while others may suffer nearly continuous symptoms. Asthma symptoms may occur spontaneously or may be precipitated or exacerbated by many different triggers as discussed above. Asthma symptoms are frequently worse at night; circadian variations in bronchomotor tone and bronchial reactivity reach their nadir between 3 AM and 4 AM, increasing symptoms of bronchoconstriction.

Some physical examination findings increase the probability of asthma. Nasal mucosal swelling, increased nasal secretions, and nasal polyps are often seen in patients with allergic asthma. Eczema, atopic dermatitis, or other manifestations of allergic skin disorders may also be present. Wheezing during normal breathing or a prolonged forced expiratory phase correlates well with the presence of airflow obstruction. Wheezing during forced expiration does not. Chest examination may be normal between exacerbations in patients with mild asthma. During severe asthma exacerbations, airflow may be too limited to produce wheezing, and the only diagnostic clue on auscultation may be globally reduced breath sounds with prolonged expiration . Hunched shoulders and use of accessory muscles of respiration suggest an increased work of breathing.

 

Clinicians are able to identify airflow obstruction on examination, but they have limited ability to assess it or to predict whether it is reversible. The evaluation for asthma should therefore include spirometry (FEV1, FVC, FEV1/FVC) before and after the administration of a short-acting bronchodilator (see illustration). These measurements help determine the presence and extent of airflow obstruction and whether it is immediately reversible. Airflow obstruction is indicated by a reduced FEV1/FVC ratio. Significant reversibility of airflow obstruction is defined by an increase of greaterorequal 12% and 200 mL in FEV1 or greaterorequal 15% and 200 mL in FVC after inhaling a short-acting bronchodilator. A positive bronchodilator response strongly confirms the diagnosis of asthma but a lack of responsiveness in the pulmonary function laboratory does not preclude success in a clinical trial of bronchodilator therapy. Severe airflow obstruction results in significant air trapping, with an increase in residual volume and consequent reduction in FVC, resulting in a pattern that suggests a restrictive ventilatory defect.

Fig.

 

loadBinaryCAG8BU2Y

Representative spirograms (upper panel) and expiratory flow-volume curves (lower panel) for normal (A), obstructive (B), and restrictive (C) patterns.

Bronchial provocation testing with inhaled histamine or methacholine may be useful when asthma is suspected but spirometry is nondiagnostic. Bronchial provocation is not recommended if the FEV1 is less than 65% of predicted. A positive methacholine test is defined as a greaterorequal 20% fall in the FEV1 at exposure to a concentration of 8 mg/mL or less. A negative test has a negative predictive value for asthma of 95%. Exercise challenge testing may be useful in patients with symptoms of exercise-induced bronchospasm.

Arterial blood gas measurements may be normal during a mild asthma exacerbation, but respiratory alkalosis and an increase in the alveolar-arterial oxygen difference (A–a–DO2) are common. During severe exacerbations, hypoxemia develops and the PaCO2 returns to normal. The combination of an increased PaCO2 and respiratory acidosis may indicate impending respiratory failure and the need for mechanical ventilation.

Peak expiratory flow (PEF) meters are handheld devices designed as personal monitoring tools. PEF monitoring can establish peak flow variability, quantify asthma severity, and provide both the patient and the clinician with objective measurements on which to base treatment decisions. There are conflicting data about whether measuring PEF improves asthma outcomes, but doing so is recommended to help confirm the diagnosis of asthma, to improve asthma control in patients with poor perception of airflow obstruction, and to identify environmental and occupational causes of symptoms. Predicted values for PEF vary with age, height, and gender but are poorly standardized. Comparison with reference values is less helpful than comparison with the patient's own baseline. PEF shows diurnal variation. It is generally lowest on first awakening and highest several hours before the midpoint of the waking day. PEF should be measured in the morning before the administration of a bronchodilator and in the afternoon after taking a bronchodilator. A 20% change in PEF values from morning to afternoon or from day to day suggests inadequately controlled asthma. PEF values less than 200 L/min indicate severe airflow obstruction.

ADDITIONAL TESTING

Routine chest radiographs in patients with asthma are usually normal or show only hyperinflation. Other findings may include bronchial wall thickening and diminished peripheral lung vascular shadows. Chest imaging is indicated when pneumonia, another disorder mimicking asthma, or a complication of asthma such as pneumothorax is suspected.

Skin testing or in vitro testing to assess sensitivity to environmental allergens can identify atopy in patients with persistent asthma who may benefit from therapies directed at their allergic diathesis. Evaluations for paranasal sinus disease or gastroesophageal reflux should be considered in patients with pertinent symptoms and in asthmatics with severe or refractory symptoms.

Noninvasive assessment of underlying airway inflammation through measurement of eosinophilia in induced sputum, or nitric oxide concentration in exhaled breath condensates (eNO), offers the promise of improved diagnosis and treatment strategies. Adjusting corticosteroid dose to minimize sputum eosinophilia appears to reduce the frequency of exacerbations compared with conventional clinical management, but the data are conflicting regarding the impact of eNO on asthma outcomes. This is an exciting and rapidly changing area of asthma care.

Complications

Complications of asthma include exhaustion, dehydration, airway infection, and tussive syncope. Pneumothorax occurs but is rare. Acute hypercapnic and hypoxic respiratory failure occurs in severe disease.

Differential Diagnosis

It is prudent to consider conditions that mimic asthma in patients who have atypical symptoms or poor response to therapy. These disorders typically fall into one of four categories: upper airway disorders, lower airway disorders, systemic vasculitides, and psychiatric disorders. Upper airway disorders that mimic asthma include vocal fold paralysis, vocal fold dysfunction syndrome, foreign body aspiration, laryngotracheal masses, tracheal narrowing, tracheomalacia, and airway edema as in the setting of angioedema or inhalation injury. Lower airway disorders include nonasthmatic COPD (chronic bronchitis or emphysema), bronchiectasis, allergic bronchopulmonary mycosis, cystic fibrosis, eosinophilic pneumonia, and bronchiolitis obliterans. Systemic vasculitides with pulmonary involvement may have an asthmatic component, such as Churg-Strauss syndrome. Psychiatric causes include conversion disorders, which have been variably referred to as functional asthma, emotional laryngeal wheezing, vocal fold dysfunction, or episodic laryngeal dyskinesis. Münchausen syndrome or malingering may rarely explain a patient's complaints.

NAEPP 3 Diagnosis & Management Guidelines

The National Asthma Education and Prevention Program (NAEPP), in conjunction with the Global Initiative for Asthma (GINA), a collaboration between the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO), recently released its third Expert Panel Report providing guidelines for diagnosis and management of asthma (NAEPP 3). This report identifies four components of chronic asthma diagnosis and management: (1) assessing and monitoring asthma severity and asthma control, (2) patient education designed to foster a partnership for care, (3) control of environmental factors and comorbid conditions that affect asthma, and (4) pharmacologic agents for asthma.

Assessing and monitoring asthma severity and asthma control

Severity is the intrinsic intensity of the disease process. Control is the degree to which symptoms and limitations on activity are minimized by therapy. Responsiveness is the ease with which control is achieved with therapy. NAEPP 3 guidelines now emphasize control over classifications of severity, since the latter is variable over time and in response to therapy. A measure of severity on initial presentation (see Figure 9–1) is helpful, however, in guiding the initiation of therapy. Control of asthma is assessed in terms of impairment (frequency and intensity of symptoms and functional limitations) and risk (the likelihood of acute exacerbations or chronic decline in lung function). A key insight is that these two domains of control may respond differently to treatment: some patients may have minimal impairment yet remain at risk for severe exacerbations, for example, in the setting of an upper respiratory tract infection. Table 9–1 is used to assess the adequacy of asthma control and is used in conjunction with Figure 9–2 to guide adjustments in therapy based on the level of control.

Figure 9–2.

 

loadBinaryCAT0BXNZ

Stepwise approach to managing asthma.

(Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm)

Patient education designed to foster a partnership for care

Active self-management reduces urgent care visits and hospitalizations and improves perceived control of asthma. Therefore, an outpatient preventive approach that includes self-management education is an integral part of effective asthma care. All patients, but particularly those with poorly controlled symptoms or a history of severe exacerbations, should have a written asthma action plan that includes instructions for daily management and measures to take in response to specific changes in status. Patients should be taught to recognize symptoms—especially patterns indicating inadequate asthma control or predicting the need for additional therapy.

Control of environmental factors and comorbid conditions that affect asthma

Significant reduction in exposure to nonspecific airway irritants or to inhaled allergens in atopic patients may reduce symptoms as well as medication needs. Comorbid conditions that impair asthma management, such as rhinosinusitis, gastroesophageal reflux, obesity, and obstructive sleep apnea, should be identified and treated. This search for complicating conditions is particularly crucial in the initial evaluation of a new diagnosis, and in patients whose asthma is difficult to control or subject to frequent exacerbations.

Pharmacologic agents for asthma

Asthma medications can be divided into two categories: quick-relief (reliever) medications that act principally by direct relaxation of bronchial smooth muscle, thereby promoting prompt reversal of acute airflow obstruction to relieve accompanying symptoms, and long-term control (controller) medications that act primarily to attenuate airway inflammation and are taken daily independent of symptoms to achieve and maintain control of persistent asthma. NAEPP 3 recommendations emphasize daily anti-inflammatory therapy with inhaled corticosteroids as the cornerstone of treatment of persistent asthma.

Most asthma medications are administered orally or by inhalation. Inhalation of an appropriate agent results in a more rapid onset of pulmonary effects as well as fewer systemic effects compared with oral administration of the same dose. Metered-dose inhalers (MDIs) propelled by chlorofluorocarbons (CFCs) have been the most widely used delivery system, but non-CFC propellant systems and dry powder inhalers (DPIs) are increasingly available. Proper MDI technique and the use of an inhalation chamber improve drug delivery to the lung and decrease oropharyngeal deposition. Nebulizer therapy is reserved for acutely ill patients and those who cannot use MDIs because of difficulties with coordination or cooperation.

TREATMENT

The goals of asthma therapy are to minimize chronic symptoms that interfere with normal activity (including exercise), to prevent recurrent exacerbations, to reduce or eliminate the need for emergency department visits or hospitalizations, and to maintain normal or near-normal pulmonary function. These goals should be met while providing pharmacotherapy with the fewest adverse effects and while meeting patients' and families' expectations of satisfaction with asthma care.

LONG-TERM CONTROL MEDICATIONS

Anti-inflammatory agents, long-acting bronchodilators, and leukotriene modifiers comprise the important long-term control medications (Tables 9–4 and 9–5). Other classes of agents are mentioned briefly below.

Table 9–4. Long-term control medications for asthma.

 

Medication

Dosage Form

Adult Dose

 

Inhaled Corticosteroids

Systemic Corticosteroids

(Applies to all three corticosteroids)

Methylprednisolone

2, 4, 6, 8, 16, 32 mg tablets

7.5-60 mg daily in a single dose in AM or every other day as needed for control

bullsm For long-term treatment of severe persistent asthma, administer single dose in a.m. either daily or on alternate days (alternate-day therapy may produce less adrenal suppression). Short courses or "bursts" are effective for establishing control when initiating therapy or during a period of gradual deterioration.

Prednisolone

5 mg tablets, 5 mg/5 mL, 15 mg/5 mL

Short-course "burst": to achieve control, 40-60 mg per day as single or 2 divided doses for 3-10 days

Prednisone

1, 2.5, 5, 10, 20, 50 mg tablets; 5 mg/mL, 5 mg/mL

 

bullsm There is no evidence that tapering the dose following improvement in symptom control and pulmonary function prevents relapse.

Inhaled Long-Acting betalower2-Agonists

bullsm Should not be used for symptom relief or exacerbations. Use with inhaled corticosteroids.

Salmeterol

DPI 50 mcg/blister

1 blister every 12 hors

bullsm Decreased duration of protection against EIB may occur with regular use.

bullsm Decreased duration of protection against EIB may occur with regular use.

Formoterol

DPI 12 mcg/single-use capsule

1 capsule every 12 hours

bullsm Each capsule is for single use only; additional doses should not be administered for at least 12 hours.

bullsm Capsules should be used only with the AerolizorTM inhaler and should not be taken orally.

 

Combined Medication

Fluticasone/Salmeterol

DPI

1 inhalation twice daily; dose depends on severity of asthma

bullsm 100/50 DPI or 45/21 HFA for patient not controlled on low- to medium-dose inhaled corticosteroids

100 mcg/50 mcg,

250 mcg/50 mcg, or

500 mcg/50 mcg

HFA

bullsm 250/50 DPI or 115/21 HFA for patients not controlled on medium- to high-dose inhaled corticosteroids

45 mcg/21 mcg

115 mcg/21 mcg

 

Budesonide/Formoterol

HFA MDI

2 inhalations twice daily; dose depends on severity of asthma

bullsm 80/4.5 for patients who have asthma not controlled on low- to medium-dose inhaled corticosteroids

80 mcg/4.5 mcg

bullsm 160/4.5 for patients who have asthma not controlled on medium- to high-dose inhaled corticosteroids

160 mcg/4.5 mcg

Cromolyn and Nedocromil

Cromolyn

MDI

2 puffs four times daily

bullsm 4–6 week trial may be needed to determine maximum benefit.

0.8 mg/puff

Nebulizer

1 ampule four times daily

bullsm Dose by MDI may be inadequate to affect hyperresponsiveness.

20 mg/ampule

Nedocromil

MDI

 

bullsm One dose before exercise or allergen exposure provides effective prophylaxis for 1-2 hours. Not as effective for EIB as SABA.

1.75 mg/puff

bullsm Once control is achieved, the frequency of dosing may be reduced.

Leukotriene Modifiers

Leukotriene Receptor Antagonists

Montelukast

4 mg or 5 mg chewable tablet

10 mg each night at bedtime

bullsm Montelukast exhibits a flat dose-response curve. Doses > 10 mg will not produce a greater response in adults.

10 mg tablet

Zafirlukast

10 or 20 mg tablet

40 mg daily (20 mg tablet twice daily)

bullsm For zafirlukast, administration with meals decreases bioavailability; take at least one hour before or 2 hours after meals.

bullsm Monitor for signs and symptoms of hepatic dysfunction.

5-Lipoxygenase inhibitor

Zileuton

600 mg tablet

2400 mg daily (600 mg four times daily)

bullsm For zileuton, monitor hepatic enzymes (ALT).

Methylxanthines

Theophylline

 

Starting dose 10 mg/kg/d up to 300 mg maximum; usual maximum 800 mg/d

bullsm Adjust dosage to achieve serum concentration of 5-15 mcg/mL at steady-state (at least 48 hours on same dosage).

 

 

 

bullsm Due to wide interpatient variability in theophylline metabolic clearance, routine serum theophylline level monitoring is important.

 

 

 

bullsm See below for factors that can affect theophylline levels.

Immunomodulators

Omalizumab

Subcutaneous injection, 150 mg/1.2 mL following reconstitution with 1.4 mL sterile water for injection

150–375 mg SC every 2–4 weeks, depending on body weight and pretreatment serum IgE level

bullsm Do not administer more than 150 mg per injection site.

bullsm Monitor for anaphylaxis for 2 hours following at least the first 3 injections.

Factor1,2

 

Decreases Theophylline Concentrations

Increases Theophylline Concentrations

Recommended Action

Food

downarrow or delays absorption of some sustained-release theophylline (SRT) products

uparrow rate of absorption (fatty foods)

bullsm Select theophylline preparation that is not affected by food.

 

uparrow metabolism (high protein)

downarrow metabolism (high carbohydrate)

bullsm Inform patients that major changes in diet are not recommended while taking theophylline.

Systemic, febrile viral illness (eg, influenza)

 

downarrow metabolism

bullsm Decrease theophylline dose according to serum concentration. Decrease dose by 50% if serum concentration measurement is not available.

 

 

downarrow metabolism

bullsm Decrease dose according to serum concentration.

Age

uparrow metabolism (1–9 years)

downarrow metabolism (< 6 months, elderly)

bullsm Adjust dose according to serum concentration.

Phenobarbital, phenytoin, carbamazepine

uparrow metabolism

 

bullsm Increase dose according to serum concentration.

Cimetidine

 

downarrow metabolism

bullsm Use alternative H2 blocker (eg, famotidine or ranitidine).

 

Macrolides: erythromycin, clarithromycin, troleandomycin

 

downarrow metabolism

bullsm Use alternative macrolide antibiotic, azithromycin, or alternative antibiotic or adjust theophylline dose.

Quinolones: ciprofloxacin, enoxacin, pefloxacin

 

downarrow metabolism

bullsm Use alternative antibiotic or adjust theophylline dose. Circumvent with ofloxacin if quinolone therapy is required.

Rifampin

uparrow metabolism

 

bullsm Increase dose according to serum concentration.

Ticlopidine

 

downarrow metabolism

bullsm

Smoking

uparrow metabolism

 

bullsm Advise patient to stop smoking; increase dose according to serum concentration.

1Factors affecting serum theophylline concentration.

2This list is not all inclusive; for discussion of other factors, see package inserts.

DPI, dry powder inhaler; EIB, exercise-induced bronchospasm; HFA, hydrofluoroalkane; IgE, immunoglobulin E; MDI, metered-dose inhaler; SABA, short-acting betalower2-agonist.

Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007.

http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

Table 9–5. Estimated comparative daily dosages for inhaled corticosteroids for asthma

 

Drug

Low Daily Dose Adult

Medium Daily Dose Adult

High Daily Dose Adult

Beclomethasone HFA

80–240 mcg

>240–480 mcg

>480 mcg

40 or 80 mcg/puff

Budesonide DPI

180–600 mcg

>600–1200 mcg

>1200 mcg

90, 180, or 200 mcg/inhalation

Flunisolide

500–1000 mcg

>1000–2000 mcg

 

250 mcg/puff

Flunisolide HFA

320 mcg

>320–640 mcg

>640 mcg

80 mcg/puff

Fluticasone

 

 

 

HFA/MDI: 44, 110, or 220 mcg/puff

88–264 mcg

>264–440 mcg

>440 mcg

DPI: 50, 100, or 250 mcg/inhalation

100–300 mcg

>300–500 mcg

 

Mometasone DPI

200 mcg

400 mcg

>400 mcg

 

Triamcinolone acetonide

300–750 mcg

>750–1500 mcg

>1500 mcg

75 mcg/puff

 

Notes:

The most important determinant of appropriate dosing is the clinician's judgment of the patient's response to therapy.
Some doses may be outside packaging labeling, especially in the high-dose range.
MDI dosages are expressed as the actuator dose (the amount of drug leaving the actuator and delivered to the patient), which is the labeling required in the United States. This is different from the dosage expressed as the valve dose (the amount of drug leaving the valve, not all of which is available to the patient), which is used in many European countries and in some scientific literature. DPI doses are expressed as the amount of drug in the inhaler following activation.
Comparative dosages are based on published comparative clinical trials. The rationale for some key comparisons is summarized as follows:
—The high dose is the dose that appears likely to be the threshold beyond which significant hypothalamic-pituitary adrenal (HPA) axis suppression is produced, and, by extrapolation, the risk is increased for other clinically significant systemic effects if used for prolonged periods of time.
—The low- and medium-doses reflect findings from dose-ranging studies in which incremental efficacy within the low- to medium-dose ranges was established without increased systemic effect as measured by overnight cortisol excretion. The studies demonstrated a relatively flat-dose response curve for efficacy at the medium-dose range; that is, increasing the dose of high-dose range did not significantly increase efficacy but did increase systemic effect.
—The dose for budesonide DPI is based on recently available comparative data with other medications. These new data, including meta-analyses, show that budesonide DPI is comparable to approximately twice the microgram dose of fluticasone MDI or DPI.
—The dose for beclomethasone in HFA inhaler should be approximately one-half the dose for beclomethasone in chlorofluorocarbon (CFC) inhaler for adults and children, based on studies demonstrating that the different pharmaceutical properties of the medications result in enhanced lung delivery for the HFA (a less forceful spray from the HFA propellant and a reengineered nozzle that allows a smaller particle size) and clinical trials demonstrating similar potency to fluticasone at 1:1 dose ratio.
—The dose for mometasone DPI is based on product information and current literature. Mometasone is approved for once daily administration. Mometasone furoate by dry powder achieved effects similar to twice the dose of budesonide by dry powder and comparable to a slightly higher dose of fluticasone propionate by dry powder.
—The dose for flunisolide HFA is based on product information and current literature.
Bioavailability Both the relative potency and the relative bioavailability (systemic availability) determine the potential for systemic activity of an inhaled corticosteroid preparation. As illustrated here, the bioavailability of an inhaled corticosteroid is dependent on the absorption of the dose delivered to the lungs and the oral bioavailability of the swallowed portion of the dose received.
loadBinary(3)
—Absorption of the dose delivered to the lungs:
Approximately 10–50% of the dose from the MDI is delivered to the lungs. This amount varies among preparations and delivery devices.
Nearly all of the amount delivered to the lungs is bioavailable.
—Oral bioavailability of the swallowed portion of the dose received:
Approximately 50–80% of the dose from the MDI without a spacer/holding chamber is swallowed.
The oral bioavailability of this amount varies:
Either a high first-pass metabolism or the use of a spacer/holding chamber with an MDI can decrease oral bioavailability, thus enhancing safety.
The approximate oral bioavailability of inhaled corticosteroids has been reported as: beclomethasone dipropionate 20% flunisolide, 21%; triamcinolone acetonide, 10.6%; budesonide, 11%; fluticasone propionate, 1%; mometasone, <1%.
Potential drug interactions A number of the inhaled corticosteroids, including fluticasone, budesonide, and mometasone, are metabolized in the gastrointestinal tract and liver by CYP 3A4 isoenzymes. Potent inhibitors of CYP 3A4, such as ritonavir and ketoconazole, have the potential for increasing systemic concentrations of these inhaled corticosteroids by increasing oral availability and decreasing systemic clearance. Some cases of clinically significant Cushing syndrome and secondary adrenal insufficiency have been reported (Johnson et al. 2006; Samaras et al. 2005).

Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007.

 

Anti-inflammatory agents

Corticosteroids are the most potent and consistently effective anti-inflammatory agents currently available. They reduce both acute and chronic inflammation, resulting in fewer asthma symptoms, improvement in airflow, decreased airway hyper-responsiveness, and fewer asthma exacerbations. These agents may also potentiate the action of betalower-adrenergic agonists.

Inhaled corticosteroids are preferred, first-line agents for all patients with persistent asthma. Patients with persistent symptoms or asthma exacerbations who are not taking inhaled corticosteroids should be started on an inhaled corticosteroid. The most important determinants of agent selection and appropriate dosing are the patient's status and response to treatment. Dosages for inhaled corticosteroids vary depending on the specific agent and delivery device. For most patients, twice-daily dosing provides adequate control of asthma. Once-daily dosing may be sufficient in selected patients. Maximum responses from inhaled corticosteroids may not be observed for months. The use of an inhalation chamber coupled with mouth washing after MDI use decreases local side effects (cough, dysphonia, oropharyngeal candidiasis) and systemic absorption. DPIs are not used with an inhalation chamber. Systemic effects (adrenal suppression, osteoporosis, skin thinning, easy bruising, and cataracts) may occur with high-dose inhaled corticosteroid therapy.

Systemic corticosteroids (oral or parenteral) are most effective in achieving prompt control of asthma during exacerbations or when initiating long-term asthma therapy in patients with severe symptoms. In patients with refractory, poorly controlled asthma, systemic corticosteroids may be required for the long-term suppression of symptoms. Repeated efforts should be made to reduce the dose to the minimum needed to control symptoms. Alternate-day treatment is preferred to daily treatment. Rapid discontinuation of systemic corticosteroids after chronic use may precipitate adrenal insufficiency. Concurrent treatment with calcium supplements and vitamin D should be initiated to prevent corticosteroid-induced bone mineral loss in long-term administration. Bisphosphonates may offer additional protection to these patients.

 

MEDIATOR INHIBITORS

Cromolyn sodium and nedocromil are long-term control medications that prevent asthma symptoms and improve airway function in patients with mild persistent asthma or exercise-induced symptoms. These agents modulate mast cell mediator release and eosinophil recruitment and inhibit both early and late asthmatic responses to allergen challenge and exercise-induced bronchospasm. They can be effective when taken before an exposure or exercise but do not relieve asthmatic symptoms once present. The clinical response to these agents is less predictable than the response to inhaled corticosteroids. Nedocromil may help reduce the dose requirements for inhaled corticosteroids. Both agents have excellent safety profiles.

betalower-ADRENERGIC AGONISTS

betalower2-agonists provide bronchodilation for up to 12 hours after a single dose. Salmeterol and formoterol are the two long-acting betalower2-agonists available in the United States. They are administered via dry powder delivery devices. They are indicated for long-term prevention of asthma symptoms, nocturnal symptoms, and for prevention of exercise-induced bronchospasm. When added to standard doses of inhaled corticosteroids, long-acting betalower2-agonists provide control equivalent to what is achieved by doubling the inhaled corticosteroid dose. Side effects are minimal at standard doses. Long-acting betalower2-agonists should not be used as monotherapy since they have no anti-inflammatory effect and since monotherapy with long-acting betalower2-agonists has been associated in two large studies with a small but statistically significant increased risk of severe or fatal asthma attacks. This increased risk may relate to genetic variation in the betalower-adrenergic receptor, but it has not been fully explained and remains an area of controversy. The efficacy of combined inhaled corticosteroid and long-acting betalower2-agonist therapy has led to marketing of combination medications that deliver both agents simultaneously (see Table 9–4). Combination inhalers containing formoterol and budesonide have shown efficacy in both maintenance and rescue, given formoterol's short time to onset.

PHOSPHODIESTERASE INHIBITORS

Theophylline provides mild bronchodilation in asthmatic patients. This drug has modest anti-inflammatory properties, enhances mucociliary clearance, and strengthens diaphragmatic contractility. Sustained-release theophylline preparations are effective in controlling nocturnal asthma and are usually reserved for use as adjuvant therapy in patients with moderate or severe persistent asthma. Theophylline serum concentrations need to be monitored closely owing to the drug's narrow toxic-therapeutic range, individual differences in metabolism, and the effects of many factors on drug absorption and metabolism. Decreases in theophylline clearance accompany the use of cimetidine, macrolide and quinolone antibiotics, and oral contraceptives. Increases in theophylline clearance are caused by rifampin, phenytoin, barbiturates, and tobacco.

Adverse effects at therapeutic doses include insomnia, upset stomach, aggravation of dyspepsia and gastroesophageal reflux symptoms, and urination difficulties in elderly men with prostatism. Dose-related toxicities are common and include nausea, vomiting, tachyarrhythmias, headache, seizures, hyperglycemia and hypokalemia.

Leukotriene modifiers

Leukotrienes are potent biochemical mediators that contribute to airway obstruction and asthma symptoms by contracting airway smooth muscle, increasing vascular permeability and mucus secretion, and attracting and activating airway inflammatory cells. Zileuton is a 5-lipoxygenase inhibitor that decreases leukotriene production, and zafirlukast and montelukast are cysteinyl leukotriene receptor antagonists. They cause modest improvements in lung function and reductions in asthma symptoms and lessen the need for betalower2-agonist rescue therapy. These agents are alternatives to low-dose inhaled corticosteroids in patients with mild persistent asthma, although, as monotherapy, their effect is generally less than inhaled corticosteroids. Zileuton can cause reversible elevations in plasma aminotransferase levels, and Churg-Strauss syndrome has been diagnosed in a small number of patients who have taken montelukast or zafirlukast, although this is suspected to be an effect of corticosteroid withdrawal as opposed to a direct drug effect.

Desensitization

Immunotherapy for specific allergens may be considered in selected asthma patients who have exacerbations of asthma symptoms when exposed to allergens to which they are sensitive and who do not respond to environmental control measures or other forms of conventional therapy. Studies show a reduction in asthma symptoms in patients treated with single-allergen immunotherapy. Because of the risk of immunotherapy-induced bronchoconstriction, it should be administered only in a setting where such complications can be immediately treated.

Vaccination

Patients with asthma should receive pneumococcal vaccination (Pneumovax) and annual influenza vaccinations. Inactive vaccines (Pneumovax) are associated with few side effects but use of the live attenuated influenza vaccine intranasally may be associated with an increase in asthma exacerbations in young children.

Miscellaneous agents

Oral sustained-release betalower2-agonists are reserved for patients with bothersome nocturnal asthma symptoms or moderate to severe persistent asthma who do not respond to other therapies. Omalizumab is a recombinant antibody that binds IgE without activating mast cells. In clinical trials in moderate to severe asthmatic patients with elevated IgE levels, it reduces the need for corticosteroids. Etanercept, a soluble TNF-alphalower receptor antagonist, has shown modest efficacy in one small study of severe asthma.

QUICK-RELIEF MEDICATIONS

Short-acting bronchodilators and systemic corticosteroids comprise the important medications in this group of agents (Table 9–6).

Table 9–6. Quick-relief medications for asthma.

 

Medication

Dosage form

Adult dose

Comments

betalower2-Agonists

 

MDI

 

 

Albuterol CFC

90 mcg/puff, 200 puffs/canister

2 puffs 5 minutes before exercise

An increasing use or lack of expected effect indicates diminished control of asthma.
Not recommended for long-term daily treatment. Regular use exceeding 2 days/week for symptom control (not prevention of EIB) indicates the need to step up therapy.
Differences in potency exist, but all products are essentially comparable on a per puff basis.
May double usual dose for mild exacerbations.
Should prime the inhaler by releasing four actuations prior to use.
Periodically clean HFA activator, as drug may block/plug orifice.
Nonselective agents (ie epinephrine, isoproterenol, metaproterenol) are not recommended due to their potential for excessive cardiac stimulation, especially in high doses.

Albuterol HFA

90 mcg/puff, 200 puffs/canister

2 puffs every 4–6 hours as needed

Pirbuterol CFC

200 mcg/puff, 400 puffs/canister

 

Levalbuterol HFA

45 mcg/puff, 200 puffs/canister

 

 

Nebulizer solution

 

 

Albuterol

0.63 mg/3 mL

1.25–5 mg in 3 mL of saline every 4–8 hours as needed

May mix with budesonide inhalant suspension, cromolyn or ipratropium nebulizer solutions. May double dose for severe exacerbations.

1.25 mg/3 mL

2.5 mg/3 mL

5 mg/mL (0.5%)

Levalbuterol (R-albuterol)

0.31 mg/3 mL

0.63–1.25 mg every 8 hours as needed

Compatible with budesonide inhalant suspension. The product is a sterile-filled, preservative-free, unit dose vial.

0.63 mg/3 mL

1.25 mg/0.5 mL

1.25 mg/3 mL

Anticholinergics

 

MDI

 

 

 

17 mcg/puff, 200 puffs/canister

2–3 puffs every 6 hours

Evidence is lacking for anticholinergics producing added benefit to betalower2-agonists in long-term control asthma therapy.

Nebulizer solution

 

 

0.25 mg/mL (0.025%)

0.25 mg every 6 hours

 

MDI

 

 

Ipratropium with albuterol

18 mcg/puff of ipratropium bromide and 90 mcg/puff of albuterol

2–3 puffs every 6 hours

 

200 puffs/canister

 

 

Nebulizer solution

 

 

0.5 mg/3 mL ipratropium bromide and 2.5 mg/3 mL albuterol

3 mL every 4–6 hours

Contains EDTA to prevent discolorations of the solution. This additive does not induce bronchospasm.

Systemic Corticosteroids

Methylprednisolone

2, 4, 6, 8, 16, 32 mg tablets

Short course "burst": 40–60 mg/d as single or 2 divided doses for 3–10 days

Short courses or "bursts" are effective for establishing control when initiating therapy or during a period of gradual deterioration.
The burst should be continued until symptoms resolve and the PEF is at least 80% of personal best. This usually requires 3–10 days but may require longer. There is no evidence that tapering the dose following improvements prevents relapse.
May be used in place of a short burst of oral corticosteroids in patients who are vomiting or if adherence is a problem.

Prednisolone

5 mg tablets, 5 mg/5 mL, 15 mg/5 mL

 

Prednisone

 

 

 

Repository injection

 

 

(Methylprednisolone acetate)

40 mg/mL

240 mg IM once

 

80 mg/mL

CFC, chlorofluorocarbon; EIB, exercise-induced bronchospasm; HFA, hydrofluoroalkane; IM, intramuscular; MDI, metered-dose inhaler; PEF, peak expiratory flow.

Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007.

http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

betalower-Adrenergic agonists

Short-acting inhaled betalower2-agonists, including albuterol, levalbuterol, bitolterol, pirbuterol, and terbutaline, are the most effective bronchodilators during exacerbations. All patients with acute symptoms should take one of these agents. There is no convincing evidence to support the use of one agent over another. betalower2-Agonists relax airway smooth muscle and cause a prompt increase in airflow and reduction of symptoms. Administration before exercise effectively prevents exercise-induced bronchoconstriction. betalower2-Selective agents may produce less cardiac stimulation than those with mixed betalower1 and betalower2 activities, although clinical trials have not consistently demonstrated this finding.

Inhaled betalower-adrenergic therapy is as effective as oral or parenteral therapy in relaxing airway smooth muscle and improving acute asthma and offers the advantages of rapid onset of action (< 5 minutes) with fewer systemic side effects. Repetitive administration produces incremental bronchodilation. Intravenous and subcutaneous routes of administration should be reserved for patients who because of age or mechanical factors are unable to inhale medications.

One or two inhalations of a short-acting inhaled betalower2-agonist from an MDI are usually sufficient for mild to moderate symptoms. Severe exacerbations frequently require higher doses: 6–12 puffs every 30–60 minutes of albuterol by MDI with an inhalation chamber or 2.5 mg by nebulizer provide equivalent bronchodilation. Administration by wet nebulization does not offer more effective delivery than MDIs but does provide higher doses. With most betalower2-agonists, the recommended dose by nebulizer for acute asthma (albuterol, 2.5 mg) is 25–30 times that delivered by a single activation of the MDI (albuterol, 0.09 mg). This difference suggests that standard dosing of inhalations from an MDI will often be insufficient in the setting of an acute exacerbation. Independent of dose, nebulizer therapy may be more effective in patients who are unable to coordinate inhalation of medication from an MDI because of age, agitation, or severity of the exacerbation.

Scheduled daily use of short-acting betalower2-agonists is not recommended. Increased use (more than one canister a month) or lack of expected effect indicates diminished asthma control and dictates the need for additional long-term control therapy.

Anticholinergics

Anticholinergic agents reverse vagally mediated bronchospasm but not allergen- or exercise-induced bronchospasm. They may decrease mucus gland hypersecretion seen in asthma. Ipratropium bromide, a quaternary derivative of atropine free of atropine's side effects, is less effective than betalower2-agonists for relief of acute bronchospasm, but it is the inhaled drug of choice for patients with intolerance to betalower2betalower-blocker medications. Ipratropium bromide reduces the rate of hospital admissions when added to inhaled short-acting betalower2-agonists in patients with moderate to severe asthma exacerbations. The role of anticholinergic agents in long-term management of asthma has not been clarified.

Phosphodiesterase inhibitors

Methylxanthines are not recommended for therapy of asthma exacerbations. Aminophylline has clearly been shown to be less effective than betalower2-agonists when used as single-drug therapy for acute asthma and adds little except toxicity to the acute bronchodilator effects achieved by nebulized metaproterenol alone. Patients with exacerbations who are currently taking a theophylline-containing preparation should have their serum theophylline concentration measured to exclude theophylline toxicity.

Corticosteroids

Systemic corticosteroids are effective primary treatment for patients with moderate to severe asthma exacerbations and for patients with exacerbations who do not respond promptly and completely to inhaled betalower2-agonist therapy. These medications speed the resolution of airflow obstruction and reduce the rate of relapse. Delays in administering corticosteroids may result in delayed benefits from these important agents. Therefore, oral corticosteroids should be available for early administration at home in many patients with moderate to severe asthma. The minimal effective dose of systemic corticosteroids for asthma patients has not been identified. Outpatient prednisone "burst" therapy is 0.5–1 mg/kg/d (typically 40–60 mg) as a single or in two divided doses for 3–10 days. Severe exacerbations requiring hospitalization typically require 1 mg/kg of prednisone equivalent every 6–12 hours for 48 hours or until the FEV1 (or PEF rate) returns to 50% of predicted (or 50% of baseline). The dose is then decreased to 60–80 mg/d until the PEF reaches 70% of predicted or personal best. No clear advantage has been found for higher doses of corticosteroids in severe exacerbations. It may be prudent to administer corticosteroids to critically ill patients via the intravenous route in order to avoid concerns about altered gastrointestinal absorption.

Antimicrobials

Empiric antibiotics are not recommended in routine asthma exacerbations, although antibiotics that cover atypical organisms (eg, telithromycin) are an area of ongoing research. Antibiotics may be useful if bacterial respiratory tract infections are thought to contribute. Thus, patients with fever or purulent sputum and evidence of pneumonia or bacterial sinusitis are reasonable candidates for such therapy.

Treatment of Asthma Exacerbations

NAEPP 3 asthma treatment algorithms begin with an assessment of the severity of a patient's baseline asthma. Adjustments to that algorithm follow a stepwise approach based on a careful assessment of asthma control. Most instances of uncontrolled asthma are mild and can be managed successfully by patients at home with the telephone assistance of a clinician (Figure 9–3).

 

 

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Management of asthma exacerbations: home treatment. (Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm)

 

More severe exacerbations require evaluation and management in an urgent care or emergency department setting (Figure 9–4).

Figure 9–4.

 

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Management of asthma exacerbations: emergency department and hospital-based treatment. (Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 08-4051. Bethesda, MD, 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm)

MILD EXACERBATIONS

betalower2-agonist alone. However, an inhaled short-acting betalower2-agonist may need to be continued at increased doses, eg, every 3–4 hours for 24–48 hours. In patients not taking an inhaled corticosteroid, initiation of this agent should be considered.

In patients already taking an inhaled corticosteroid, a 7-day course of oral corticosteroids (0.5–1.0 mg/kg/d) may be necessary. Doubling the dose of inhaled corticosteroid is not effective and is not recommended in the NAEPP 3 guidelines.

MODERATE EXACERBATIONS

betalower2-agonist and the early administration of systemic corticosteroids. Serial measurements of lung function to quantify the severity of airflow obstruction and its response to treatment are useful. The improvement in FEV1 after 30 minutes of treatment correlates significantly with a broad range of indices of the severity of asthma exacerbations. Serial measurement of airflow in the emergency department is an important factor in disposition and may reduce the rate of hospital admissions for asthma exacerbations. The post-exacerbation care plan is an important aspect of management. Regardless of the severity, all patients should be provided with necessary medications and education in how to use them, instruction in self-assessment, a follow-up appointment, and instruction in an action plan for managing recurrence.

SEVERE EXACERBATIONS

Owing to the life-threatening nature of severe exacerbations of asthma, treatment should be started immediately once the exacerbation is recognized. All patients with a severe exacerbation should immediately receive oxygen, high doses of an inhaled short-acting betalower2-agonist, and systemic corticosteroids. A brief history pertinent to the exacerbation can be completed while treatment is being initiated. More detailed assessments, including laboratory studies, usually add little in the early phase of evaluation and management and should be postponed until after therapy is instituted.

Asphyxia is a common cause of fatal asthma, and oxygen therapy is therefore very important. Supplemental oxygen should be given to maintain an SaO > 90% or a PaO2 > 60 mm Hg. Oxygen-induced hypoventilation is extremely rare, and concern for hypercapnia should never delay correction of hypoxemia.

Frequent high-dose delivery of an inhaled short-acting betalower-agonist is indicated and is usually well tolerated in the setting of severe airway obstruction. Some studies suggest that continuous therapy is more efficacious than intermittent administration of these agents, but there is no clear consensus as long as similar doses are administered. At least three MDI or nebulizer treatments should be given in the first hour of therapy. Thereafter, the frequency of administration varies according to the improvement in airflow and associated symptoms and the occurrence of side effects. Ipratropium bromide reduces the rate of hospital admissions when added to inhaled short-acting betalower2-agonists in patients with moderate to severe asthma exacerbations.

1 < 25% of predicted on presentation, or failure to respond to initial treatment), intravenous magnesium sulfate (2 g intravenously over 20 minutes) produces a detectable improvement in airflow and may reduce hospitalization rates.

Repeat assessment of patients with severe exacerbations should be made after the initial dose of inhaled bronchodilator and after three doses of inhaled bronchodilators (60–90 minutes after initiating treatment). The response to initial treatment is a better predictor of the need for hospitalization than is the severity of an exacerbation on presentation. The decision to hospitalize a patient should be based on the duration and severity of symptoms, severity of airflow obstruction, course and severity of prior exacerbations, medication use at the time of the exacerbation, access to medical care and medications, adequacy of social support and home conditions, and presence of psychiatric illness. In general, discharge to home is appropriate if the PEF or FEV1 has returned to greaterorequal 60% of predicted or personal best and symptoms are minimal or absent. Patients with a rapid response to treatment should be observed for 30 minutes after the most recent dose of bronchodilator to ensure stability of response before discharge to home.

A small subset of patients will not respond well to treatment and will show signs of impending respiratory failure due to a combination of worsening airflow obstruction and respiratory muscle fatigue (Table 9–3). Such patients can deteriorate rapidly and thus should be monitored in a critical care setting. Intubation of an acutely ill asthma patient is technically difficult and is best done semi-electively, before the crisis of a respiratory arrest. At the time of intubation, close attention should be given to maintaining intravascular volume because hypotension commonly accompanies the administration of sedation and the initiation of positive-pressure ventilation in patients dehydrated due to poor recent oral intake and high insensible losses.

The main goals of mechanical ventilation are to ensure adequate oxygen and to avoid barotrauma. Controlled hypoventilation with permissive hypercapnia is often required to limit airway pressures. Frequent high-dose delivery of inhaled short-acting betalower2-agonists should be continued along with anti-inflammatory agents as discussed above. Many questions remain regarding the optimal delivery of inhaled betalower2-agonists to intubated, mechanically ventilated patients. Further studies are needed to determine the comparative efficacy of MDIs and nebulizers, optimal ventilator settings to use during drug delivery, ideal site along the ventilator circuit for introduction of the delivery system, and maximal acceptable drug doses. In acute severe asthma (FEV1 < 25% of predicted), intravenous magnesium sulfate produces a detectable but clinically insignificant improvement in airflow. Unconventional therapies such as helium-oxygen mixtures and inhalational anesthetic agents are of unclear benefit but may be appropriate in selected patients.

When to Refer

Atypical presentation or uncertain diagnosis, particularly if additional diagnostic testing is required (bronchoprovocation challenge, skin testing for allergies, rhinoscopy, consideration of occupational exposure).
Complicating comorbid problems, such as rhinosinusitis, tobacco use, multiple environmental allergies, suspected allergic bronchopulmonary aspergillosis.
Suboptimal response to therapy.
Patient is not meeting goals of asthma therapy after 3–6 months of treatment.
Adult patient requires high-dose inhaled corticosteroids for control.
Patient has required more than two courses of oral prednisone therapy in the past 12 months.
Patient has an exacerbation requiring hospitalization in the past 12 months.
Patient has ever had a life-threatening asthma exacerbation.
Presence of social or psychological issues interfering with asthma management.

Aldington S et al. Asthma exacerbations. 5: Assessment and management of severe asthma in adults in hospital. Thorax. 2007 May ;62(5):447–58. [PMID: 17468458]

 

Global Initiative for Asthma. Full text available online at http://www.ginasthma.com

 

Ibrahim WH et al. Paradoxical vocal cord motion disorder: past, present and future. Postgrad Med J. 2007 Mar;83(977):164–72. [PMID: 17344570]

 

National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051). Full text available online: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

 

Panettieri RA Jr. In the clinic. Asthma. Ann Intern Med. 2007 Jun 5;146(11):ITC6-1–ITC6-16. [PMID: 17548407]

 

Pinnock H et al. Asthma. BMJ. 2007 Apr 21;334(7598):847–50. [PMID: 17446617]

 

Rey E et al. Asthma in pregnancy. BMJ. 2007 Mar 17;334(7593):582–5. [PMID: 17363831]

 

Tilles SA. Differential diagnosis of adult asthma. Med Clin North Am. 2006 Jan;90(1):61–76. [PMID: 16310524]

 

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Essentials of Diagnosis

History of cigarette smoking.
Chronic cough, dyspnea (in emphysema), and sputum production (in chronic bronchitis).
Rhonchi, decreased intensity of breath sounds, and prolonged expiration on physical examination ; .
Airflow limitation on pulmonary function testing that is not fully reversible and most often progressive (see illustration).

Audio

 


Breath sound from a patient with severe long-term chronic obstructive lung disease. The patient was in respiratory distress because of a cyst on his larynx, causing stridor. The stridor can be distinguished by the inspiratory extenuation of the higher-pitched continuous noise. (Reproduced, with permission, from "Self-Assessment on Sounds of the Chest," narrated by Raymond Murphy, Jr., MD [vinyl record distributed by ACCP at 43rd Annual Scientific Assembly, Las Vegas, 1977].)

General Considerations

 

Most patients with COPD have features of both emphysema and chronic bronchitis. Chronic bronchitis is a clinical diagnosis defined by excessive secretion of bronchial mucus and is manifested by daily productive cough for 3 months or more in at least 2 consecutive years. Emphysema is a pathologic diagnosis that denotes abnormal permanent enlargement of air spaces distal to the terminal bronchiole, with destruction of their walls and without obvious fibrosis (see micrograph).

Fig.

 

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Normal lung (A) compared with emphysema (B) at equivalent magnification, showing destruction of lung parenchyma and marked dilation of terminal air spaces in emphysema, both microscopically (B) and grossly (C)Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)

Cigarette smoking is clearly the most important cause of COPD in North America and Western Europe. Nearly all smokers suffer an accelerated decline in lung function that is dose- and duration-dependent. Fifteen percent develop progressively disabling symptoms in their 40s and 50s. It is estimated that 80% of patients seen for COPD have significant exposure to tobacco smoke. The remaining 20% frequently have a combination of exposures to environmental tobacco smoke, occupational dusts and chemicals, and indoor air pollution from biomass fuel used for cooking and heating in poorly ventilated buildings. Outdoor air pollution, airway infection, familial factors, and allergy have also been implicated in chronic bronchitis, and hereditary factors (deficiency of alphalower1-antiprotease [alphalower1-antitrypsin]) have been implicated in COPD. The pathogenesis of emphysema may involve excessive lysis of elastin and other structural proteins in the lung matrix by elastase and other proteases derived from lung neutrophils, macrophages, and mononuclear cells. Atopy and the tendency for bronchoconstriction to develop in response to nonspecific airway stimuli may be important risks for COPD.

Clinical Findings

SYMPTOMS AND SIGNS

Patients with COPD characteristically present in the fifth or sixth decade of life complaining of excessive cough, sputum production, and shortness of breath. Symptoms have often been present for 10 years or more. Dyspnea is noted initially only on heavy exertion, but as the condition progresses it occurs with mild activity. In severe disease, dyspnea occurs at rest. Pneumonia, pulmonary hypertension, cor pulmonale, and chronic respiratory failure characterize the late stage of COPD. A hallmark of COPD is the exacerbation of symptoms beyond normal day-to-day variation, often including increased dyspnea, an increased frequency or severity of cough, increased sputum volume or changes in sputum character. These exacerbations are commonly precipitated by infection (more common viral than bacterial) or environmental factors. Exacerbations of COPD typically require a change in regular therapy, and vary widely in severity.

 

Table 9–7. Patterns of disease in advanced COPD.

 

 

Type A: Pink Puffer (Emphysema Predominant)

Type B: Blue Bloater (Bronchitis Predominant)

History and physical examination

Major complaint is dyspnea, often severe, usually presenting after age 50. Cough is rare, with scant clear, mucoid sputum. Patients are thin, with recent weight loss common. They appear uncomfortable, with evident use of accessory muscles of respiration. Chest is very quiet without adventitious sounds. No peripheral edema.

Major complaint is chronic cough, productive of mucopurulent sputum, with frequent exacerbations due to chest infections. Often presents in late 30s and 40s. Dyspnea usually mild, though patients may note limitations to exercise. Patients frequently overweight and cyanotic but seem comfortable at rest. Peripheral edema is common. Chest is noisy, with rhonchi invariably present; wheezes are common.

Laboratory studies

Hemoglobin usually normal (12–15 g/dL). PaO2 normal to slightly reduced (65–75 mm Hg) but SaO normal at rest. PaCO2 normal to slightly reduced (35–40 mm Hg). Chest radiograph shows hyperinflation with flattened diaphragms. Vascular markings are diminished, particularly at the apices.

 

Hemoglobin usually elevated (15–18 g/dL). PaO2 reduced (45–60 mm Hg) and PaCO2 slightly to markedly elevated (50–60 mm Hg). Chest radiograph shows increased interstitial markings ("dirty lungs"), especially at bases. Diaphragms are not flattened.

 

Pulmonary function tests

Airflow obstruction ubiquitous. Total lung capacity increased, sometimes markedly so. DL reduced. Static lung compliance increased.

 

Airflow obstruction ubiquitous. Total lung capacity generally normal but may be slightly increased. DL normal. Static lung compliance normal.

 

Special evaluations

vdot/qdot

Increased ventilation to high vdot/qdot areas, ie, high dead space ventilation.

Increased perfusion to low vdot/qdot areas.

 Hemodynamics

Cardiac output normal to slightly low. Pulmonary artery pressures mildly elevated and increase with exercise.

Cardiac output normal. Pulmonary artery pressures elevated, sometimes markedly so, and worsen with exercise.

 Nocturnal ventilation

Mild to moderate degree of oxygen desaturation not usually associated with obstructive sleep apnea.

Severe oxygen desaturation, frequently associated with obstructive sleep apnea.

 Exercise ventilation

Increased minute ventilation for level of oxygen consumption. PaO tends to fall, PaCO2 rises slightly.

 

Decreased minute ventilation for level of oxygen consumption. PaO2 may rise; PaCO2 may rise significantly.

 

DLCO, single-breath diffusing capacity for carbon monoxide; vdot/qdot, ventilation-perfusion.

LABORATORY FINDINGS

Spirometry provides objective information about pulmonary function and assesses the results of therapy. Pulmonary function tests early in the course of COPD reveal only evidence of abnormal closing volume and reduced midexpiratory flow rate. Reductions in FEV1 and in the ratio of forced expiratory volume to vital capacity (FEV1% or FEV1/FVC ratio) occur later. In severe disease, the FVC is markedly reduced. Lung volume measurements reveal a marked increase in residual volume (RV), an increase in total lung capacity (TLC), and an elevation of the RV/TLC ratio, indicative of air trapping, particularly in emphysema (see illustration).

A–a–DO2. Indeed, they are unnecessary unless (1) hypoxemia or hypercapnia is suspected, (2) the FEV1 is < 40% of predicted, or (3) there are clinical signs of right heart failure. Hypoxemia occurs in advanced disease, particularly when chronic bronchitis predominates. Compensated respiratory acidosis occurs in patients with chronic respiratory failure, particularly in chronic bronchitis, with worsening of acidemia during acute exacerbations.

Examination of the sputum may reveal Streptococcus pneumoniae, H influenzae, or Moraxella catarrhalis. Positive sputum cultures are poorly correlated with acute exacerbations, and research techniques demonstrate evidence of preceding viral infection in a majority of patients with exacerbations. The ECG may show sinus tachycardia and, in advanced disease, chronic pulmonary hypertension may produce electrocardiographic abnormalities typical of cor pulmonale (see ECG). Supraventricular arrhythmias (multifocal atrial tachycardia, atrial flutter, and atrial fibrillation) and ventricular irritability also occur.

Fig.

 

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Right atrial and right ventricular hypertrophy. The P waves are abnormally tall in leads II, III, and aVF, indicating right atrial abnormality. The frontal plane QRS axis is oriented rightward (deep S in I) and superiorly (QS complexes in II, III, and aVF); the axis is -110 degrees. A tall R wave is present in V1. The rightward axis and tall R wave in V1 indicate right ventricular hypertrophy. In the presence of right ventricular hypertrophy, QS complexes need not indicate myocardial infarction. (Reproduced, with permission, from Goldschlager N, Goldman MJ: Principles of Clinical Electrocardiography, 13th ed. Originally published by Appleton & Lange. Copyright © 1989 by The McGraw-Hill Companies, Inc.)

IMAGING

Radiographs of patients with chronic bronchitis typically show only nonspecific peribronchial and perivascular markings. Plain radiographs are insensitive for the diagnosis of emphysema; they show hyperinflation with flattening of the diaphragm or peripheral arterial deficiency in about half of cases (see x-ray); (see x-ray). Pulmonary hypertension becomes evident as enlargement of central pulmonary arteries in advanced disease. Doppler echocardiography is an effective noninvasive way to estimate pulmonary artery pressure if pulmonary hypertension is suspected. CT of the chest, particularly using a high-resolution reconstruction algorithm, is more sensitive and specific than plain radiographs for the diagnosis of emphysema.

Fig.

 

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Emphysematous bullae of left lung. A: Posteroanterior projection. B: Pulmonary angiogram. (Reproduced, with permission, from Way LW [editor]: Current Surgical Diagnosis & Treatment

 

Fig.

 

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Bullous disease. There is almost a complete paucity of lung markings in both lungs. The edge of some bullae can be seen in the left lung. (Courtesy of H Goldberg.)

 

Clinical, roentgenographic, and laboratory findings should enable the clinician to distinguish COPD from other obstructive pulmonary disorders such as bronchial asthma, bronchiectasis, cystic fibrosis, bronchopulmonary mycosis, and central airflow obstruction. Simple asthma is characterized by complete or near-complete reversibility of airflow obstruction. Bronchiectasis is distinguished from COPD by features such as recurrent pneumonia and hemoptysis, digital clubbing, and characteristic radiographic abnormalities. Patients with severe alphalower1-antiprotease (alphalower1-antitrypsin) deficiency are recognized by family history and the appearance of panacinar bibasilar emphysema early in life, usually in the third or fourth decade; hepatic cirrhosis and hepatocellular carcinoma may occur. Cystic fibrosis occurs in children and younger adults. Rarely, mechanical obstruction of the central airways simulates COPD. Flow-volume loops may help separate patients with central airway obstruction from those with diffuse intrathoracic airway obstruction characteristic of COPD.

Complications

Acute bronchitis, pneumonia, pulmonary thromboembolism, and concomitant left ventricular failure may worsen otherwise stable COPD. Pulmonary hypertension, cor pulmonale, and chronic respiratory failure are common in advanced COPD. Spontaneous pneumothorax occurs in a small fraction of patients with emphysema. Hemoptysis may result from chronic bronchitis or may signal bronchogenic carcinoma.

Prevention

COPD is largely preventable through elimination of long-term exposure to tobacco smoke. Smokers with early evidence of airflow limitation can significantly alter their disease by smoking cessation. Smoking cessation slows the decline in FEV in middle-aged smokers with mild airways obstruction. Vaccination against influenza and pneumococcal infection may also be of benefit.

Treatment

The treatment of COPD is guided by the severity of symptoms, and the determination of the presence of an exacerbation or stable symptoms. Standards for the management of patients with stable COPD and COPD exacerbations have been published by the American Thoracic Society and the Global Initiative for Obstructive Lung Disease (GOLD), a joint expert committee of the NHLBI and the WHO. See Chapter 37: Environmental Disorders for a discussion of air travel in patients with lung disease.

AMBULATORY PATIENTS

Smoking cessation

The single most important intervention in smokers with COPD is to encourage smoking cessation. Simply telling a patient to quit succeeds 5% of the time. A behavioral approach—ranging from clinician advice to an intensive group program—may improve cessation rates. Pharmacologic therapy includes nicotine replacement, (transdermal patch, gum, lozenge, inhaler, or nasal spray), bupropion, and varenicline (a partial agonist of nicotine acetylcholine receptors) (see Chapter 1: Disease Prevention & Health Promotion). Combined pharmacotherapies (two forms of nicotine replacement, or nicotine replacement and bupropion), with or without behavioral approaches have also been recommended. The Lung Health Study reported 22% sustained abstinence at 5 years in their intervention group (behavior modification plus nicotine gum).

Oxygen therapy

The only drug therapy that is documented to improve the natural history of COPD is supplemental oxygen in those patients with resting hypoxemia. Proved benefits of home oxygen therapy in hypoxemic patients include longer survival, reduced hospitalization needs, and better quality of life. Survival in hypoxemic patients with COPD treated with supplemental oxygen therapy is directly proportionate to the number of hours per day oxygen is administered: in patients treated with continuous oxygen, the survival after 36 months is about 65%—significantly better than the survival rate of about 45% in those who are treated with only nocturnal oxygen. Oxygen by nasal prongs must be given at least 15 hours a day unless therapy is intended only for exercise or sleep.

Requirements for Medicare coverage for a patient's home use of oxygen and oxygen equipment are listed in Table 9–8. Arterial blood gas analysis is preferred over pulse oximetry to guide initial oxygen therapy. Hypoxemic patients with pulmonary hypertension, chronic cor pulmonale, erythrocytosis, impaired cognitive function, exercise intolerance, nocturnal restlessness, or morning headache are particularly likely to benefit from home oxygen therapy.

Table 9–8. Home oxygen therapy: requirements for Medicare coverage.1

 

Group I (any of the following):

O2 lesserorequal 55 mm Hg or SaO2 lesserorequal 88% taken at rest breathing room air, while awake.

 

 2. During sleep (prescription for nocturnal oxygen use only):

   a. PaO2 lesserorequal 55 mm Hg or SaO2 lesserorequal 88% for a patient whose awake, resting, room air PaO2 is greaterorequal 56 mm Hg or SaO2 greaterorequal 89%,

 

      or

   b. Decrease in PaO2 > 10 mm Hg or decrease in SaO2 > 5% associated with symptoms or signs reasonably attributed to hypoxemia (eg, impaired cognitive processes, nocturnal restlessness, insomnia).

 

 3. During exercise (prescription for oxygen use only during exercise):

   a. PaO2 lesserorequal 55 mg Hg or SaO2 lesserorequal 88% taken during exercise for a patient whose awake, resting, room air PaO2 is greaterorequal 56 mm Hg or SaO2 greaterorequal 89%,

 

      and

   b. There is evidence that the use of supplemental oxygen during exercise improves the hypoxemia that was demonstrated during exercise while breathing room air.

Group II

 PaO= 56–59 mm Hg or SaO2 = 89% if there is evidence of any of the following:

 

 1. Dependent edema suggesting congestive heart failure.

 2. P pulmonale on ECG (P wave > 3 mm in standard leads II, III, or aVF).

 3. Hematocrit > 56%.

1Health Care Financing Administration, 1989.

2Patients in this group must have a second oxygen test 3 months after the initial oxygen set-up.

Home oxygen may be supplied by liquid oxygen systems (LOX), compressed gas cylinders, or oxygen concentrators. Most patients benefit from having both stationary and portable systems. For most patients, a flow rate of 1–3 L/min achieves a PaO2 greater than 55 mm Hg. The monthly cost of home oxygen therapy ranges from $300.00 to $500.00 or more, higher for liquid oxygen systems. Medicare covers approximately 80% of home oxygen expenses. Transtracheal oxygen is an alternative method of delivery and may be useful for patients who require higher flows of oxygen than can be delivered via the nose or who are experiencing troublesome side effects from nasal delivery such as nasal drying or epistaxis. Reservoir nasal cannulas or "pendants" and demand (pulse) oxygen delivery systems are also available to conserve oxygen.

Inhaled bronchodilators

Bronchodilators are agents in the pharmacologic management of patients with COPD. Bronchodilators do not alter the inexorable decline in lung function that is a hallmark of the disease, but they offer some patients improvement in symptoms, exercise tolerance, and overall health status. Aggressiveness of bronchodilator therapy should be matched to the severity of the patient's disease. In patients who experience no symptomatic improvement, bronchodilators should be discontinued.

The most commonly prescribed short-acting bronchodilators are the anticholinergic ipratropium bromide and betalower2-agonists (eg, albuterol, metaproterenol), delivered by MDI or as an inhalation solution by nebulizer. Ipratropium bromide is generally preferred to the short-acting betalower2-agonists as a first-line agent because of its longer duration of action and absence of sympathomimetic side effects. Some studies have suggested that ipratropium achieves superior bronchodilation in COPD patients. Typical doses are two to four puffs (36–72 mcg) every 6 hours. There is a dose response above this level without additional side effects. Short-acting betalower2-agonists are less expensive and have a more rapid onset of action, commonly leading to greater patient satisfaction. At maximal doses, betalower2-agonists have bronchodilator action equivalent to that of ipratropium but may cause tachycardia, tremor, or hypokalemia. There does not appear to be any advantage of scheduled use of short-acting betalower2-agonists compared with as-needed administration. Use of both short-acting betalower2-agonists and anticholinergics at submaximal doses leads to improved bronchodilation compared with either agent alone but does not improve dyspnea.

Long-acting betalower2-agonists (eg, formoterol, salmeterol) and anticholinergics (tiotropium) appear to achieve bronchodilation that is equivalent or superior to what is experienced with ipratropium in addition to similar improvements on health status. Although they are more expensive than short-acting agents, long-acting bronchodilators are recommended in persons with advanced disease.

Corticosteroids

Multiple large clinical trials have reported a small reduction in the frequency of COPD exacerbations and an increase in self-reported functional status in COPD patients treated with inhaled corticosteroids. These same trials demonstrate no effect of inhaled corticosteroids on the characteristic decline in lung function experienced by COPD patients and no impact of inhaled corticosteroids on mortality. At this time, inhaled corticosteroids should not be considered first-line therapy in stable COPD patients, who benefit more from bronchodilators, smoking cessation, and pulmonary rehabilitation. Inhaled corticosteroids may benefit certain subgroups, including persons with moderate to severe COPD or frequent exacerbations. The place of combination therapy—inhaled corticosteroids plus a long-acting bronchodilator or tiotropium, or both—is still being defined.

Apart from acute exacerbations, COPD is not generally responsive to oral corticosteroid therapy. Only 10–20% of stable outpatients with COPD given oral corticosteroids will have a greater than 20% increase in FEV1 compared with patients receiving placebo. There may be a subset of steroid-responsive COPD patients more likely to benefit from long-term oral or inhaled corticosteroids. Since there are no clinical predictors to identify such responders, empiric trials of oral corticosteroids are common. Current research provides little guidance to interpret clinically relevant benefit and clinically significant changes in spirometry, however. If empiric trials of oral corticosteroids are conducted, rigorous outcome assessment as advocated by the McMaster group is appropriate. The use of oral or systemic corticosteroids has well-recognized adverse effects, and it seems prudent management to seek to minimize cumulative oral corticosteroid exposure. Some patients may be truly "corticosteroid-dependent," but clinical experience suggests that this is rare when all other available therapies are optimized.

Theophylline

Oral theophylline is a third-line agent for treating patients with COPD who do not achieve adequate symptom control with anticholinergics, betalower-agonists, and inhaled corticosteroid therapy. Sustained-release theophylline improves arterial oxygen hemoglobin saturation during sleep in COPD patients and is a first-line agent for those with sleep-related breathing disorders. Theophylline has fallen out of favor because of its narrow therapeutic window and the availability of potent inhaled bronchodilators. Nonetheless, theophylline does improve dyspnea, exercise performance, and pulmonary function in many patients with stable COPD. Its benefits may result from anti-inflammatory properties and extrapulmonary effects on diaphragm strength, myocardial contractility, and renal function.

Antibiotics

Antibiotics are commonly prescribed to outpatients with COPD for the following indications: (1) to treat an acute exacerbation, (2) to treat acute bronchitis, and (3) to prevent acute exacerbations of chronic bronchitis (prophylactic antibiotics). Antibiotics appear to improve outcomes slightly in the first two situations, but there is no convincing evidence to support the use of prophylactic antibiotics in patients with COPD. Patients with a COPD exacerbation associated with dyspnea and a change in the quantity or character of sputum benefit the most from antibiotic therapy. In the past, common agents included trimethoprim-sulfamethoxazole (160/800 mg every 12 hours), amoxicillin (500 mg every 8 hours), or doxycycline (100 mg every 12 hours) given for 7–10 days. Prescribing patterns have changed, and a recent meta-analysis of antibiotic therapy in acute bronchitis complicating COPD found macrolides (azithromycin 500 mg followed by 250 mg daily for 5 days), fluoroquinolones (ciprofloxacin 500 mg every 12 hours), and amoxicillin-clavulanate (875/125 mg every 12 hours) to be more effective than older therapies. There are few controlled trials of antibiotics in severe COPD exacerbations but prompt administration of antibiotics is appropriate, particularly in those with risk factors for poor outcomes.

Pulmonary rehabilitation

 

Other measures

In patients with chronic bronchitis, increased mobilization of secretions may be accomplished through the use of adequate systemic hydration, effective cough training methods, or use of a hand-held flutter device and postural drainage, sometimes with chest percussion or vibration. Postural drainage and chest percussion should be used only in selected patients with excessive amounts of retained secretions that cannot be cleared by coughing and other methods; these measures are of no benefit in pure emphysema. Expectorant-mucolytic therapy has generally been regarded as unhelpful in patients with chronic bronchitis. Cough suppressants and sedatives should be avoided as routine measures.

Human alphalower1-antitrypsin is available for replacement therapy in emphysema due to congenital deficiency of alphalower1-antiprotease (alphalower-antitrypsin). Patients over 18 years of age with airflow obstruction by spirometry and levels less than 11 mcmol/L are potential candidates for replacement therapy. alphalower1-Antitrypsin is administered intravenously in a dose of 60 mg/kg body weight once weekly.

Severe dyspnea in spite of optimal medical management may warrant a clinical trial of an opioid. Sedative-hypnotic drugs (eg, diazepam, 5 mg three times daily) are controversial in intractable dyspnea but may benefit very anxious patients. Intermittent negative-pressure (cuirass) ventilation and transnasal positive-pressure ventilation at home to rest the respiratory muscles are promising approaches to improve respiratory muscle function and reduce dyspnea in patients with severe COPD. A bilevel transnasal ventilation system has been reported to reduce dyspnea in ambulatory patients with severe COPD, but the long-term benefits of this approach and compliance with it have not been defined.

HOSPITALIZED PATIENTS

Management of the hospitalized patient with an acute exacerbation of COPD includes supplemental oxygen, inhaled ipratropium bromide plus betalower2-agonists, and broad-spectrum antibiotics, corticosteroids and, in selected cases, chest physiotherapy. Theophylline should not be initiated in the acute setting, but patients taking theophylline prior to acute hospitalization should have their theophylline serum levels measured and maintained in the therapeutic range. Oxygen therapy should not be withheld for fear of worsening respiratory acidemia; hypoxemia is more detrimental than hypercapnia. Cor pulmonale usually responds to measures that reduce pulmonary artery pressure, such as supplemental oxygen and correction of acidemia; bed rest, salt restriction, and diuretics may add some benefit. Cardiac arrhythmias, particularly multifocal atrial tachycardia, usually respond to aggressive treatment of COPD itself. Atrial flutter may require DC cardioversion after initiation of the above therapy. If progressive respiratory failure ensues, tracheal intubation and mechanical ventilation are necessary. In clinical trials of COPD patients with hypercapnic acute respiratory failure, noninvasive positive-pressure ventilation (NPPV) delivered via face mask reduced the need for intubation and shortened lengths of stay in the intensive care unit (ICU). Other studies have suggested a lower risk of hospital-acquired infections and less use of antibiotics in COPD patients treated with NPPV. These benefits do not appear to extend to hypoxemic respiratory failure or to patients with acute lung injury or ARDS.

SURGERY FOR COPD

Lung transplantation

Experience with both single and bilateral sequential lung transplantation for severe COPD is extensive. Requirements for lung transplantation are severe lung disease, limited activities of daily living, exhaustion of medical therapy, ambulatory status, potential for pulmonary rehabilitation, limited life expectancy without transplantation, adequate function of other organ systems, and a good social support system. Average total charges for lung transplantation through the end of the first postoperative year exceed $250,000. The 2-year survival rate after lung transplantation for COPD is 75%. Complications include acute rejection, opportunistic infection, and obliterative bronchiolitis. Substantial improvements in pulmonary function and exercise performance have been noted after transplantation.

Lung volume reduction surgery

Lung volume reduction surgery (LVRS), or reduction pneumoplasty, is a surgical approach to relieve dyspnea and improve exercise tolerance in patients with advanced diffuse emphysema and lung hyperinflation. Bilateral resection of 20–30% of lung volume in selected patients results in modest improvements in pulmonary function, exercise performance, and dyspnea. The duration of any improvement as well as any mortality benefit remains uncertain. Prolonged air leaks occur in up to 50% of patients postoperatively. Mortality rates in centers with the largest experience with LVRS range from 4% to 10%.

The National Emphysema Treatment Trial compared LVRS with medical treatment in a randomized, multicenter clinical trial of 1218 patients with severe emphysema. Overall, surgery improved exercise capacity but not mortality when compared with medical therapy. The persistence of this benefit remains to be defined. Subgroup analysis suggested that patients with upper lobe predominant emphysema and low exercise capacity might have improved survival, while other groups suffered excess mortality when randomized to surgery.

Bullectomy

Bullectomy is an older surgical procedure for palliation of dyspnea in patients with severe bullous emphysema. Bullectomy is most commonly pursued when a single bulla occupies at least 30–50% of the hemithorax. In this procedure, the surgeon removes a large emphysematous bulla that demonstrates no ventilation or perfusion on lung scanning and compresses adjacent lung with preserved function. Bullectomy can be performed with a CO2 laser via thoracoscopy.

Prognosis

The outlook for patients with clinically significant COPD is poor. The degree of pulmonary dysfunction at the time the patient is first seen is an important predictor of survival: median survival of patients with severe FEV1 lesserorequal 1 L is about 4 years. A multidimensional index (the BODE index), which includes body mass index (BMI), airway obstruction (FEV1), dyspnea (Medical Research Council dyspnea score), and exercise capacity is a tool that predicts death and hospitalization better than FEV1 alone. Comprehensive care programs, cessation of smoking, and supplemental oxygen may reduce the rate of decline of pulmonary function, but therapy with bronchodilators and other approaches probably has little, if any, impact on the natural course of COPD.

Dyspnea at the end of life can be extremely uncomfortable and distressing to the patient and family. Dyspnea can be effectively managed with a combination of medications and mechanical interventions. As patients near the end of life, meticulous attention to palliative care is essential (see Chapter 5: Palliative Care & Pain Management).

When to Refer

COPD onset occurs before the age of 40.
Frequent exacerbations (two or more a year) despite optimal treatment.
Severe or rapidly progressive COPD.
Symptoms disproportionate to the severity of airflow obstruction.
Need for long-term oxygen therapy.
Onset of comorbid illnesses (such as bronchiectasis, heart failure, or lung cancer).

When to Admit

Severe symptoms or acute worsening that fails to respond to outpatient management.
Acute or worsening hypoxemia, hypercapnia, peripheral edema, or change in mental status.
Inadequate home care, or inability to sleep or maintain nutrition/hydration due to symptoms.

Ambrosino N et al. The clinical management in extremely severe COPD. Respir Med. 2007 Aug;101(8):1613–24. [PMID: 17383170]

 

Cote CG et al. Predictors of mortality in chronic obstructive pulmonary disease. Clin Chest Med. 2007 Sep;28(3):515–24. [PMID: 17720040]

 

 

 

Qaseem A et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2007 Nov 6;147(9):633–8. [PMID: 17975186]

 

Rabe KF et al; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007 Sep 15;176(6):532–55. [PMID: 17507545]

 

Viegi G et al. Definition, epidemiology and natural history of COPD. Eur Respir J. 2007 Nov 30;(5):993–1013. [PMID: 17978157]

 

Wilson JF. In the clinic. Smoking cessation. Ann Intern Med. 2007 Feb 6;146(3):ITC2-1–ICT2-16. [PMID: 17283345]

 

Wilt TJ et al. Management of stable chronic obstructive pulmonary disease: a systemic review for a clinical practice guideline. Ann Intern Med. 2007 Nov 6;147(9):639–653. [PMID: 17975187]

 

Yang IA et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database of Syst Rev. 2007 Apr 18;(2):CD002991. [PMID: 17443520]

 

Zuwallack R. The nonpharmacologic treatment of chronic obstructive pulmonary disease: advances in our understanding of pulmonary rehabilitation. Proc Am Thorac Soc. 2007 Oct 1;4(7):549–53. [PMID: 17878468]

 

BRONCHIECTASIS

Essentials of Diagnosis

Chronic productive cough with dyspnea and wheezing.
Recurrent pulmonary infections requiring antibiotics.
A preceding history of recurrent pulmonary infections or inflammation, or a predisposing condition.
Radiographic findings of dilated, thickened airways and scattered, irregular opacities.

General Considerations

Bronchiectasis is a congenital or acquired disorder of the large bronchi characterized by permanent, abnormal dilation and destruction of bronchial walls. It may be caused by recurrent inflammation or infection of the airways and may be localized or diffuse. Cystic fibrosis causes about half of all cases of bronchiectasis. Other causes include lung infection (tuberculosis, fungal infections, lung abscess, pneumonia), abnormal lung defense mechanisms (humoral immunodeficiency, alphalower1-antiprotease [alphalower1-antitrypsin] deficiency with cigarette smoking, mucociliary clearance disorders, rheumatic diseases), and localized airway obstruction (foreign body, tumor, mucoid impaction). Immunodeficiency states that may lead to bronchiectasis include congenital or acquired panhypogammaglobulinemia; common variable immunodeficiency; selective IgA, IgM, and IgG subclass deficiencies; and acquired immunodeficiency from cytotoxic therapy, AIDS, lymphoma, multiple myeloma, leukemia, and chronic renal and hepatic diseases. However, most patients with bronchiectasis have panhypogammaglobulinemia, presumably reflecting an immune system response to chronic airway infection. Acquired primary bronchiectasis is now uncommon in the United States because of improved control of bronchopulmonary infections.

Clinical Findings

SYMPTOMS AND SIGNS

Symptoms of bronchiectasis include chronic cough with production of copious amounts of purulent sputum, hemoptysis, and pleuritic chest pain. Dyspnea and wheezing occur in 75% of patients. Weight loss, anemia, and other systemic manifestations are common. Physical findings are nonspecific, but persistent crackles at the lung bases are common. Clubbing is infrequent in mild cases but is common in severe disease. Copious, foul-smelling, purulent sputum is characteristic. Obstructive pulmonary dysfunction with hypoxemia is seen in moderate or severe disease.

IMAGING

Radiographic abnormalities include dilated and thickened bronchi that may appear as "tram-tracks" or as ring-like markings. Scattered irregular opacities, atelectasis, and focal consolidation may be present. High-resolution CT is the diagnostic study of choice.

Treatment

Treatment of acute exacerbations consists of antibiotics (selected on the basis of sputum smears and cultures), daily chest physiotherapy with postural drainage and chest percussion, and inhaled bronchodilators. Hand-held flutter valve devices may be as effective as chest physiotherapy in clearing secretions. Empiric oral antibiotic therapy for 10–14 days with amoxicillin or amoxicillin-clavulanate (500 mg every 8 hours), ampicillin or tetracycline (250–500 mg four times daily), or trimethoprim-sulfamethoxazole (160/800 mg every 12 hours) is reasonable therapy in an acute exacerbation if a specific bacterial pathogen cannot be isolated. Preventive or suppressive treatment is sometimes given to stable outpatients with bronchiectasis who have copious purulent sputum. Clinical trial data to guide this practice are scant. Common regimens include macrolides (azithromycin, 500 mg three times a week; erythromycin, 500 mg twice daily), high-dose (3 g/d) amoxicillin or alternating cycles of the antibiotics listed above given orally for 2–4 weeks. Inhaled aerosolized aminoglycosides reduce colonization by Pseudomonas species. In patients with underlying cystic fibrosis, inhaled antibiotics improve FEV1 and reduce hospitalizations, but these benefits are not consistently seen in the non–cystic fibrosis population. Complications of bronchiectasis include hemoptysis, cor pulmonale, amyloidosis, and secondary visceral abscesses at distant sites (eg, brain). Bronchoscopy is sometimes necessary to evaluate hemoptysis, remove retained secretions, and rule out obstructing airway lesions. Massive hemoptysis may require embolization of bronchial arteries or surgical resection. Surgical resection is otherwise reserved for the few patients with localized bronchiectasis and adequate pulmonary function in whom conservative management fails.

Barker AF. Bronchiectasis. N Engl J Med. 2002 May 2;346(18):1383–93. [PMID: 11986413]

 

Morrissey BM. Pathogenesis of bronchiectasis. Clin Chest Med. 2007 Jun;28(2):289–96. [PMID: 17467548]

 

Noone PG et al. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med. 2004 Feb 15;169(4):459–67. [PMID: 14656747]

 

ALLERGIC BRONCHOPULMONARY MYCOSIS

Allergic bronchopulmonary mycosis is a pulmonary hypersensitivity disorder caused by allergy to fungal antigens that colonize the tracheobronchial tree. It usually occurs in atopic asthmatic individuals who are 20–40 years of age, in response to antigens of Aspergillus species. For this reason, the disorder is commonly referred to as allergic bronchopulmonary aspergillosis (ABPA). Primary criteria for the diagnosis of ABPA include (1) a clinical history of asthma, (2) peripheral eosinophilia, (3) immediate skin reactivity to Aspergillus antigen, (4) precipitating antibodies to Aspergillus antigen, (5) elevated serum IgE levels, (6) pulmonary infiltrates (transient or fixed), and (7) central bronchiectasis. If the first six of these seven primary criteria are present, the diagnosis is almost certain. Secondary diagnostic criteria include identification of Aspergillus in sputum, a history of brown-flecked sputum, and late skin reactivity to Aspergillus antigen. High-dose prednisone (0.5–1 mg/kg orally per day) for at least 2 months is the treatment of choice, and the response in early disease is usually excellent. Depending on the overall clinical situation, prednisone can then be cautiously tapered. Relapses are frequent, and protracted or repeated treatment with corticosteroids is not uncommon. Patients with corticosteroid-dependent disease may benefit from itraconazole (200 mg orally once or twice daily) without added toxicity. Bronchodilators (Table 9–6) are also helpful. Complications include hemoptysis, severe bronchiectasis, and pulmonary fibrosis.

Gibson PG. Allergic bronchopulmonary aspergillosis. Semin Respir Crit Care Med. 2006 Apr;27(2):185–91. [PMID: 16612769]

 

Virnig C et al. Allergic bronchopulmonary aspergillosis: a US perspective. Curr Opin Pulm Med. 2007 Jan;13(1):67–71. [PMID: 17133128]

 

CYSTIC FIBROSIS

 

Chronic or recurrent cough, sputum production, dyspnea, and wheezing.
Recurrent infections or chronic colonization of the airways with nontypeable H influenzae, mucoid and nonmucoid Pseudomonas aeruginosa, Staphylococcus aureus, or Burkholderia cepacia.
Pancreatic insufficiency, recurrent pancreatitis, distal intestinal obstruction syndrome, chronic hepatic disease, nutritional deficiencies, or male urogenital abnormalities.
Bronchiectasis and scarring on chest radiographs.
Airflow obstruction on spirometry.
Sweat chloride concentration above 60 mEq/L on two occasions or gene mutation known to cause cystic fibrosis.

General Considerations

Cystic fibrosis is the most common cause of severe chronic lung disease in young adults and the most common fatal hereditary disorder of whites in the United States. It is an autosomal recessive disorder affecting about one in 3200 whites; 1 in 25 is a carrier. Cystic fibrosis is caused by abnormalities in a membrane chloride channel (the cystic fibrosis transmembrane conductance regulator [CFTR] protein) that results in altered chloride transport and water flux across the apical surface of epithelial cells. Almost all exocrine glands produce an abnormal mucus that obstructs glands and ducts. Obstruction results in glandular dilation and damage to tissue. In the respiratory tract, inadequate hydration of the tracheobronchial epithelium impairs mucociliary function. High concentrations of DNA in airway secretions (due to chronic airways inflammation and autolysis of neutrophils) increases sputum viscosity. Over 1000 mutations in the gene that encodes CFTR have been described, and at least 230 mutations are known to be associated with clinical abnormalities. The mutation referred to as deltaupperF508 accounts for about 60% of cases of cystic fibrosis.

Over one-third of the nearly 30,000 cystic fibrosis patients in the United States are adults. Because of the wide range of alterations seen in the CFTR protein structure and function, cystic fibrosis in adults may present with a variety of pulmonary and nonpulmonary manifestations. Pulmonary manifestations in adults include acute and chronic bronchitis, bronchiectasis, pneumonia, atelectasis, and peribronchial and parenchymal scarring. Pneumothorax and hemoptysis are common. Hypoxemia, hypercapnia, and cor pulmonale occur in advanced cases. Biliary cirrhosis and gallstones may occur. Nearly all men with cystic fibrosis have congenital bilateral absence of the vas deferens with azoospermia. Patients with cystic fibrosis have an increased risk of malignancies of the gastrointestinal tract, osteopenia, and arthropathies.

Clinical Findings

SYMPTOMS AND SIGNS

Cystic fibrosis should be suspected in a young adult with a history of chronic lung disease (especially bronchiectasis), pancreatitis, or infertility. Cough, sputum production, decreased exercise tolerance, and recurrent hemoptysis are typical complaints. Patients also often complain of facial (sinus) pain or pressure and purulent nasal discharge. Steatorrhea, diarrhea, and abdominal pain are also common. Digital clubbing (see photograph), increased anteroposterior chest diameter, hyperresonance to percussion, and apical crackles are noted on physical examination. Sinus tenderness, purulent nasal secretions, and nasal polyps may also be seen.

LABORATORY FINDINGS

Arterial blood gas studies often reveal hypoxemia and, in advanced disease, a chronic, compensated respiratory acidosis. Pulmonary function studies show a mixed obstructive and restrictive pattern. There is a reduction in FVC, airflow rates, and TLC. Air trapping (high ratio of RV to TLC) and reduction in pulmonary diffusing capacity are common.

IMAGING

Hyperinflation is seen early in the disease process. Peribronchial cuffing, mucus plugging, bronchiectasis (ring shadows and cysts), increased interstitial markings, small rounded peripheral opacities, and focal atelectasis may be seen separately or in various combinations (see x-ray). Pneumothorax can also be seen. Thin-section CT scanning may confirm the presence of bronchiectasis.

Fig.

 

loadBinaryCA80EQ3J

Cystic fibrosis. This chest radiograph is of an adult with advanced cystic fibrosis, resulting in huge blebs in both apices, considerable pulmonary fibrosis, and restrictive lung disease. (Courtesy of H Goldberg.)

DIAGNOSIS

The quantitative pilocarpine iontophoresis sweat test reveals elevated sodium and chloride levels (> 60 mEq/L) in the sweat of patients with cystic fibrosis. Two tests on different days are required for accurate diagnosis. Facilities must perform enough tests to maintain laboratory proficiency and quality. A normal sweat chloride test does not exclude the diagnosis. Genotyping or other alternative diagnostic studies (such as measurement of nasal membrane potential difference, semen analysis, or assessment of pancreatic function) should be pursued if the test is repeatedly negative but there is a high clinical suspicion of cystic fibrosis. Standard genotyping is a limited diagnostic tool because it screens for only a fraction of the known cystic fibrosis mutations, although complete genetic testing is available.

Treatment

Early recognition and comprehensive multidisciplinary therapy improve symptom control and the chances of survival. Referral to a regional cystic fibrosis center is strongly recommended. Conventional treatment programs focus on the following areas: clearance and reduction of lower airway secretions, reversal of bronchoconstriction, treatment of respiratory tract infections and airway bacterial burden, pancreatic enzyme replacement, and nutritional and psychosocial support (including genetic and occupational counseling). The Pulmonary Therapies Committee, established by the Cystic Fibrosis Foundation, has issued evidenced-based recommendations regarding long-term use of medications for maintenance of lung function and reduction of exacerbations in patients with cystic fibrosis.

Clearance of lower airway secretions can be promoted by postural drainage, chest percussion or vibration techniques, positive expiratory pressure (PEP) or flutter valve breathing devices, directed cough, and other breathing techniques; these approaches require detailed patient instruction by experienced personnel. Sputum viscosity in cystic fibrosis is increased by the large quantities of extracellular DNA that result from chronic airway inflammation and autolysis of neutrophils. Inhaled recombinant human deoxyribonuclease (rhDNase, dornase alpha) cleaves extracellular DNA in sputum; when administered long-term at a daily nebulized dose of 2.5 mg, this therapy leads to improved FEV1 and reduces the risk of cystic fibrosis–related respiratory exacerbations and the need for intravenous antibiotics. Pharyngitis, laryngitis, and voice alterations are common adverse effects. Inhalation of hypertonic saline has been associated with small improvements in pulmonary function and fewer pulmonary exacerbations. The beneficial effects of hypertonic saline in cystic fibrosis may derive from improved airway mucous clearance. Short-term antibiotics are used to treat active airway infections based on results of culture and susceptibility testing of sputum. S aureus (including methicillin-resistant strains) and a mucoid variant of P aeruginosa are commonly present. H influenzae, Stenotrophomonas maltophilia, and B cepacia (which is a highly drug-resistant organism) are occasionally isolated. Long-term antibiotics (azithromycin, 500 mg orally three times a week, and inhalation of an aerosolized tobramycin solution) are helpful in slowing disease progression and reducing exacerbations in patients with cultures of airway secretions persistently positive for P aeruginosa.

Inhaled bronchodilators (eg, albuterol, two puffs every 4 hours as needed) should be considered in patients who demonstrate an increase of at least 12% in FEV1 after an inhaled bronchodilator. Vaccination against pneumococcal infection and annual influenza vaccination are advised. Screening of family members and genetic counseling are suggested.

Lung transplantation is currently the only definitive treatment for advanced cystic fibrosis. Double-lung or heart-lung transplantation is required. A few transplant centers offer living lobar lung transplantation to selected patients. The 3-year survival rate following transplantation for cystic fibrosis is about 55%.

Prognosis

The longevity of patients with cystic fibrosis is increasing, and the median survival age is over 35 years. Death occurs from pulmonary complications (eg, pneumonia, pneumothorax, or hemoptysis) or as a result of terminal chronic respiratory failure and cor pulmonale.

Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med. 2006 Mar 1;173(5):475–82. [PMID: 16126935]

 

Flume PA et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007 Nov 15;176(10):957–69. [PMID: 17761616]

 

Yankaskas JR et al. Cystic fibrosis adult care: consensus conference report. Chest. 2004 Jan;125(1 Suppl):1S–39S. [PMID: 14734689]

 

BRONCHIOLITIS

Bronchiolitis is a generic term applied to varied inflammatory processes that affect the bronchioles, which are small conducting and respiratory airways < 2 mm in diameter. In infants and children, bronchiolitis is common and usually caused by respiratory syncytial virus or adenovirus infection. In adults, bronchiolitis is encountered in a variety of clinical settings, including infections, connective tissue diseases, inhalational injuries, drug reactions, and allograft transplantation. No single classification scheme has been widely accepted and, as a result, there is a confusing and overlapping array of terms to describe these disorders from the viewpoints of the clinician, the radiologist, and the pathologist.

The pathologic classification has two variants. Constrictive bronchiolitis (also referred to as obliterative bronchiolitis, or bronchiolitis obliterans) is characterized by chronic inflammation, concentric scarring, and smooth muscle hypertrophy causing luminal obstruction. These patients have airflow obstruction on spirometry, minimal radiographic abnormalities, and a progressive, deteriorating clinical course. Proliferative bronchiolitis occurs when there is an organizing intraluminal exudate, consisting of fibroblasts, foamy macrophages, and other cells that obstruct the lumen. When this exudate extends to the alveolar space, the pattern is referred to as bronchiolitis obliterans with organizing pneumonia (BOOP; now more commonly referred to as cryptogenic organizing pneumonitis [COP]) (see Table 9–14).

The clinical classification approach divides patients into groups based primarily upon etiology. Inhalational injuries, postinfectious, and drug-induced causes are identified by association with a known exposure or illness prior to the onset of symptoms. Disorders associated with bronchiolitis include organ transplantation, connective tissue diseases, and hypersensitivity pneumonitis. Idiopathic cases are characterized by the insidious onset of dyspnea or cough, and include COP. This disorder affects men and women between the ages of 50 and 70 years, typically with a dry cough, dyspnea, and constitutional symptoms present for weeks to months prior to presentation. Pulmonary function testing typically shows a restrictive ventilatory defect. The chest radiograph frequently shows bilateral patchy, ground-glass or alveolar infiltrates, although other patterns have been described (see Table 9–14). Corticosteroids are effective in two-thirds of patients, and improvement can be prompt. Therapy is initiated at 1 mg/kg/d for 1–3 months. The dose is then tapered slowly to 20–40 mg/d, depending on the response, and weaned over the subsequent 3–6 months as tolerated. Relapses are common if corticosteroids are stopped prematurely or tapered too quickly.

Other idiopathic disorders associated with bronchiolitis include respiratory bronchiolitis, Diffuse panbronchiolitis is an idiopathic disorder of respiratory bronchioles, more frequently diagnosed in Japan. Men are affected about twice as often as women, two-thirds are nonsmokers, and most patients have a history of chronic pansinusitis. Marked dyspnea, cough, and sputum production are frequent, and chest examination shows crackles and rhonchi. Pulmonary function tests reveal obstructive abnormalities, and the chest radiograph shows a distinct pattern of diffuse, small, nodular shadows with hyperinflation.

It is important to consider both the clinical and pathologic classification schemes when evaluating bronchiolitis. Both "constrictive" and "proliferative" pathology can be seen in postinfectious and connective tissue diseases, and an integration with the clinical history is important. Compared with constrictive bronchiolitis, proliferative bronchiolitis is overall more common, more likely to show a restrictive or mixed ventilatory defect, more likely to have an abnormal chest radiograph, and more likely to be responsive to corticosteroids. Constrictive bronchiolitis is relatively infrequent but can be seen in a variety of inhalation disorders; hypersensitivity pneumonitis; and chronic rejection in heart-lung, lung, and bone marrow transplant recipients. There is often an obstructive defect with hyperinflation, and chest radiographs may be normal or show hyperinflation. Constrictive bronchiolitis is relatively unresponsive to corticosteroids and is frequently progressive. For both constrictive and proliferative bronchiolitis, open or thoracoscopic lung biopsy is required to make the definitive diagnosis in the majority of cases.

Cordier JF. Cryptogenic organising pneumonia. Eur Respir J. 2006 Aug;28(2):422–46. [PMID: 16880372]

 

Ryu JH. Classification and approach to bronchiolar diseases. Curr Opin Pulm Med. 2006 Mar;12(2):145–51. [PMID: 16456385]

 

Smyth RL et al. Bronchiolitis. Lancet. 2006 Jul 22;368(9532):312–22. [PMID: 16860701]

 

PNEUMONIA

Lower respiratory tract infections continue to be a major health problem despite advances in the identification of etiologic organisms and the availability of potent antimicrobial drugs. In addition, there is still much controversy regarding optimal diagnostic approaches and treatment choices for pneumonia.

 

Table 9–9. Characteristics and treatment of selected pneumonias.

 

 

Clinical Setting

Complications

 

Antimicrobial Therapy1,2

 

Streptococcus pneumoniae (pneumococcus). Gram-positive diplococci (see micrograph); (see micrograph).

Chronic cardiopulmonary disease; follows upper respiratory tract infection

Bacteremia, meningitis, endocarditis, pericarditis, empyema

Gram stain and culture of sputum, blood, pleural fluid

Preferred3: Penicillin G, amoxicillin.

 

Alternative: Macrolides, cephalosporins, doxycycline, fluoroquinolones, clindamycin, vancomycin, TMP-SMZ, linezolid.

Haemophilus influenzae. Pleomorphic gram-negative coccobacilli (see micrograph).

Chronic cardiopulmonary disease; follows upper respiratory tract infection

Empyema, endocarditis

Gram stain and culture of sputum, blood, pleural fluid

Preferred3: Cefotaxime, ceftriaxone, cefuroxime, doxycycline, azithromycin, TMP-SMZ.

 

Alternative: Fluoroquinolones, clarithromycin.

Staphylococcus aureus. Plump gram-positive cocci in clumps.

Residence in chronic care facility, hospital-acquired, influenza epidemics; cystic fibrosis, bronchiectasis, injection drug use

Empyema, cavitation

Gram stain and culture of sputum, blood, pleural fluid

For methicillin-susceptible strains:

 Preferred: A penicillinase-resistant penicillin with or without rifampin, or gentamicin.

 Alternative: A cephalosporin; clindamycin, TMP-SMZ, vancomycin, a fluoroquinolone.

For methicillin-resistant strains:

 Vancomycin with or without gentamicin or rifampin, linezolid.

Klebsiella pneumoniae. Plump gram-negative encapsulated rods (see micrograph).

Alcohol abuse, diabetes mellitus; hospital-acquired

Cavitation, empyema

Gram stain and culture of sputum, blood, pleural fluid

Preferred: Third-generation cephalosporin. For severe infections, add an aminoglycoside.

Alternative: Aztreonam, imipenem, meropenem, betalower-lactam/betalower-lactamase inhibitor, an aminoglycoside, or a fluoroquinolone.

Escherichia coli. Gram-negative rods.

Hospital-acquired; rarely, community-acquired

Empyema

Gram stain and culture of sputum, blood, pleural fluid

Same as for Klebsiella pneumoniae.

Pseudomonas aeruginosa. Gram-negative rods.

Hospital-acquired; cystic fibrosis, bronchiectasis

Cavitation

 

Preferred: An antipseudomonal betalower-lactam plus an aminoglycoside.

Alternative: Ciprofloxacin plus an aminoglycoside or an antipseudomonal betalower-lactam.

Anaerobes. Mixed flora.

 

Necrotizing pneumonia, abscess, empyema

Culture of pleural fluid or of material obtained by transtracheal or transthoracic aspiration

Preferred: Clindamycin, betalower-lactam/betalower-lactamase inhibitor, imipenem.

Mycoplasma pneumoniae. PMNs and monocytes; no bacteria.

Young adults; summer and fall

Skin rashes, bullous myringitis; hemolytic anemia

PCR. Culture.4 Complement fixation titer. Cold agglutinin serum titers are not helpful as they lack sensitivity and specificity.

 

Preferred: Doxycycline or erythromycin.

Alternative: Clarithromycin; azithromycin, or a fluoroquinolone.

Legionella species. Few PMNs; no bacteria.

Summer and fall; exposure to contaminated construction site, water source, air conditioner; community-acquired or hospital-acquired

Empyema, cavitation, endocarditis, pericarditis

Direct immunofluorescent examination or PCR of sputum or tissue; culture of sputum or tissue.4

Urinary antigen assay for L pneumophila serogroup 1.

Preferred: A macrolide with or without rifampin; a fluoroquinolone.

Alternative: Doxycycline with or without rifampin, TMP-SMZ.

Chlamydophila pneumoniae. Nonspecific.

Clinically similar to M pneumoniae, but prodromal symptoms last longer (up to 2 weeks). Sore throat with hoarseness common. Mild pneumonia in teenagers and young adults.

Reinfection in older adults with underlying COPD or heart failure may be severe or even fatal

 

Preferred: Doxycycline.

Alternative: Erythromycin, clarithromycin, azithromycin, or a fluoroquinolone.

Moraxella catarrhalis. Gram-negative diplococci (see micrograph).

Preexisting lung disease; elderly; corticosteroid or immunosuppressive therapy

Rarely, pleural effusions and bacteremia

Gram stain and culture of sputum, blood, pleural fluid

Preferred: A second- or third-generation cephalosporin; a fluoroquinolone.

Alternative: TMP-SMZ, amoxicillin-clavulanic acid, or a macrolide.

Pneumocystis jiroveci. Nonspecific.

AIDS, immunosuppressive or cytotoxic drug therapy, cancer

Pneumothorax, respiratory failure, ARDS, death

Methenamine silver, Giemsa, or DFA stains of sputum or bronchoalveolar lavage fluid

Preferred: TMP-SMZ or pentamidine isethionate plus prednisone.

 

Alternative: Dapsone plus trimethoprim; clindamycin plus primaquine; trimetrexate plus folinic acid.

1Antimicrobial sensitivities should guide therapy when available. (Modified from: The choice of antibacterial drugs. Med Lett Drugs Ther 2004;43:69, and from Bartlett JG et al: Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000;31:347.)

For additional antimicrobial therapy information, see Infectious Disease: Antimicrobial Therapy: Tables 30–4 (drugs of choice), 30–6 (doses per day), and 30–7, 30–8, and 30–11 (pharmacology and dosage adjustment for renal dysfunction).

3Consider penicillin resistance when choosing therapy. See text.

4Selective media are required.

5Fourfold rise in titer is diagnostic.

TMP-SMZ, trimethoprim-sulfamethoxazole; PCR, polymerase chain reaction; COPD, chronic obstructive pulmonary disease; ARDS, acute respiratory distress syndrome.

Fig.

 

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Comparison of findings in sputum and saliva (inadequate sample). A: True sputum should show an abundance of inflammatory cells and no squamous epithelial cells. In acute bacterial pneumonia, large numbers of a single organism are usually present. This Gram smear shows large numbers of polymorphonuclear leukocytes and Streptococcus pneumoniae. B: Saliva typically contains squamous epithelial cells and a mixed bacterial population. (Reproduced, with permission, from Ryan KJ [editor]: Sherris Medical Microbiology: An Introduction to Infectious Diseases, 3rd ed. Originally published by Appleton & Lange. Copyright © 1994 by The McGraw-Hill Companies, Inc.)

 

Fig.

 

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Streptococcus pneumoniae. (Courtesy of J Stauffer.)

 

Fig.

 

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Haemophilus influenzae. (Courtesy of J Stauffer.)

 

Fig.

 

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Klebsiella pneumoniae. (Courtesy of J Stauffer.)

 

Fig.

 

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Moraxella catarrhalis. (Courtesy of J Stauffer.)

This section sets forth the evaluation and management of immunocompetent hosts separately from the approach to the evaluation and management of pulmonary infiltrates in immunocompromised hosts—defined as patients with HIV disease, absolute neutrophil counts < 1000/mcL, current or recent exposure to myelosuppressive or immunosuppressive drugs, or those currently taking prednisone in a dosage of over 5 mg/d.

Community-Acquired Pneumonia

 

Symptoms and signs of an acute lung infection: fever or hypothermia, cough with or without sputum, dyspnea, chest discomfort, sweats, or rigors.
Bronchial breath sounds or rales are frequent auscultatory findings.
Parenchymal infiltrate on chest radiograph.
Occurs outside of the hospital or less than 48 hours after admission in a patient who is not hospitalized or residing in a long-term care facility for more than 14 days before the onset of symptoms.

General Considerations

greaterorequal 30 breaths/min, hypotension (defined by systolic blood pressure < 90 mm Hg or diastolic blood pressure < 60 mm Hg), and increased blood urea nitrogen (BUN).

In immunocompetent patients, the history, physical examination, radiographs, and sputum examination are neither sensitive nor specific for identifying the microbiologic cause of community-acquired pneumonia. While helpful in selected patients, these modalities do not consistently differentiate bacterial from viral causes or distinguish "typical" from "atypical" causes. As a result, the American Thoracic Society recommends empiric treatment based on epidemiologic data. In contrast, practice guidelines proposed by the Infectious Disease Society of America advocate systematic use of the microbiology laboratory in an attempt to administer pathogen-directed antimicrobial therapy whenever possible, especially in hospitalized patients.

Definition & Pathogenesis

Community-acquired pneumonia is diagnosed outside of the hospital or is diagnosed within 48 hours after admission to the hospital in a patient who has not been hospitalized in an acute care hospital for 2 or more days within 90 days of the infection; or has resided in a long-term care facility; or has received intravenous antimicrobial therapy, chemotherapy, or wound care within the 30 days prior to the current infection; or has attended a hospital or hemodialysis clinic.

Pulmonary defense mechanisms (cough reflex, mucociliary clearance system, immune responses) normally prevent the development of lower respiratory tract infections following aspiration of oropharyngeal secretions containing bacteria or inhalation of infected aerosols. Community-acquired pneumonia occurs when there is a defect in one or more of the normal host defense mechanisms or when a very large infectious inoculum or a highly virulent pathogen overwhelms the host.

Prospective studies have failed to identify the cause of community-acquired pneumonia in 40–60% of cases; two or more causes are identified in up to 5% of cases. Bacteria are more commonly identified than viruses. The most common bacterial pathogen identified in most studies of community-acquired pneumonia is S pneumoniae, accounting for approximately two-thirds of bacterial isolates. Other common bacterial pathogens include H influenzae, M pneumoniae, C pneumoniae, S aureus, Neisseria meningitidis, M catarrhalis, Klebsiella pneumoniae, other gram-negative rods, and  species. Common viral causes of community-acquired pneumonia include influenza virus, respiratory syncytial virus, adenovirus, and parainfluenza virus. A detailed assessment of epidemiologic risk factors may aid in diagnosing pneumonias due to the following causes: Chlamydia psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), endemic fungi (), and sin nombre virus (hantavirus pulmonary syndrome).

Clinical Findings

SYMPTOMS AND SIGNS

Most patients with community-acquired pneumonia experience an acute or subacute onset of fever, cough with or without sputum production, and dyspnea. Other common symptoms include rigors, sweats, chills, chest discomfort, pleurisy, hemoptysis, fatigue, myalgias, anorexia, headache, and abdominal pain.

Common physical findings include fever or hypothermia, tachypnea, tachycardia, and mild arterial oxygen desaturation. Many patients will appear acutely ill. Chest examination is often remarkable for altered breath sounds and rales . Dullness to percussion may be present if a parapneumonic pleural effusion is present.

The differential diagnosis of lower respiratory tract symptoms and signs is extensive and includes upper respiratory tract infections, reactive airway diseases, congestive heart failure, COP, lung cancer, pulmonary vasculitis, pulmonary thromboembolic disease, and atelectasis.

LABORATORY FINDINGS

Controversy surrounds the role of Gram stain and culture analysis of expectorated sputum in patients with community-acquired pneumonia. Most reports suggest that these tests have poor positive and negative predictive value in most patients. Some argue, however, that the tests should still be performed to try to identify etiologic organisms in the hope of reducing microbial resistance to drugs, unnecessary drug costs, and avoidable side effects of empiric antibiotic therapy. Expert panel guidelines suggest that sputum Gram stain should be attempted in all patients with community-acquired pneumonia and that sputum culture should be obtained for all patients who require hospitalization. Sputum should be obtained before antibiotics are initiated except in a case of suspected antibiotic failure. The specimen is obtained by deep cough and should be grossly purulent. Culture should be performed only if the specimen meets strict cytologic criteria, eg, more than 25 neutrophils and fewer than 10 squamous epithelial cells per low power field. There criteria do not apply to cultures of legionalla or mycobacteria.

Additional testing is generally recommended for patients who require hospitalization: preantibiotic blood cultures (at least two sets with needle sticks at separate sites), arterial blood gases, complete blood count with differential, and a chemistry panel (including serum glucose, electrolytes, urea nitrogen, creatinine, bilirubin, and liver enzymes). The results of these tests help assess the severity of the disease and guide evaluation and therapy. HIV testing should be considered in all adult patients, and performed in those with risk factors.

IMAGING

 

Plate 44.

 

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Left lower lobe pneumonia. (Courtesy of Dr. Thomas Hooten, Public Health Image Library, CDC.)

 

Fig.

 

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Haemophilus influenzae pneumonia. A diffuse, ill-defined, poorly marginated infiltrate occupies the upper portion of the left lung, radiating from the hilum to the periphery. There is no obvious associated mediastinal adenopathy, nor is there any pleural effusion. This ill-defined picture without significant change in lung volume is frequently seen with Haemophilus influenzae pneumonia. (Courtesy of H Goldberg.)

 

Fig.

 

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Cavitary pneumonia. Posteroanterior (A) and lateral (B) chest radiographs demonstrate consolidation with cavitation () in the superior segment of the left lower lobe secondary to  pneumonia. A small left pleural effusion is present, best seen on the lateral view (arrowhead). Changes of chronic obstructive pulmonary disease are present. (Reproduced, with permission, from Bongard FS, Sue DY [editors]: Current Critical Care Diagnosis & Treatment. Originally published by Appleton & Lange. Copyright © 1994 by The McGraw-Hill Companies, Inc.)

Progression of pulmonary infiltrates during antibiotic therapy or lack of radiographic improvement over time are poor prognostic signs and also raise concerns about secondary or alternative pulmonary processes. Clearing of pulmonary infiltrates in patients with community-acquired pneumonia can take 6 weeks or longer and is usually fastest in young patients, nonsmokers, and those with only single lobe involvement.

SPECIAL EXAMINATIONS

P jiroveci or Mycobacterium tuberculosis pneumonia. Transtracheal aspiration, fiberoptic bronchoscopy, and transthoracic needle aspiration techniques to obtain samples of lower respiratory secretions or tissues are reserved for selected patients.

Thoracentesis with pleural fluid analysis (Gram stain and cultures; glucose, lactate dehydrogenase (LD), and total protein levels; leukocyte count with differential; pH determination) should be performed on most patients with pleural effusions to assist in diagnosis of the etiologic agent and assess for empyema or complicated parapneumonic process. Serologic assays, polymerase chain reaction tests, specialized culture tests, and other new diagnostic tests for organisms such as M pneumoniae, and C pneumoniae are performed when these diagnoses are suspected. Limitations of many of these tests include delay in obtaining test results and poor sensitivity and specificity.

Treatment

Antimicrobial therapy should be initiated promptly after the diagnosis of pneumonia is established and appropriate specimens are obtained, especially in patients who require hospitalization. Delays in obtaining diagnostic specimens or the results of testing should not preclude the early administration of antibiotics to acutely ill patients. Decisions regarding hospitalization should be based on prognostic criteria as outlined above in the section on general considerations. Treatment recommendations can be divided into those for patients who can be treated as outpatients and those for patients who require hospitalization.

See Related Guideline from CURRENT Practice Guidelines in Primary Care 2008

Special consideration must be given to penicillin-resistant strains of S pneumoniae strains to penicillin. Intermediate resistance to penicillin is defined as a minimum inhibitory concentration (MIC) of 0.1–1 mcg/mL. Strains with high-level resistance usually require an MIC greaterorequal 2 mcg/mL for penicillin. Resistance to other antibiotics (beta-lactams, trimethoprim-sulfamethoxazole, macrolides, others) often accompanies resistance to penicillin. The prevalence of resistance varies by patient group, geographic region, and over time. Local resistance pattern data should therefore guide empiric therapy of suspected or documented S pneumoniae infections until specific susceptibility test results are available.

TREATMENT OF OUTPATIENTS

Empiric antibiotic options for patients with community-acquired pneumonia who do not require hospitalization include the following: (1) Macrolides (clarithromycin, 500 mg orally twice a day, or azithromycin, 500 mg orally as a first dose and then 250 mg once a day for 4 days, or 500 mg daily for 3 days). (2) Doxycycline (100 mg orally twice a day). (3) Fluoroquinolones (with enhanced activity against S pneumoniae, such as levofloxacin 500 mg orally once a day, or moxifloxacin 400 mg orally once a day). Some experts prefer doxycycline or macrolides for patients under 50 years of age without comorbidities and a fluoroquinolone for patients with comorbidities or who are older than 50 years of age. Alternatives include erythromycin (250–500 mg orally four times daily), amoxicillin-potassium clavulanate—especially for suspected aspiration pneumonia—500 mg orally three times a day or 875 mg orally twice a day, and some second- and third-generation cephalosporins such as cefuroxime axetil (250–500 mg orally twice a day), cefpodoxime proxetil (100–200 mg orally twice a day), or cefprozil (250–500 mg orally twice a day).

There are limited data to guide recommendations for duration of treatment. The decision is influenced by the severity of illness, the etiologic agent, response to therapy, other medical problems, and complications. Therapy until the patient is afebrile for at least 72 hours is usually sufficient for pneumonia due to S pneumoniae. A minimum of 2 weeks of therapy is appropriate for pneumonia due to S aureus, P aeruginosa, Klebsiella, anaerobes, M pneumoniae, C pneumoniae, or Legionella species.

 

Empiric antibiotic options for patients with community-acquired pneumonia who require hospitalization can be divided into those for patients who can be cared for on a general medical ward and those for patients who require care in an ICU. Patients who only require general medical ward care usually respond to an extended-spectrum betalower-lactam (such as ceftriaxone or cefotaxime) with a macrolide (clarithromycin or azithromycin is preferred if H influenzae infection is suspected) or a fluoroquinolone (with enhanced activity against S pneumoniae) such as levofloxacin or moxifloxacin. Alternatives include a betalower-lactam/betalower-lactamase inhibitor (ampicillin-sulbactam or piperacillin-tazobactam) with a macrolide.

Patients requiring admission to the ICU require a macrolide or a fluoroquinolone (with enhanced activity against ) plus an extended-spectrum cephalosporin (ceftriaxone, cefotaxime) or a betalower-lactam/betalower-lactamase inhibitor (ampicillin-sulbactam or piperacillin-tazobactam). Patients with penicillin allergies can be treated with a fluoroquinolone (with enhanced activity against S pneumoniae) with or without clindamycin. Patients with suspected aspiration pneumonia should receive a fluoroquinolone (with enhanced activity against S pneumoniae) with or without clindamycin, metronidazole, or a betalower-lactam/betalower-lactamase inhibitor. Patients with structural lung diseases such as bronchiectasis or cystic fibrosis benefit from empiric therapy with an antipseudomonal penicillin, carbapenem, or cefepime plus a fluoroquinolone (including high-dose ciprofloxacin) until sputum culture and sensitivity results are available. For expanded discussions of specific antibiotics, see Chapter 29: Common Problems in Infectious Diseases & Antimicrobial Therapy.

Almost all patients who are admitted to a hospital for therapy of community-acquired pneumonia receive intravenous antibiotics. Despite this preference, no studies demonstrate superior outcomes when hospitalized patients are treated intravenously instead of orally if patients can tolerate oral therapy and the drug is well absorbed. Duration of antibiotic treatment is the same as for outpatients with community-acquired pneumonia.

Prevention

Polyvalent pneumococcal vaccine (containing capsular polysaccharide antigens of 23 common strains of S pneumoniae) has the potential to prevent or lessen the severity of the majority of pneumococcal infections in immunocompetent patients. Indications for pneumococcal vaccination include the following: age greaterorequal 65 years or any chronic illness that increases the risk of community-acquired pneumonia (see Chapter 29: Common Problems in Infectious Diseases & Antimicrobial Therapy). Immunocompromised patients and those at highest risk of fatal pneumococcal infections should receive a single revaccination 6 years after the first vaccination. Immunocompetent persons 65 years of age or older should receive a second dose of vaccine if the patient first received the vaccine 6 or more years previously and was under 65 years old at the time of vaccination.

greaterorequal 65 years, residents of long-term care facilities, patients with pulmonary or cardiovascular disorders, patients recently hospitalized with chronic metabolic disorders) as well as health care workers and others who are able to transmit influenza to high-risk patients.

Hospitalized patients who would benefit from pneumococcal and influenza vaccines should be vaccinated during hospitalization. The vaccines can be given simultaneously, and there are no contraindications to use immediately after an episode of pneumonia.

When To Admit

Failure of outpatient therapy, including inability to maintain oral intake and medications.
Exacerbations of underlying disease that would benefit from hospitalization.
Complications of pneumonia (such as hypoxemia, pleural effusion, sepsis, encephalopathy).
Other medical or psychosocial needs (such as cognitive dysfunction, psychiatric disease, homelessness, drug abuse, lack of outpatient resources, or poor overall functional status).

Armitage K et al. New guidelines for the management of adult community-acquired pneumonia. Curr Opin Infect Dis. 2007 Apr;20(2):170–6. [PMID: 17496576]

 

Lutfiyya MN et al. Diagnosis and treatment of community-acquired pneumonia. Am Fam Physician. 2006 Feb 1;73(3): 442–50. [PMID: 16477891]

 

Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44(Suppl 2):S27–72. [PMID: 17278083]

 

 

 

Hospital-Acquired Pneumonia

Essentials of Diagnosis

Occurs more than 48 hours after admission to the hospital and excludes any infection present at the time of admission.
At least two of the following: fever, cough, leukocytosis, purulent sputum.
New or progressive parenchymal infiltrate on chest radiograph.
Especially common in patients requiring intensive care or mechanical ventilation.

General Considerations

Hospital-acquired pneumonia is an important cause of morbidity and mortality despite widespread use of preventive measures, advances in diagnostic testing, and potent new antimicrobial agents. Hospital-acquired pneumonia is the second most common cause of infection among inpatients and is the leading cause of death due to infection with mortality rates ranging from 20% to 50%. While the majority of cases occur in patients who are not in the ICU, the highest-risk patients are those in such units or who are being mechanically ventilated; these patients also experience higher morbidity and mortality from hospital-acquired pneumonias.

Definition & Pathogenesis

Hospital-acquired pneumonia is defined as pneumonia developing more than 48 hours after admission to the hospital. Ventilator-associated pneumonia develops in a mechanically ventilated patient more than 48 hours after intubation.

Colonization of the pharynx and possibly the stomach with bacteria is the most important step in the pathogenesis of hospital-acquired pneumonia. Pharyngeal colonization is promoted by exogenous factors (instrumentation of the upper airway with nasogastric and endotracheal tubes, contamination by dirty hands and equipment, and treatment with broad-spectrum antibiotics that promote the emergence of drug-resistant organisms) and patient factors (malnutrition, advanced age, altered consciousness, swallowing disorders, and underlying pulmonary and systemic diseases). Aspiration of infected pharyngeal or gastric secretions delivers bacteria directly to the lower airway. Impaired cellular and mechanical defense mechanisms in the lungs of hospitalized patients raise the risk of infection after aspiration has occurred. Tracheal intubation increases the risk of lower respiratory infection by mechanical obstruction of the trachea, impairment of mucociliary clearance, trauma to the mucociliary escalator system, and interference with coughing. Tight adherence of bacteria such as Pseudomonas to the tracheal epithelium and the biofilm that lines the endotracheal tube makes clearance of these organisms from the lower airway difficult. Less important pathogenetic mechanisms of hospital-acquired pneumonia include inhalation of contaminated aerosols and hematogenous dissemination of microorganisms.

The role of the stomach in the pathogenesis of hospital-acquired pneumonia remains controversial. Observational studies have suggested that elevations of gastric pH due to antacids, H2-receptor antagonists, or enteral feeding is associated with gastric microbial overgrowth, tracheobronchial colonization, and hospital-acquired pneumonia. Sucralfate, a cytoprotective agent that does not alter gastric pH, is associated with a trend toward a lower incidence of ventilator-associated pneumonia.

The most common organisms responsible for hospital-acquired pneumonia are P aeruginosa, S aureus, Enterobacter, K pneumoniae, and Escherichia coli. Proteus, Serratia marcescens, H influenzaeP aeruginosa and  tend to cause pneumonia in the most debilitated patients, those with previous antibiotic therapy, and those requiring mechanical ventilation. Anaerobic organisms (bacteroides, anaerobic streptococci, fusobacterium) may also cause pneumonia in the hospitalized patient; when isolated, they are commonly part of a polymicrobial flora. Mycobacteria, fungi, chlamydiae, viruses, rickettsiae, and protozoal organisms are uncommon causes of hospital-acquired pneumonia.

Clinical Findings

SYMPTOMS AND SIGNS

The symptoms and signs associated with hospital-acquired pneumonia are nonspecific; however, one or more clinical findings (fever, leukocytosis, purulent sputum, and a new or progressive pulmonary infiltrate on chest radiograph) are present in most patients. Other findings associated with hospital-acquired pneumonia include those listed above for community-acquired pneumonia.

The differential diagnosis of new lower respiratory tract symptoms and signs in hospitalized patients includes congestive heart failure, atelectasis, aspiration, ARDS, pulmonary thromboembolism, pulmonary hemorrhage, and drug reactions.

LABORATORY FINDINGS

The minimum evaluation for suspected hospital-acquired pneumonia includes blood cultures from two different sites and an arterial blood gas or pulse oximetry determination. Blood cultures can identify the pathogen in up to 20% of all patients with hospital-acquired pneumonia; positivity is associated with increased risk for complications and other sites of infection. The assessment of oxygenation helps define the severity of illness and determines the need for supplemental oxygen. Blood counts and clinical chemistry tests are not helpful in establishing a specific diagnosis of hospital-acquired pneumonia; however, they can help define the severity of illness and identify complications. Thoracentesis for pleural fluid analysis (stains, cultures; glucose, LD, and total protein levels; leukocyte count with differential; pH determination) should be performed in patients with pleural effusions.

Examination of sputum is attended by the same disadvantages as in community-acquired pneumonia. Gram stains and cultures of sputum are neither sensitive nor specific in the diagnosis of hospital-acquired pneumonia. The identification of a bacterial organism by culture of sputum does not prove that the organism is a lower respiratory tract pathogen. However, it can be used to help identify antibiotic sensitivity patterns of bacteria and as a guide to therapy. If hospital-acquired pneumonia from Legionella pneumophila is suspected, direct fluorescent antibody staining can be performed. Sputum stains and cultures for mycobacteria and certain fungi may be diagnostic.

IMAGING

Radiographic findings are nonspecific and can range from patchy airspace infiltrates to lobar consolidation with air bronchograms to diffuse alveolar or interstitial infiltrates. Additional findings can include pleural effusions and cavitation. Progression of pulmonary infiltrates during antibiotic therapy and lack of radiographic improvement over time are poor prognostic signs and also raise concerns about secondary or alternative pulmonary processes. Clearing of pulmonary infiltrates can take 6 weeks or longer.

SPECIAL EXAMINATIONS

Endotracheal aspiration using a sterile suction catheter and fiberoptic bronchoscopy with bronchoalveolar lavage or a protected specimen brush can be used to obtain lower respiratory tract secretions for analysis, most commonly in patients with ventilator-associated pneumonias. Endotracheal aspiration cultures have significant negative predictive value but limited positive predictive value in the diagnosis of specific etiologic agents in patients with hospital-acquired pneumonia. An invasive diagnostic approach using quantitative culture of bronchoalveolar lavage samples or protected specimen brush samples in patients suspected of having ventilator-associated pneumonia leads to significantly less antibiotic use, earlier attenuation of organ dysfunction, and fewer deaths at 14 days.

Treatment

Treatment of hospital-acquired pneumonia, like treatment of community-acquired pneumonia, is usually empiric. Because of the high mortality rate, therapy should be started as soon as pneumonia is suspected. Initial regimens must be broad in spectrum and tailored to the specific clinical setting. There is no uniform consensus on the best regimens.

Recommendations for the treatment of hospital-acquired pneumonia have been proposed by many organizations, including the American Thoracic Society. Initial empiric therapy with antibiotics is determined by the severity of illness, risk factors, and the length of hospitalization. Empiric therapy for mild to moderate hospital-acquired pneumonia in a patient without unusual risk factors or a patient with severe early-onset (within 5 days after hospitalization) hospital-acquired pneumonia may consist of a second-generation cephalosporin, a non-antipseudomonal third-generation cephalosporin, or a combination of a betalower-lactam and betalower-lactamase inhibitor.

Empiric therapy for patients with severe, late-onset (greaterorequal 5 days after hospitalization) hospital-acquired pneumonia or with ICU- or ventilator-associated pneumonia should include a combination of antibiotics directed against the most virulent organisms, particularly P aeruginosa, Acinetobacter species, and Enterobacter species. The antibiotic regimen should include an aminoglycoside or fluoroquinolone plus one of the following: an antipseudomonal penicillin, an antipseudomonal cephalosporin, a carbapenem, or aztreonam—aztreonam alone with an aminoglycoside will be inadequate if coverage for gram-positive organisms or H influenzae is required. Vancomycin is added if infection with methicillin-resistant S aureus is of concern (especially in patients with coma, head trauma, diabetes mellitus, or renal failure, or who are in the ICU). Anaerobic coverage with clindamycin or a betalower-lactam/betalower-lactamase inhibitor combination may be added for patients who have risk factors for anaerobic pneumonia, including aspiration, recent thoracoabdominal surgery, or an obstructing airway lesion. A macrolide is added when patients are at risk for Legionella infection, such as those receiving high-dose corticosteroids. After results of sputum, blood, and pleural fluid cultures have been obtained, it may be possible to switch to a regimen with a narrower spectrum. Duration of antibiotic therapy should be individualized based on the pathogen, severity of illness, response to therapy, and comorbid conditions. Therapy for gram-negative bacterial pneumonia should continue for at least 14–21 days.

For expanded discussions of specific antibiotics, see Chapter 29: Common Problems in Infectious Diseases & Antimicrobial Therapy.

Craven DE. What is healthcare-associated pneumonia, and how should it be treated? Curr Opin Infect Dis. 2006 Apr;19(2): 153–60. [PMID: 16514340]

 

Flanders SA et al. Nosocomial pneumonia: state of the science. Am J Infect Control. 2006 Mar;34(2):84–93. [PMID: 16490612]

 

Klompas M. Does this patient have ventilator-associated pneumonia? JAMA. 2007 Apr 11;297(14):1583–93. [PMID: 17426278]

 

Masterton R. The place of guidelines in hospital-acquired pneumonia. J Hosp Infect. 2007 Jun;66(2):116–22. [PMID: 17482718]

 

Anaerobic Pneumonia & Lung Abscess

Essentials of Diagnosis

History of or predisposition to aspiration.
Indolent symptoms, including fever, weight loss, malaise.
Poor dentition.
Foul-smelling purulent sputum (in many patients).
Infiltrate in dependent lung zone, with single or multiple areas of cavitation or pleural effusion.

General Considerations

Aspiration of small amounts of oropharyngeal secretions occurs during sleep in normal individuals but rarely causes disease. Sequelae of aspiration of larger amounts of material include nocturnal asthma, chemical pneumonitis, mechanical obstruction of airways by particulate matter, bronchiectasis, and pleuropulmonary infection. Individuals predisposed to disease induced by aspiration include those with depressed levels of consciousness due to drug or alcohol use, seizures, general anesthesia, or central nervous system disease; those with impaired deglutition due to esophageal disease or neurologic disorders; and those with tracheal or nasogastric tubes, which disrupt the mechanical defenses of the airways.

Periodontal disease and poor dental hygiene, which increase the number of anaerobic bacteria in aspirated material, are associated with a greater likelihood of anaerobic pleuropulmonary infection. Aspiration of infected oropharyngeal contents initially leads to pneumonia in dependent lung zones, such as the posterior segments of the upper lobes and superior and basilar segments of the lower lobes. Body position at the time of aspiration determines which lung zones are dependent. The onset of symptoms is insidious. By the time the patient seeks medical attention, necrotizing pneumonia, lung abscess, or empyema may be apparent.

Most aspiration patients with necrotizing pneumonia, lung abscess, and empyema are found to be infected with multiple species of anaerobic bacteria. Most of the remainder are infected with both anaerobic and aerobic bacteria. Prevotella melaninogenica, Peptostreptococcus, Fusobacterium nucleatum, and Bacteroides

Clinical Findings

SYMPTOMS AND SIGNS

Patients with anaerobic pleuropulmonary infection usually present with constitutional symptoms such as fever, weight loss, and malaise. Cough with expectoration of foul-smelling purulent sputum suggests anaerobic infection, though the absence of productive cough does not rule out such an infection. Dentition is often poor. Patients are rarely edentulous; if so, an obstructing bronchial lesion is usually present.

LABORATORY FINDINGS

Expectorated sputum is inappropriate for culture of anaerobic organisms because of contaminating mouth flora. Representative material for culture can be obtained only by transthoracic aspiration, thoracentesis, or bronchoscopy with a protected brush. Transthoracic aspiration is rarely indicated, because drainage occurs via the bronchus and anaerobic pleuropulmonary infections usually respond well to empiric therapy.

IMAGING

The different types of anaerobic pleuropulmonary infection are distinguished on the basis of their radiographic appearance. Lung abscess appears as a thick-walled solitary cavity surrounded by consolidation (see x-ray); (see x-ray). An air-fluid level is usually present. Other causes of cavitary lung disease (tuberculosis, mycosis, cancer, infarction, Wegener granulomatosis) should be excluded. Necrotizing pneumonia is distinguished by multiple areas of cavitation within an area of consolidation. Empyema is characterized by the presence of purulent pleural fluid and may accompany either of the other two radiographic findings (see CT scan). Ultrasonography is of value in locating fluid and may also reveal pleural loculations.

Fig.

 

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Abscess in the left upper lobe of the lung. The large, irregularly marginated lesion with a central air collection represents an abscess. In contrast to a pneumatocele, which has sharp, thin walls, this has a thick, shaggy wall indicative of abscess or cavitating tumor. (Courtesy of H Goldberg.)

 

Fig.

 

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Current Surgical Diagnosis & Treatment, 10th ed. Originally published by Appleton & Lange. Copyright © 1994 by The McGraw-Hill Companies, Inc.)

 

Fig.

 

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Pneumonia with loculated empyema. A: CT shows a loculated pleural effusion in the left hemithorax (arrowsB: More caudally, dense consolidation with air bronchograms secondary to pneumonia is present in the left lower lobe. The consolidated lung enhances with contrast and is easily distinguished from the surrounding pleural effusion. (Reproduced, with permission, from Bongard FS, Sue DY [editors]: Current Critical Care Diagnosis & Treatment

Treatment

Penicillins have been the standard treatment for anaerobic pleuropulmonary infections. However, an increasing number of anaerobic organisms produce betalower-lactamases, and up to 20% of patients do not respond to penicillins. Improved responses have been documented with clindamycin (600 mg intravenously every 8 hours until improvement, then 300 mg orally every 6 hours) or amoxicillin-clavulanate (875 mg orally every 12 hours). Penicillin (amoxicillin, 500 mg every 8 hours, or penicillin G, 1–2 million units intravenously every 4–6 hours) plus metronidazole (500 mg orally or intravenously every 8–12 hours) is another option. Antibiotic therapy should be continued until the chest radiograph improves, a process that may take a month or more; patients with lung abscesses should be treated until radiographic resolution of the abscess cavity is demonstrated. Anaerobic pleuropulmonary disease requires adequate drainage with tube thoracostomy for the treatment of empyema. Open pleural drainage is sometimes necessary because of the propensity of these infections to produce loculations in the pleural space.

Paintal HS et al. Aspiration syndromes: 10 clinical pearls every physician should know. Int J Clin Pract. 2007 May;61(5):846–52. [PMID: 17493092]

 

Schiza S et al. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med. 2006 May;12(3):205–11. [PMID: 16582676]

 

Shigemitsu H et al. Aspiration pneumonias: under-diagnosed and under-treated. Curr Opin Pulm Med. 2007 May;13(3):192–8. [PMID: 17414126]

 

PULMONARY INFILTRATES IN THE IMMUNOCOMPROMISED HOST

Pulmonary infiltrates in immunocompromised patients may arise from infectious or noninfectious causes. Infection may be due to bacterial, mycobacterial, fungal, protozoal, helminthic, or viral pathogens. Noninfectious processes such as pulmonary edema, alveolar hemorrhage, drug reactions, pulmonary thromboembolic disease, malignancy, and radiation pneumonitis may mimic infection.

Although almost any pathogen can cause pneumonia in a compromised host, two clinical tools help the clinician narrow the differential diagnosis. The first is knowledge of the underlying immunologic defect. Specific immunologic defects are associated with particular infections. Defects in humoral immunity predispose to bacterial infections; defects in cellular immunity lead to infections with viruses, fungi, mycobacteria, and protozoa. Neutropenia and impaired granulocyte function predispose to infections from S aureus, Aspergillus, gram-negative bacilli, and Candida. Second, the time course of infection also provides clues to the etiology of pneumonia in immunocompromised patients. A fulminant pneumonia is often caused by bacterial infection, whereas an insidious pneumonia is more apt to be caused by viral, fungal, protozoal, or mycobacterial infection. Pneumonia occurring within 2–4 weeks after organ transplantation is usually bacterial, whereas several months or more after transplantation P jiroveci,Aspergillus) are encountered more often.

Chest radiography is rarely helpful in narrowing the differential diagnosis. Examination of expectorated sputum for bacteria, fungi, mycobacteria, Legionella, and P jiroveci is important and may preclude the need for expensive, invasive diagnostic procedures. Sputum induction is often necessary for diagnosis. The sensitivity of induced sputum for detection of P jiroveci depends on institutional expertise, number of specimens analyzed, and detection methods.

Routine evaluation frequently fails to identify a causative organism. The clinician may begin empiric antimicrobial therapy and proceed to invasive procedures such as bronchoscopy, transthoracic needle aspiration, or open lung biopsy. The approach to management must be based on the severity of the pulmonary infection, the underlying disease, the risks of empiric therapy, and local expertise and experience with diagnostic procedures. Bronchoalveolar lavage using the flexible bronchoscope is a safe and effective method for obtaining representative pulmonary secretions for microbiologic studies. It involves less risk of bleeding and other complications than bronchial brushing and transbronchial biopsy. Bronchoalveolar lavage is especially suitable for the diagnosis of

Beck JM. The immunocompromised host: HIV infection. Proc Am Thorac Soc. 2005;2(5):423–7. [PMID: 16322594]

 

Rano A et al. Pulmonary infections in non-HIV-immunocompromised patients. Curr Opin Pulm Med. 2005 May;11(3) :213–7. [PMID: 15818182]

 

Scaglione S et al. Evaluation of pulmonary infiltrates in patients after stem cell transplantation. Hematology. 2005 Dec;10(6):469–81. [PMID: 16321812]

 

PULMONARY TUBERCULOSIS

Essentials of Diagnosis

Fatigue, weight loss, fever, night sweats, and cough.
Pulmonary infiltrates on chest radiograph, most often apical.
Positive tuberculin skin test reaction (most cases).
Acid-fast bacilli on smear of sputum or sputum culture positive for M tuberculosis.

General Considerations

Tuberculosis is one of the world's most widespread and deadly illnesses. M tuberculosis, the organism that causes tuberculosis infection and disease, infects an estimated 20–43% of the world's population. Each year, 3 million people worldwide die of the disease. In the United States, it is estimated that 15 million people are infected with M tuberculosis. Tuberculosis occurs disproportionately among disadvantaged populations such as the malnourished, homeless, and those living in overcrowded and substandard housing. There is an increased occurrence of tuberculosis among HIV-positive individuals.

Infection with M tuberculosis begins when a susceptible person inhales airborne droplet nuclei containing viable organisms. Tubercle bacilli that reach the alveoli are ingested by alveolar macrophages. Infection follows if the inoculum escapes alveolar macrophage microbicidal activity. Once infection is established, lymphatic and hematogenous dissemination of tuberculosis typically occurs before the development of an effective immune response. This stage of infection, primary tuberculosis, is usually clinically and radiographically silent. In most persons with intact cell-mediated immunity, T cells and macrophages surround the organisms in granulomas that limit their multiplication and spread. The infection is contained but not eradicated, since viable organisms may lie dormant within granulomas for years to decades.

Individuals with this latent tuberculosis infection do not have active disease and cannot transmit the organism to others. However, reactivation of disease may occur if the host's immune defenses are impaired. Active tuberculosis will develop in approximately 10% of individuals with latent tuberculosis infection who are not given preventive therapy; half of these cases occur in the 2 years following primary infection. Up to 50% of HIV-infected patients will develop active tuberculosis within 2 years after infection with tuberculosis. Diverse conditions such as gastrectomy, silicosis, and diabetes mellitus and disorders associated with immunosuppression (eg, HIV infection or therapy with corticosteroids or other immunosuppressive drugs) are associated with an increased risk of reactivation.

In approximately 5% of cases, the immune response is inadequate and the host develops progressive primary tuberculosis, accompanied by both pulmonary and constitutional symptoms that are described below. Standard teaching has held that 90% of tuberculosis in adults represents activation of latent disease. New diagnostic technologies such as DNA fingerprinting suggest that as many as one-third of new cases of tuberculosis in urban populations are primary infections resulting from person-to-person transmission.

The percentage of patients with atypical presentations—particularly elderly patients, patients with HIV infection, and those in nursing homes—has increased. Extrapulmonary tuberculosis is especially common in patients with HIV infection, who often display lymphadenitis or miliary disease (see x-ray).

Fig.

 

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Miliary tuberculosis. Multiple fine nodular densities are distributed throughout the central and peripheral areas of both lungs. This finely nodular pattern is often called a miliary pattern and is typical of miliary tuberculosis. (Courtesy of H Goldberg.)

Strains of M tuberculosis resistant to one or more first-line antituberculous drugs are being encountered with increasing frequency. Risk factors for drug resistance include immigration from parts of the world with a high prevalence of drug-resistant tuberculosis, close and prolonged contact with individuals with drug-resistant tuberculosis, unsuccessful previous therapy, and patient noncompliance. Resistance to one or more antituberculous drugs has been found in 15% of tuberculosis patients in the United States. Outbreaks of multidrug-resistant tuberculosis in hospitals and correctional facilities in Florida and New York have been associated with mortality rates of 70–90% and median survival rates of 4–16 weeks.

Clinical Findings

SYMPTOMS AND SIGNS

The patient with pulmonary tuberculosis typically presents with slowly progressive constitutional symptoms of malaise, anorexia, weight loss, fever, and night sweats. Chronic cough is the most common pulmonary symptom. It may be dry at first but typically becomes productive of purulent sputum as the disease progresses. Blood-streaked sputum is common, but significant hemoptysis is rarely a presenting symptom; life-threatening hemoptysis may occur in advanced disease. Dyspnea is unusual unless there is extensive disease. Rarely, the patient is asymptomatic. On physical examination, the patient appears chronically ill and malnourished. On chest examination, there are no physical findings specific for tuberculosis infection. The examination may be normal or may reveal classic findings such as posttussive apical rales.

LABORATORY FINDINGS

Definitive diagnosis depends on recovery of M tuberculosis from cultures or identification of the organism by DNA or RNA amplification techniques. Three consecutive morning sputum specimens are advised. Sputum induction may be helpful in patients who cannot voluntarily produce satisfactory specimens. Fluorochrome staining with rhodamine-auramine of concentrated, digested sputum specimens is performed initially as a screening method, with confirmation by the Kinyoun or Ziehl-Neelsen stains. Demonstration of acid-fast bacilli on sputum smear does not confirm a diagnosis of tuberculosis, since saprophytic nontuberculous mycobacteria may colonize the airways and rarely may cause pulmonary disease.

In patients thought to have tuberculosis despite negative sputum smears, fiberoptic bronchoscopy can be considered (see bronchoscopy). Bronchial washings are helpful; however, transbronchial lung biopsies increase the diagnostic yield. Postbronchoscopy expectorated sputum specimens may also be useful. Early morning aspiration of gastric contents after an overnight fast is an alternative to bronchoscopy but is suitable only for culture and not for stained smear, because nontuberculous mycobacteria may be present in the stomach in the absence of tuberculous infection. M tuberculosis may be cultured from blood in up to 15% of patients with tuberculosis.

Fig.

 

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Right B9a is stenotic and filled with stones caused by tuberculosis. The stone in this figure was yellowish and was extirpated by biopsy forceps. A small protrusion was observed at the bifurcation of B9a and B9b, where biopsy had been performed 2 weeks previously. (Reproduced, with permission, from Oho K, Amemiya R: . Igaku-Shoin, 1980.)

Cultures on solid media to identify M tuberculosis may require 12 weeks. Liquid medium culture systems allow detection of mycobacterial growth in several days, although this depends on the number of organisms in the inoculum. The slow rate of mycobacterial growth has fostered interest in rapid diagnostic techniques. Nucleic acid amplification or high-performance liquid chromatography can be used to identify the type of mycobacterium within hours of sputum processing. Rapid confirmation of M tuberculosis

M tuberculosis should be interpreted in the clinical context and on the basis of local laboratory performance. A patient whose sputum culture is positive for acid fast bacilli but whose nucleic acid amplification test result is negative for M tuberculosis may have a false-negative amplification test, a false-positive smear, or a nontuberculous mycobacterial infection. Clinical suspicion remains a critical factor in interpreting these studies. Drug susceptibility testing of culture isolates is considered routine for the first isolate of M tuberculosis, when a treatment regimen is failing, and when sputum cultures remain positive after 2 months of therapy.

M tuberculosis. Pleural fluid cultures for M tuberculosis are positive in less than 25% of cases of pleural tuberculosis. Culture of three pleural biopsy specimens combined with microscopic examination of a pleural biopsy yields a diagnosis in up to 90% of patients with pleural tuberculosis.

IMAGING

Radiographic abnormalities in primary tuberculosis include small homogeneous infiltrates, hilar and paratracheal lymph node enlargement, and segmental atelectasis (see x-ray). Pleural effusion may be present, especially in adults, sometimes as the sole radiographic abnormality. Cavitation may be seen with progressive primary tuberculosis (Plate 45). Ghon (calcified primary focus) and Ranke (calcified primary focus and calcified hilar lymph node) complexes are seen in a minority of patients and represent residual evidence of healed primary tuberculosis (see illustration).

Fig.

 

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A: Pulmonary tuberculosis. The chest film in this child with primary pulmonary tuberculosis demonstrates a large right hilar mass, the result of enlarged hilar lymph nodes. B: In the same patient, on the lateral view, the large hilar mass is clearly outlined, with a normal tracheal air column seen above it. (Courtesy of H Goldberg.)

 

Plate 45.

 

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Advanced bilateral pulmonary tuberculosis. (Public Health Image Library, CDC.)

 

Fig.

 

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Pulmonary tuberculosis. (Reproduced, with permission, from Chandrasoma P, Taylor CR: Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)

 

 

Fig.

 

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Cavitary tuberculosis of the right upper lobe. (Reproduced, with permission, from Way LW [editor]: Current Surgical Diagnosis & Treatment, 10th ed. Originally published by Appleton & Lange. Copyright © 1994 by The McGraw-Hill Companies, Inc.)

In patients with early HIV infection, the radiographic features of tuberculosis resemble those in patients without HIV infection. In contrast, atypical radiographic features predominate in patients with late-stage HIV infection. These patients often display lower lung zone, diffuse, or miliary infiltrates, pleural effusions, and involvement of hilar and, in particular, mediastinal lymph nodes.

SPECIAL EXAMINATIONS

The tuberculin skin test identifies individuals who have been infected with M tuberculosis but does not distinguish between active and latent infection. The test is used to evaluate a person who has symptoms of tuberculosis, an asymptomatic person who may be infected with M tuberculosis (eg, after contact exposure), or to establish the prevalence of tuberculous infection in a population. Routine testing of individuals at low risk for tuberculosis is not recommended. The Mantoux test is the preferred method: 0.1 mL of purified protein derivative (PPD) containing 5 tuberculin units is injected intradermally on the volar surface of the forearm using a 27-gauge needle on a tuberculin syringe. The transverse width in millimeters of induration at the skin test site should be measured after 48–72 hours. Table 9–10 summarizes the criteria established by the Centers for Disease Control and Prevention (CDC) for interpretation of the Mantoux tuberculin skin test. Different criteria for determination of a positive reaction are used, based on the prior likelihood of infection, to maximize the performance of the test. In patients who have serial testing, a tuberculin skin test conversion is defined as an increase of greaterorequal 10 mm of induration within a 2-year period regardless of patient age.

See Related Guideline from CURRENT Practice Guidelines in Primary Care 2008

Table 9–10. Classification of positive tuberculin skin test reactions.1

 

Reaction Size

Group

greaterorequal 5 mm

1. HIV-positive persons.

2. Recent contacts of individuals with active tuberculosis.

3. Persons with fibrotic changes on chest x-rays suggestive of prior tuberculosis.

4. Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of > 15 mg/d of prednisone for 1 month or more).

greaterorequal 10 mm

1. Recent immigrants (< 5 years) from countries with a high prevalence of tuberculosis (eg, Asia, Africa, Latin America).

2. HIV-negative injection drug users.

3. Mycobacteriology laboratory personnel.

4. Residents of and employees2 in the following high-risk congregate settings: correctional institutions; nursing homes and other long-term facilities for the elderly; hospitals and other health care facilities; residential facilities for AIDS patients; and homeless shelters.

5. Persons with the following medical conditions that increase the risk of tuberculosis: gastrectomy, greaterorequal 10% below ideal body weight, jejunoileal bypass, diabetes mellitus, silicosis, chronic renal failure, some hematologic disorders, (eg leukemias, lymphomas), and other specific malignancies (eg, carcinoma of the head or neck and lung).

6. Children < 4 years of age or infants, children, and adolescents exposed to adults at high risk.

greaterorequal 15 mm

1. Persons with no risk factors for tuberculosis.

1A tuberculin skin test reaction is considered positive if the transverse diameter of the indurated area reaches the size required for the specific group. All other reactions are considered negative.

2For persons who are otherwise at low risk and are tested at entry into employment, a reaction of > 15 mm induration is considered positive.

Source: Screening for tuberculosis and tuberculosis infection in high-risk populations: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1995;44(RR-11):19.

In general, it takes 2–10 weeks after tuberculosis infection for an immune response to PPD to develop. Both false-positive and false-negative results occur. False-positive tuberculin skin test reactions occur in persons previously vaccinated against M tuberculosis with bacillus Calmette-Guérin (BCG) (extract of Mycobacterium bovis) and in those infected with nontuberculous mycobacteria. False-negative tuberculin skin test reactions may result from improper testing technique, concurrent infections, malnutrition, advanced age, immunologic disorders, lymphoreticular malignancies, corticosteroid therapy, chronic renal failure, HIV infection, and fulminant tuberculosis. Some individuals with latent tuberculosis infection may have a negative skin test reaction when tested many years after exposure.

Serial testing may create a false impression of skin test conversion. Dormant mycobacterial sensitivity is sometimes restored by the antigenic challenge of the initial skin test. This phenomenon is called "boosting." A two-step testing procedure is used to reduce the likelihood that a boosted tuberculin reaction will be misinterpreted as a recent infection. Following a negative tuberculin skin test, the person is retested in 1–3 weeks. If the second test is negative, the person is uninfected or anergic; if positive, a boosted reaction is likely. Two-step testing should be used for the initial tuberculin skin testing of individuals who will be tested repeatedly, such as health care workers. Anergy testing is not recommended for routine use to distinguish a true-negative result from anergy. Poor anergy test standardization and lack of outcome data limit the evaluation of its effectiveness. Interpretation of the tuberculin skin test in persons who have previously received BCG vaccination is the same as in those who have not had BCG.

Novel in vitro T-cell based assays promise significant change in the identification of persons with latent M tuberculosis infection. Potential advantages of in vitro testing include reduced variability and subjectivity associated with placing and reading the PPD, fewer false-positive results from prior BCG vaccination, and better discrimination of positive responses due to nontuberculous mycobacteria.

Persons with concomitant HIV and tuberculosis infection usually respond best when the HIV infection is treated concurrently. In some cases, prolonged antituberculous therapy may be warranted. Therefore, all patients with tuberculosis infection should be tested for HIV within 2 months after diagnosis.

Treatment

GENERAL MEASURES

The goals of therapy are to eliminate all tubercle bacilli from an infected individual while avoiding the emergence of clinically significant drug resistance. The basic principles of antituberculous treatment are (1) to administer multiple drugs to which the organisms are susceptible; (2) to add at least two new antituberculous agents to a regimen when treatment failure is suspected; (3) to provide the safest, most effective therapy in the shortest period of time; and (4) to ensure adherence to therapy.

All suspected and confirmed cases of tuberculosis should be reported promptly to local and state public health authorities. Public health departments will perform case investigations on sources and patient contacts to determine if other individuals with untreated, infectious tuberculosis are present in the community. They can identify infected contacts eligible for treatment of latent tuberculous infection, and ensure that a plan for monitoring adherence to therapy is established for each patient with tuberculosis. Patients with tuberculosis should be treated by physicians who are skilled in the management of this infection. Clinical expertise is especially important in cases of drug-resistant tuberculosis.

Nonadherence to antituberculous treatment is a major cause of treatment failure, continued transmission of tuberculosis, and the development of drug resistance. Adherence to treatment can be improved by providing detailed patient education about tuberculosis and its treatment in addition to a case manager who oversees all aspects of an individual patient's care. Directly observed therapy (DOT), which requires that a health care worker physically observe the patient ingest antituberculous medications in the home, clinic, hospital, or elsewhere, also improves adherence to treatment. The importance of direct observation of therapy cannot be overemphasized. The CDC recommends DOT for all patients with drug-resistant tuberculosis and for those receiving intermittent (twice- or thrice-weekly) therapy.

Hospitalization for initial therapy of tuberculosis is not necessary for most patients. It should be considered if a patient is incapable of self-care or is likely to expose new, susceptible individuals to tuberculosis. Hospitalized patients with active disease require a private room with negative-pressure ventilation until tubercle bacilli are no longer found in their sputum ("smear-negative") on three consecutive smears taken on separate days.

Additional treatment considerations can be found in Chapter 33: Bacterial & Chlamydial Infections. Characteristics of antituberculous drugs are provided in Table 9–11. More complete information can be obtained from the CDC's Division of Tuberculosis Elimination Web site at http://www.cdc.gov/tb/.

Table 9–11. Characteristics of antituberculous drugs.

 

Drug

Most Common Side Effects

Tests for Side Effects

Drug Interactions

Remarks

Isoniazid

Peripheral neuropathy, hepatitis, rash, mild CNS effects.

AST and ALT; neurologic examination.

Phenytoin (synergistic); disulfiram.

Bactericidal to both extracellular and intracellular organisms. Pyridoxine, 10 mg orally daily as prophylaxis for neuritis; 50–100 mg orally daily as treatment.

 

Hepatitis, fever, rash, flu-like illness, gastrointestinal upset, bleeding problems, renal failure.

CBC, platelets, AST and ALT.

Rifampin inhibits the effect of oral contraceptives, quinidine, corticosteroids, warfarin, methadone, digoxin, oral hypoglycemics; aminosalicylic acid may interfere with absorption of rifampin. Significant interactions with protease inhibitors and nonnucleoside reverse transcriptase inhibitors.

Bactericidal to all populations of organisms. Colors urine and other body secretions orange. Discoloring of contact lenses.

Pyrazinamide

Hyperuricemia, hepatotoxicity, rash, gastrointestinal upset, joint aches.

Uric acid, AST, ALT.

Rare.

Bactericidal to intracellular organisms.

Ethambutol

Optic neuritis (reversible with discontinuance of drug; rare at 15 mg/kg); rash.

Red-green color discrimination and visual acuity (difficult to test in children under 3 years of age).

Rare.

Bacteriostatic to both intracellular and extracellular organisms. Mainly used to inhibit development of resistant mutants. Use with caution in renal disease or when ophthalmologic testing is not feasible.

Streptomycin

Eighth nerve damage, nephrotoxicity.

Vestibular function (audiograms); BUN and creatinine.

Neuromuscular blocking agents may be potentiated and cause prolonged paralysis.

Bactericidal to extracellular organisms. Use with caution in older patients or those with renal disease.

AST, aspartate aminotransferase; ALT, alanine aminotransferase; CBC, complete blood count; BUN, blood urea nitrogen.

TREATMENT OF TUBERCULOSIS IN HIV-NEGATIVE PERSONS

Most patients with previously untreated pulmonary tuberculosis can be effectively treated with either a 6-month or a 9-month regimen, though the 6-month regimen is preferred. The initial phase of a 6-month regimen consists of 2 months of daily isoniazid, rifampin, pyrazinamide, and ethambutol. Once the isolate is determined to be isoniazid-sensitive, ethambutol may be discontinued. If the M tuberculosis isolate is susceptible to isoniazid and rifampin, the second phase of therapy consists of isoniazid and rifampin for a minimum of 4 additional months, with treatment to extend at least 3 months beyond documentation of conversion of sputum cultures to negative for . If DOT is used, medications may be given intermittently using one of three regimens: (1) Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin two or three times each week for 4 months if susceptibility to isoniazid and rifampin is demonstrated. (2) Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 weeks, then administration of the same agents twice weekly for 6 weeks followed by administration of isoniazid and rifampin twice each week for 4 months if susceptibility to isoniazid and rifampin is demonstrated. (3) Thrice-weekly administration of isoniazid, rifampin, pyrazinamide, and ethambutol for 6 months.

Patients who cannot or should not (eg, pregnant women) take pyrazinamide should receive daily isoniazid and rifampin along with ethambutol for 4–8 weeks. If susceptibility to isoniazid and rifampin is demonstrated or drug resistance is unlikely, ethambutol can be discontinued and isoniazid and rifampin may be given twice a week for a total of 9 months of therapy. If drug resistance is a concern, patients should receive isoniazid, rifampin, and ethambutol for 9 months. Patients with smear- and culture-negative disease (eg, pulmonary tuberculosis diagnosed on clinical grounds) and patients for whom drug susceptibility testing is not available can be treated with 6 months of isoniazid and rifampin combined with pyrazinamide for the first 2 months. This regimen assumes low prevalence of drug resistance. Previous guidelines have used streptomycin interchangeably with ethambutol. Increasing worldwide streptomycin resistance has made this drug less useful as empiric therapy.

When a twice-weekly or thrice-weekly regimen is used instead of a daily regimen, the dosages of isoniazid, pyrazinamide, and ethambutol or streptomycin must be increased. Recommended dosages for the initial treatment of tuberculosis are listed in Table 9–12. Fixed-dose combinations of isoniazid and rifampin (Rifamate) and of isoniazid, rifampin, and pyrazinamide (Rifater) are available to simplify treatment. Single tablets improve compliance but are more expensive than the individual drugs purchased separately.

Table 9–12. Recommended dosages for the initial treatment of tuberculosis.

 

Drugs

Daily

Cost

 

Twice a Week2

 

Cost1/wk

 

Three Times a Week2

 

Cost1/wk

 

Isoniazid

5 mg/kg

Max: 300 mg/dose

$0.13/300 mg

15 mg/kg

Max: 900 mg/dose

$0.78

15 mg/kg

Max: 900 mg/dose

$1.17

Rifampin

10 mg/kg

Max: 600 mg/dose

$3.80/600 mg

10 mg/kg

Max: 600 mg/dose

$7.60

10 mg/kg

Max: 600 mg/dose

$11.40

Pyrazinamide

15–30 mg/kg

Max: 2 g/dose

$4.64/2 g

50–70 mg/kg

Max: 4 g/dose

 

50–70 mg/kg

Max: 3 g/dose

$20.88

Ethambutol

5–25 mg/kg

Max: 2.5 g/dose

$11.27/2.5 g

50 mg/kg

Max: 2.5 g/dose

$22.54

25–30 mg/kg

Max: 2.5 g/dose

$33.81

 

15 mg/kg

Max: 1 g/dose

$9.10/1 g

25–30 mg/kg

Max: 1.5 g/dose

$36.40

25–30 mg/kg

Max: 1.5 g/dose

$54.60

1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 27, No. 2, February 2008. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

2All intermittent dosing regimens should be used with directly observed therapy.

TREATMENT OF TUBERCULOSIS IN HIV-POSITIVE PERSONS

Management of tuberculosis is rendered even more complex in patients with concomitant HIV disease. Experts in the management of both tuberculosis and HIV disease should be involved in the care of such patients. The CDC has published detailed recommendations for the treatment of tuberculosis in HIV-positive patients. These documents can be obtained by accessing the CDC Division of Tuberculosis Elimination Web site at http://www.cdc.gov/tb/.

The basic approach to HIV-positive patients with tuberculosis is similar to that detailed above for patients without HIV disease. Additional considerations in HIV-positive patients include (1) longer duration of therapy and (2) drug interactions between rifamycin derivatives such as rifampin and rifabutin, used to treat tuberculosis, and some of the protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs), used to treat HIV (see above Web site). DOT should be used for all HIV-positive tuberculosis patients. Pyridoxine (vitamin B), 25–50 mg orally each day, should be administered to all HIV-positive patients being treated with isoniazid to reduce central and peripheral nervous system side effects.

TREATMENT OF DRUG-RESISTANT TUBERCULOSIS

Patients with drug-resistant M tuberculosis infection require careful supervision and management. Clinicians who are unfamiliar with the treatment of drug-resistant tuberculosis should seek expert advice. Tuberculosis resistant only to isoniazid can be successfully treated with a 6-month regimen of rifampin, pyrazinamide, and ethambutol or streptomycin or a 12-month regimen of rifampin and ethambutol. When isoniazid resistance is documented during a 9-month regimen without pyrazinamide, isoniazid should be discontinued. If ethambutol was part of the initial regimen, rifampin and ethambutol should be continued for a minimum of 12 months. If ethambutol was not part of the initial regimen, susceptibility tests should be repeated and two other drugs to which the organism is susceptible should be added. Treatment of M tuberculosis isolates resistant to agents other than isoniazid and treatment of drug resistance in HIV-infected patients require expert consultation.

Multidrug-resistant tuberculosis (MDRTB) calls for an individualized daily directly observed treatment plan under the supervision of a clinician experienced in the management of this entity. Treatment regimens are based on the patient's overall status and the results of susceptibility studies. Most MDRTB isolates are resistant to at least isoniazid and rifampin and require a minimum of three drugs to which the organism is susceptible. These regimens are continued until culture conversion is documented, and then a two-drug regimen is then continued for at least another 12 months. Some experts recommend at least 18–24 months of a three-drug regimen.

TREATMENT OF EXTRAPULMONARY TUBERCULOSIS

In most cases, regimens that are effective for treating pulmonary tuberculosis are also effective for treating extrapulmonary disease. However, many experts recommend 9 months of therapy when miliary, meningeal, or bone and joint disease is present. Treatment of skeletal tuberculosis is enhanced by early surgical drainage and debridement of necrotic bone. Corticosteroid therapy has been shown to help prevent cardiac constriction from tuberculous pericarditis and to reduce neurologic complications from tuberculous meningitis.

TREATMENT OF PREGNANT OR LACTATING WOMEN

Tuberculosis in pregnancy is usually treated with isoniazid, rifampin, and ethambutol. Ethambutol can be excluded if isoniazid resistance is unlikely. Therapy is continued for 9 months. Since the risk of teratogenicity with pyrazinamide has not been clearly defined, pyrazinamide should be used only if resistance to other drugs is documented and susceptibility to pyrazinamide is likely. Streptomycin is contraindicated in pregnancy because it may cause congenital deafness. Pregnant women taking isoniazid should receive pyridoxine (vitamin B6), 10–25 mg orally once a day, to prevent peripheral neuropathy.

Small concentrations of antituberculous drugs are present in breast milk and are not known to be harmful to nursing newborns. Therefore, breastfeeding is not contraindicated while receiving antituberculous therapy.

TREATMENT MONITORING

Adults should have measurements of serum bilirubin, hepatic enzymes, urea nitrogen, creatinine, and a complete blood count (including platelets) before starting chemotherapy for tuberculosis. Visual acuity and red-green color vision tests are recommended before initiation of ethambutol and serum uric acid before starting pyrazinamide. Audiometry should be performed if streptomycin therapy is initiated.

M tuberculosis until cultures convert to negative. Patients with negative sputum cultures after 2 months of treatment should have at least one additional sputum smear and culture performed at the end of therapy. Patients with MDRTB should have sputum cultures performed monthly during the entire course of treatment. A chest radiograph at the end of therapy provides a useful baseline for any future films.

Patients whose cultures do not become negative or whose symptoms do not resolve despite 3 months of therapy should be evaluated for drug-resistant organisms and for nonadherence to the treatment regimen. DOT is required for the remainder of the treatment regimen, and the addition of at least two drugs not previously given should be considered pending repeat drug susceptibility testing. The clinician should seek expert assistance if drug resistance is newly found, if the patient remains symptomatic, or if smears or cultures remain positive.

Patients with only a clinical diagnosis of pulmonary tuberculosis (smears and cultures negative for M tuberculosis) whose symptoms and radiographic abnormalities are unchanged after 3 months of treatment usually either have another process or have had tuberculosis in the past.

TREATMENT OF LATENT TUBERCULOSIS

Treatment of latent tuberculous infection is essential to controlling and eliminating tuberculosis in the United States. Treatment of latent tuberculous infection substantially reduces the risk that infection will progress to active disease. Targeted testing is used to identify persons who are at high risk for tuberculosis and who stand to benefit from treatment of latent infection. Table 9–10 defines high-risk groups and gives the tuberculin skin test criteria for treatment of latent tuberculous infection. In general, patients with a positive tuberculin skin test who are at increased risk for exposure or disease are treated. It is essential that each person who meets the criteria for treatment of latent tuberculous infection undergo a careful assessment to exclude active disease. A history of past treatment for tuberculosis and contraindications to treatment should be sought. All patients at risk for HIV infection should be tested for HIV. Patients suspected of having tuberculosis should receive one of the recommended multidrug regimens for active disease until the diagnosis is confirmed or excluded.

Several treatment regimens for both HIV-negative and HIV-positive persons are available for the treatment of latent tuberculous infection: (1) Isoniazid: A 9-month regimen (minimum of 270 doses administered within 12 months) is considered optimal. Dosing options include a daily dose of 300 mg or twice-weekly doses of 15 mg/kg. Persons at risk for developing isoniazid-associated peripheral neuropathy (diabetes mellitus, uremia, malnutrition, alcoholism, HIV infection, pregnancy, seizure disorder) may be given supplemental pyridoxine (vitamin B6), 10–50 mg/d. (2) Rifampin and pyrazinamide: A 2-month regimen (60 doses administered within 3 months) of daily rifampin (10 mg/kg up to a maximum dose of 600 mg) and pyrazinamide (15–20 mg/kg up to a maximum dose of 2 g) is recommended. (3) Rifampin: Patients who cannot tolerate isoniazid or pyrazinamide can be considered for a 4-month regimen (minimum of 120 doses administered within 6 months) of rifampin. HIV-positive patients given rifampin who are receiving protease inhibitors or NNRTIs require management by experts in both tuberculosis and HIV disease (see Treatment of Tuberculosis in HIV-Positive Persons, above).

Contacts of persons with isoniazid-resistant, rifampin-sensitive tuberculosis should receive a 2-month regimen of rifampin and pyrazinamide or a 4-month regimen of daily rifampin alone. Contacts of persons with MDRTB should receive two drugs to which the infecting organism has demonstrated susceptibility. Tuberculin skin test-negative and HIV-negative contacts may be observed without treatment or treated for 6 months. HIV-positive contacts should be treated for 12 months. All contacts of persons with MDRTB should have 2 years of follow up regardless of treatment.

Persons with a positive tuberculin skin test (greaterorequal 5 mm of induration) and fibrotic lesions suggestive of old tuberculosis on chest radiographs who have no evidence of active disease and no history of treatment for tuberculosis should receive 9 months of isoniazid, or 2 months of rifampin and pyrazinamide, or 4 months of rifampin (with or without isoniazid). Pregnant or breastfeeding women with latent tuberculosis should receive either daily or twice-weekly isoniazid with pyridoxine (vitamin B6).

Baseline laboratory testing is indicated for patients at risk for liver disease, patients with HIV infection, women who are pregnant or within 3 months of delivery, and persons who use alcohol regularly. Patients receiving treatment for latent tuberculous infection should be evaluated once a month to assess for symptoms and signs of active tuberculosis and hepatitis and for adherence to their treatment regimen. Routine laboratory testing during treatment is indicated for those with abnormal baseline laboratory tests and for those at risk for developing liver disease.

Vaccine BCG is an antimycobacterial vaccine developed from an attenuated strain of M bovis. Millions of individuals worldwide have been vaccinated with BCG. However, it is not generally recommended in the United States because of the low prevalence of tuberculous infection, the vaccine's interference with the ability to determine latent tuberculous infection using tuberculin skin test reactivity, and its variable effectiveness against pulmonary tuberculosis. BCG vaccination in the United States should only be undertaken after consultation with local health officials and experts in the management of tuberculosis. Vaccination of health care workers should be considered on an individual basis in settings in which a high percentage of tuberculosis patients are infected with strains resistant to both isoniazid and rifampin, in which transmission of such drug-resistant M tuberculosis and subsequent infection are likely, and in which comprehensive tuberculous infection-control precautions have been implemented but have not been successful. The BCG vaccine is contraindicated in persons with impaired immune responses due to disease or medications.

Prognosis

Almost all properly treated patients with tuberculosis can be cured. Relapse rates are less than 5% with current regimens. The main cause of treatment failure is nonadherence to therapy.

American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. Controlling tuberculosis in the United States. Am J Respir Crit Care Med. 2005 Nov 1;172(9):1169–227. [PMID: 16249321]

 

Blumberg HM et al; American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003 Feb 15;167(4):603–62. [PMID: 12588714]

 

Blumberg HM et al. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA. 2005 Jun 8;293(22):2776–84. [PMID: 15941808]

 

Brodie D et al. The diagnosis of tuberculosis. Clin Chest Med. 2005 Jun;26(2):247–71. [PMID: 15837109]

 

Burman WJ. Issues in the management of HIV-related tuberculosis. Clin Chest Med. 2005 Jun;26(2):283–94. [PMID: 15837111]

 

Diagnostic Standards and Classification of Tuberculosis in Adults and Children. American Thoracic Society and Centers for Disease Control and Prevention. Am J Respir Crit Care Med 2000 Apr;161(4 Part 1):1376–95. [PMID: 10764337]

 

PULMONARY DISEASE CAUSED BY NONTUBERCULOUS MYCOBACTERIA

Essentials of Diagnosis

Chronic cough, sputum production, and fatigue; less commonly: malaise, dyspnea, fever, hemoptysis, and weight loss.
Parenchymal infiltrates on chest radiograph, often with thin-walled cavities, that spread contiguously and often involve overlying pleura.
Isolation of nontuberculous mycobacteria in a sputum culture.

General Considerations

Mycobacteria other than M tuberculosis—nontuberculous mycobacteria (NTM), sometimes referred to as "atypical" mycobacteria—are ubiquitous in water and soil and have been isolated from tap water. There appears to be a continuing increase in the number and prevalence of NTM species. Marked geographic variability exists, both in the NTM species responsible for disease and in the prevalence of disease. These organisms are not considered communicable from person to person, have distinct laboratory characteristics, and are often resistant to most antituberculous drugs. See Chapter 33: Bacterial & Chlamydial Infections for further information.

Definition & Pathogenesis

The diagnosis of lung disease caused by NTM is based on a combination of clinical, radiographic, and bacteriologic criteria and the exclusion of other diseases that can resemble the condition. Specific diagnostic criteria are discussed below. Complementary data are important for diagnosis because NTM organisms can reside in or colonize the airways without causing clinical disease, especially in patients with AIDS, and many patients have preexisting lung disease that may make their chest radiographs abnormal.

Mycobacterium avium complex (MAC) is the most frequent cause of NTM pulmonary disease in humans in the United States. Mycobacterium kansasii is the next most frequent pulmonary pathogen. Other NTM causes of pulmonary disease include Mycobacterium abscessus, Mycobacterium xenopi, and Mycobacterium malmoense;

Clinical Findings

SYMPTOMS AND SIGNS

Most patients with NTM infection experience a chronic cough, sputum production, and fatigue. Less common symptoms include malaise, dyspnea, fever, hemoptysis, and weight loss. Symptoms from coexisting lung disease (commonly COPD, bronchiectasis, previous mycobacterial disease, cystic fibrosis, and pneumoconiosis) may confound the evaluation.

Common physical findings include fever and altered breath sounds, including rales or rhonchi.

LABORATORY FINDINGS

The diagnosis of NTM infection rests on recovery of the pathogen from cultures. Sputum cultures positive for atypical mycobacteria do not in themselves prove infection because NTM may exist as saprophytes colonizing the airways or may be environmental contaminants. Bronchial washings are considered to be more sensitive than expectorated sputum samples; however, their specificity for clinical disease is not known.

Bacteriologic criteria have been proposed based on studies of patients with cavitary disease with MAC or M kansasii. Diagnostic criteria in HIV-seronegative or immunocompetent persons include the following: positive culture results from at least two separate expectorated sputum samples; or positive culture from at least one bronchial wash; or a positive culture from pleural fluid or any other normally sterile site. The diagnosis can also be established by demonstrating NTM cultured from a lung biopsy, bronchial wash, or sputum plus histopathologic changes such as granulomatous inflammation in a lung biopsy. Rapid species identification of some NTM is possible using DNA probes or high-pressure liquid chromatography.

Diagnostic criteria are less stringent for patients with severe immune suppression. HIV-infected patients may show significant MAC growth on culture of bronchial washings without clinical infection, and, therefore, HIV patients being evaluated for MAC infection must be considered individually.

In general, drug susceptibility testing on cultures of NTM is not recommended except for the following NTM: (1) M kansasii to rifampin; (2) rapid growers (such as Mycobacterium fortuitum, Mycobacterium chelonei, M abscessus) to amikacin, doxycycline, imipenem, fluoroquinolones, clarithromycin, cefoxitin, and a sulfonamide.

IMAGING

Chest radiographic findings include infiltrates that are progressive or persist for at least 2 months, cavitary lesions, and multiple nodular densities. The cavities are often thin-walled and have less surrounding parenchymal infiltrate than is commonly seen with MTB infections. Evidence of contiguous spread and pleural involvement is often present. High-resolution CT of the chest may show multiple small nodules with or without multifocal bronchiectasis. Progression of pulmonary infiltrates during therapy or lack of radiographic improvement over time are poor prognostic signs and also raise concerns about secondary or alternative pulmonary processes. Clearing of pulmonary infiltrates due to NTM is slow.

Treatment

Treatment regimens and responses vary with the species of NTM. Disease caused by M kansasii responds well to drug therapy. A daily regimen of rifampin, isoniazid, and ethambutol for at least 18 months with a minimum of 12 months of negative cultures is usually successful.

The treatment of the immunocompetent patient with MAC infection is controversial and largely empiric. Traditional chemotherapeutic regimens have taken an aggressive approach using a combination of agents, but these have been associated with a high incidence of drug-induced side effects. Adherence to such regimens is also difficult. Non-HIV-infected patients with MAC pulmonary disease usually receive a combination of daily clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol. Streptomycin is considered for the first 2 months as tolerated. The optimal duration of treatment is unknown, but therapy should be continued for 12 months after sputum conversion. Medical treatment is initially successful in about two-thirds of cases, but relapses after treatment are common; long-term benefit is demonstrated in about half of all patients. Those who fail to respond favorably generally have active but stable disease. Surgical resection is an alternative for the patient with progressive disease that responds poorly to chemotherapy; the success rate with surgical therapy is good.

 

 

SCREENING FOR LUNG CANCER

See Related Guideline from CURRENT Practice Guidelines in Primary Care 2008

(See Chapter 39, Lung Cancer, Secondary Lung Cancer, and Mesothelioma.) Periodic evaluation of asymptomatic people at high risk for lung cancer is an attractive strategy without demonstrated benefit. Available evidence from the Mayo Lung Project suggests that serial chest radiographs can identify a significant number of early stage malignancies but that neither disease-specific mortality from lung cancer nor all-cause mortality is affected by screening. The illusory benefits of screening have been attributed to lead time, length time, and overdiagnosis biases. To date, no major advisory organization recommends screening for lung cancer.

The availability of rapid-acquisition, low-dose helical computed tomography (LDCT) has rekindled enthusiasm for lung cancer screening. LDCT is a very sensitive test. Compared with chest radiography, LDCT identifies between four and ten times the number of asymptomatic lung malignancies. LDCT may also increase the number of false-positive tests, unnecessary diagnostic procedures, and overdiagnosis. A mortality benefit remains to be proved. The National Lung Cancer Screening Trial is an ongoing NCI-funded multicenter trial to determine whether using LDCT to screen current or former heavy smokers for lung cancer will improve mortality in this population. Information is available at http://www.cancer.gov/NLST/.

Screening for lung cancer with biomolecular markers remains an area of study. A variety of strategies that evaluate patterns of volatile organic compounds in exhaled breath, or DNA alterations in exhaled breath condensate have been described, although lack clinical validation.

Bach PB et al. Screening for lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).Chest. 2007 Sep;132(3 Suppl):69S–77S. [PMID: 17873161]

 

SOLITARY PULMONARY NODULE

A solitary pulmonary nodule, sometimes referred to as a "coin lesion," is a < 3 cm isolated, rounded opacity on the chest radiograph outlined by normal lung and not associated with infiltrate, atelectasis, or adenopathy. Most are asymptomatic and represent an unexpected finding on chest radiography or CT scanning. The finding is important because it carries a significant risk of malignancy. The frequency of malignancy in surgical series ranges from 10% to 68% depending on patient population. Most benign nodules are infectious granulomas.  such as hamartomas account for less than 5% of solitary nodules.

The goals of evaluation are to identify and resect malignant tumors in patients who stand to benefit from resection while avoiding invasive procedures in benign disease. The task is to identify nodules with a sufficiently high probability of malignancy to warrant biopsy or resection or a sufficiently low probability of malignancy to justify observation.

Symptoms alone rarely establish the cause, but clinical and radiographic data can be used to assess the probability of malignancy. The patient's age is important. Malignant nodules are rare in persons under age 30. Above age 30, the likelihood of malignancy increases with age. Smokers are at increased risk, and the likelihood of malignancy increases with the number of cigarettes smoked daily. Patients with a prior malignancy have a higher likelihood of having a malignant solitary nodule.

The first and most important step in the radiographic evaluation is to review old radiographs. Comparison with prior studies allows estimation of doubling time, which is an important marker for malignancy. Rapid progression (doubling time less than 30 days) suggests infection; long-term stability (doubling time over 465 days) suggests benignity. Certain radiographic features help in estimating the probability of malignancy. Increasing size is correlated with malignancy. A recent study of solitary nodules identified by CT scan showed a 1% malignancy rate in those measuring 2–5 mm, 24% in 6–10 mm, 33% in 11–20 mm, and 80% in 21–45 mm. The appearance of a smooth, well-defined edge is characteristic of a benign process. Ill-defined margins or a lobular appearance suggest malignancy. A high-resolution CT finding of spiculated margins and a peripheral halo are both highly associated with malignancy. Calcification and its pattern are also helpful clues. Benign lesions tend to have dense calcification in a central or laminated pattern. Malignant lesions are associated with sparser calcification that is typically stippled or eccentric. Cavitary lesions with thick (> 16 mm) walls are much more likely to be malignant. High-resolution CT offers better resolution of these characteristics than chest radiography and is more likely to detect lymphadenopathy or the presence of multiple lesions. High-resolution CT is indicated in any suspicious solitary pulmonary nodule.

Treatment

Based on clinical and radiologic data, the clinician should assign a specific probability of malignancy to the lesion. The decision whether and how to obtain a diagnostic biopsy depends on the interpretation of this probability in light of the patient's unique clinical situation. The probabilities in parentheses below represent guidelines only and should not be interpreted as prescriptive.

In the case of solitary pulmonary nodules, a continuous probability function may be grouped into three categories. In patients with a low probability (< 5%) of malignancy (eg, age under 30, lesions stable for more than 2 years, characteristic pattern of benign calcification), watchful waiting is appropriate. Management consists of serial imaging studies (CT scans or chest radiographs) at intervals that would identify growth that would suggest malignancy. Three-dimensional reconstruction of high-resolution CT images provides a more sensitive test for growth.

Patients with a high probability (> 60%) of malignancy should proceed directly to resection following staging, provided the surgical risk is acceptable. Biopsies rarely yield a specific benign diagnosis and are not indicated.

Optimal management of patients with an intermediate probability of malignancy (5–60%) remains controversial. The traditional approach is to obtain a diagnostic biopsy either through transthoracic needle aspiration (TTNA) or bronchoscopy. Bronchoscopy yields a diagnosis in 10–80% of procedures depending on the size of the nodule and its location. In general, the bronchoscopic yield for nodules that are < 2 cm and peripheral is low, although complications are generally rare. Newer bronchoscopic modalities such as electromagnetic navigation and ultrathin bronchoscopy are being studied, although their impact upon diagnostic yield remains uncertain. TTNA has a higher diagnostic yield, reported to be between 50% and 97%. The yield is strongly operator-dependent, however, and is affected by the location and size of the lesion. Complications are higher than bronchoscopy, with pneumothorax occurring in up to 30% of patients, with up to one-third of these patients requiring placement of a chest tube.

Disappointing diagnostic yields and a high false-negative rate (up to 20–30% in TTNA) have prompted alternative approaches. Positron emission tomography (PET) detects increased glucose metabolism within malignant lesions with high sensitivity (85–97%) and specificity (70–85%). Many diagnostic algorithms have incorporated PET into the assessment of patients with inconclusive high-resolution CT findings. A positive PET increases the likelihood of malignancy, and a negative PET correctly excludes cancer in most cases. False-negative PET scans can occur with tumors with low metabolic activity (well-differentiated adenocarcinomas, carcinoids, and bronchioloalveolar tumors), and follow-up imaging is typically performed at discrete intervals to ensure absence of growth. PET has several drawbacks, however: resolution below 1 cm is poor, the test is expensive, and availability remains limited.

Sputum cytology is highly specific but lacks sensitivity. It is used in central lesions and in patients who are poor candidates for invasive diagnostic procedures. Researchers have attempted to improve the sensitivity of sputum cytology through the use of monoclonal antibodies to proteins that are up-regulated in pulmonary malignancies. Such tests offer promise but remain research tools at this time.

Video-assisted thoracoscopic surgery (VATS) offers a more aggressive approach to diagnosis. VATS is more invasive than bronchoscopy or TTNA but is associated with less postoperative pain, shorter hospital stays, and more rapid return to function than traditional thoracotomy. These advantages have led some centers to recommend VATS resection of all solitary pulmonary nodules with intermediate probability of malignancy. In some cases, surgeons will remove the nodule and evaluate it in the operating room with frozen section. If the nodule is malignant, they will proceed to lobectomy and lymph node sampling, either thoracoscopically or through conversion to standard thoracotomy.

All patients should be provided with an estimate of the likelihood of malignancy, and their preferences should be used to help guide diagnostic and therapeutic decisions. A strategy that recommends observation may not be preferred by a patient who desires a definitive diagnosis. Similarly, a surgical approach may not be agreeable to all patients unless the presence of cancer is definitive. Patient preferences should be elicited, and patients should be well informed regarding the specific risks and benefits associated with the recommended approach as well as the alternative strategies.

Gould MK et al. Evaluation of patients with pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007 Sep;132(3 Suppl):108S–130S. [PMID: 17873164]

 

MacMahon H et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005 Nov;237(2):395–400. [PMID: 16244247]

 

Mott TF et al. Clinical inquiries. What is the best approach to a solitary pulmonary nodule identified by chest x-ray? J Fam Pract. 2007 Oct;56(10):845–7. [PMID: 17908518]

 

 

 

BRONCHIAL CARCINOID TUMORS

Carcinoid and bronchial gland tumors are sometimes termed "bronchial adenomas." This term should be avoided because it implies that the lesions are benign, when in fact carcinoid tumors and bronchial gland carcinomas are low-grade malignant neoplasms.

Carcinoid tumors are about six times more common than bronchial gland carcinomas, and most of them occur as pedunculated or sessile growths in central bronchi. Men and women are equally affected. Most patients are under 60 years of age. Common symptoms of bronchial carcinoid tumors are hemoptysis, cough, focal wheezing, and recurrent pneumonia. Peripherally located bronchial carcinoid tumors are rare and present as asymptomatic solitary pulmonary nodules. Carcinoid syndrome (flushing, diarrhea, wheezing, hypotension) is rare. Fiberoptic bronchoscopy may reveal a pink or purple tumor in a central airway. These lesions have a well-vascularized stroma, and biopsy may be complicated by significant bleeding. CT scanning is helpful to localize the lesion and to follow its growth over time. Octreotide scintigraphy is also available for localization of these tumors.

Bronchial carcinoid tumors grow slowly and rarely metastasize. Complications involve bleeding and airway obstruction rather than invasion by tumor and metastases. Surgical excision of clinically symptomatic lesions is often necessary, and the prognosis is generally favorable. Most bronchial carcinoid tumors are resistant to radiation and chemotherapy.

Chong S et al. Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings. Radiographics. 2006 Jan–Feb;26(1):41–57. [PMID: 16418242]

 

Hage R et al. Update in pulmonary carcinoid tumors: a review article. Ann Surg Onc. 2003 Jul;10(6):697–704. [PMID: 12839856]

 

MEDIASTINAL MASSES

Various developmental, neoplastic, infectious, traumatic, and cardiovascular disorders may cause masses that appear in the mediastinum on chest radiograph. A useful convention arbitrarily divides the mediastinum into three compartments—anterior, middle, and posterior—in order to classify mediastinal masses and assist in differential diagnosis. Specific mediastinal masses have a predilection for one or more of these compartments; most are located in the anterior or middle compartment. The differential diagnosis of an anterior mediastinal mass includes thymoma, teratoma, thyroid lesions, lymphoma, and mesenchymal tumors (lipoma, fibroma). The differential diagnosis of a middle mediastinal mass includes lymphadenopathy, pulmonary artery enlargement, aneurysm of the aorta or innominate artery, developmental cyst (bronchogenic, enteric, pleuropericardial), dilated azygous or hemiazygous vein, and foramen of Morgagni hernia. The differential diagnosis of a posterior mediastinal mass includes hiatus hernia, neurogenic tumor, meningocele, esophageal tumor, foramen of Bochdalek hernia, thoracic spine disease, and extramedullary hematopoiesis. The neurogenic tumor group includes neurilemmoma, neurofibroma, neurosarcoma, ganglioneuroma, and pheochromocytoma.

Symptoms and signs of mediastinal masses are nonspecific and are usually caused by the effects of the mass on surrounding structures. Insidious onset of retrosternal chest pain, dysphagia, or dyspnea is often an important clue to the presence of a mediastinal mass. In about half of cases, symptoms are absent, and the mass is detected on routine chest radiograph. Physical findings vary depending on the nature and location of the mass.

CT scanning is helpful in management; additional radiographic studies of benefit include barium swallow if esophageal disease is suspected, Doppler sonography or venography of brachiocephalic veins and the superior vena cava, and angiography. MRI is useful; its advantages include better delineation of hilar structures and distinction between vessels and masses. MRI also allows imaging in multiple planes, whereas CT permits only axial imaging. Tissue diagnosis is necessary if a neoplastic disorder is suspected. Treatment and prognosis depend on the underlying cause of the mediastinal mass.

Duwe BV et al. Tumors of the mediastinum. Chest. 2005 Oct;128(4):2893–909. [PMID: 16236967]

 

INTERSTITIAL LUNG DISEASE: INTRODUCTION

Interstitial lung disease, or diffuse parenchymal lung disease, comprises a heterogeneous group of disorders that share common presentations (dyspnea), physical findings (late inspiratory crackles), and chest radiographs (septal thickening and reticulonodular changes).

The term "interstitial" is misleading since the pathologic process usually begins with injury to the alveolar epithelial or capillary endothelial cells. Persistent alveolitis may lead to obliteration of alveolar capillaries and reorganization of the lung parenchyma, accompanied by irreversible fibrosis. The process does not affect the airways proximal to the respiratory bronchioles. At least 180 disease entities may present as interstitial lung disease (Table 9–13). In most patients, no specific cause can be identified. In the remainder, drugs and a variety of organic and inorganic dusts are the principal causes. The history—particularly the occupational and medication history—may provide evidence of a specific cause.

 

Drug-related

 Antiarrhythmic agents (amiodarone)

 Antibacterial agents (nitrofurantoin, sulfonamides)

  Antineoplastic agents (bleomycin, cyclophosphamide, methotrexate, nitrosoureas)

 Antirheumatic agents (gold salts, penicillamine)

 Phenytoin

Environmental and occupational (inhalation exposures)

 Dust, inorganic (asbestos, silica, hard metals, beryllium)

 Dust, organic (thermophilic actinomycetes, avian antigens, Aspergillus species)

 Gases, fumes, and vapors (chlorine, isocyanates, paraquat, sulfur dioxide)

 Ionizing radiation

 Talc (injection drug users)

Infections

 Fungus, disseminated (Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum)

 Mycobacteria, disseminated

Pneumocystis jiroveci

 Viruses

Primary pulmonary disorders

 Cryptogenic organizing pneumonitis (COP)

  Idiopathic fibrosing interstitial pneumonia: Acute interstitial pneumonitis, desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, usual interstitial pneumonitis, respiratory bronchiolitis-associated interstitial lung disease

 Pulmonary alveolar proteinosis

Systemic disorders

 Acute respiratory distress syndrome

 Amyloidosis

 Ankylosing spondylitis

 Autoimmune disease: Dermatomyositis, polymyositis, rheumatoid arthritis, systemic sclerosis (scleroderma), systemic lupus erythematosus

 

 Goodpasture syndrome

 Idiopathic pulmonary hemosiderosis

 Inflammatory bowel disease

 Langerhans cell histiocytosis (eosinophilic granuloma)

 Lymphangitic spread of cancer (lymphangitic carcinomatosis)

 

 Pulmonary edema

 Pulmonary venous hypertension, chronic

 Sarcoidosis

 Wegener granulomatosis

 

The connective tissue diseases are a group of immunologically mediated inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis-dermatomyositis, Sjögren syndrome, and other overlap conditions. The presence of diffuse parenchymal lung disease in the setting of an established connective tissue disease is suggestive of the etiology. In some cases, lung disease precedes the more typical manifestations of the underlying connective tissue disease by months or years.

Clinical Findings

SYMPTOMS AND SIGNS

The clinical consequence of widespread lung fibrosis is diminished lung compliance, which presents as restrictive lung disease. Patients usually describe an insidious onset of exertional dyspnea and cough. Sputum production is minimal. Chest examination reveals fine, late inspiratory crackles at the lung bases in 60–90% of patients. Digital clubbing is seen in 25–50% of patients at diagnosis (see photograph).

LABORATORY FINDINGS

Serologic tests for antinuclear antibodies and rheumatoid factor are positive in 20–40% of patients but are rarely diagnostic. Antineutrophil cytoplasmic antibodies (ANCAs) may be diagnostic in some clinical settings. Pulmonary function testing shows a loss of lung volume with normal to increased airflow rates (see illustration). The DLCO is decreased, and hypoxemia with exercise is common. In advanced cases, pulmonary hypertension and resting hypoxemia may be present.

IMAGING

The chest radiograph is normal on presentation in up to 10% of patients. More typically, it shows patchy distribution of ground-glass, reticular, or reticulonodular infiltratess. In advanced disease there are multiple small, thick-walled cystic spaces in the lung periphery ("honeycomb" lung). Honeycombing indicates the presence of locally advanced fibrosis with destruction of normal lung architecture. Conventional CT and high-resolution CT imaging reveal in greater detail the findings described on chest radiograph. In some cases, high-resolution CT may be strongly suggestive of a specific pathologic process.

OTHER STUDIES

Three diagnostic techniques are in common use: bronchoalveolar lavage, transbronchial biopsy, and surgical lung biopsy, either through an open procedure or using VATS.

Bronchoalveolar lavage may provide a specific diagnosis in cases of infection, particularly with P jiroveci or mycobacteria, or when cytologic examination reveals the presence of malignant cells. The findings may be suggestive and sometimes diagnostic of eosinophilic pneumonia, Langerhans cell histiocytosis, and alveolar proteinosis. Analysis of the cellular constituents of lavage fluid may suggest a specific disease, but these findings are not diagnostic.

Transbronchial biopsy through the flexible bronchoscope is easily performed in most patients. The risks of pneumothorax (5%) and hemorrhage (1–10%) are low. However, the tissue specimens recovered are small, sampling error is common, and crush artifact may complicate diagnosis. Transbronchial biopsy can make a definitive diagnosis of sarcoidosis, lymphangitic spread of carcinoma, pulmonary alveolar proteinosis, miliary tuberculosis, and Langerhans cell histiocytosis. Transbronchial biopsy cannot establish a specific diagnosis of idiopathic interstitial pneumonia. These patients generally require surgical lung biopsy.

Surgical lung biopsy is the standard for diagnosis of interstitial lung disease. Two or three biopsies taken from multiple sites in the same lung, including apparently normal tissue, may yield a specific diagnosis as well as prognostic information regarding the extent of fibrosis versus active inflammation. Patients under age 60 without a specific diagnosis generally should undergo surgical lung biopsy. In older and sicker patients, the risks and benefits must be weighed carefully for three reasons: (1) the morbidity of the procedure can be significant; (2) a definitive diagnosis may not be possible even with surgical lung biopsy; and (3) when a specific diagnosis is made, there may be no effective treatment. Empiric therapy or no treatment may be preferable to surgical lung biopsy in some patients.

Known causes of interstitial lung disease are dealt with in their specific sections. The important idiopathic forms are discussed in Idiopathic Fibrosing Interstitial Pneumonia (Formerly: Idiopathic Pulmonary Fibrosis).

IDIOPATHIC FIBROSING INTERSTITIAL PNEUMONIA (FORMERLY: IDIOPATHIC PULMONARY FIBROSIS)

The most common diagnosis among patients with interstitial lung disease is idiopathic fibrosing interstitial pneumonia, formerly known in the United States as "idiopathic pulmonary fibrosis" (known in the United Kingdom as "cryptogenic fibrosing alveolitis"). Historically, this diagnosis was based on clinical and radiographic criteria with only a small number of patients undergoing surgical lung biopsy. When biopsies were obtained, the common element of fibrosis led to the grouping together of several histologic patterns under the category of "idiopathic pulmonary fibrosis." These distinct histopathologic features are now recognized as being associated with different natural histories and responses to therapy (see Table 9–14). Therefore, in the evaluation of patients with idiopathic interstitial lung disease, clinicians should attempt to identify specific disorders and reserve the terms "idiopathic fibrosing interstitial pneumonia," or "cryptogenic fibrosing alveolitis" to denote only the histologic pattern of usual interstitial pneumonitis (UIP).

Table 9–14. Idiopathic fibrosing interstitial pneumonias.

 

 

Histopathology

Radiographic Pattern

Response to Therapy and Prognosis

Usual interstitial pneumonia (UIP)

Patchy, temporally and geographically nonuniform distribution of fibrosis, honeycomb change, and normal lung. Type I pneumocytes are lost, and there is proliferation of alveolar type II cells. "Fibroblast foci" of actively proliferating fibroblasts and myofibroblasts. Inflammation is generally mild and consists of small lymphocytes. Intra-alveolar macrophage accumulation is present but is not a prominent feature.

 

No randomized study has demonstrated improved survival compared with untreated patients. Inexorably progressive. Response to corticosteroids and cytotoxic agents at best 15%, and these probably represent misclassification of histopathology. Median survival approximately 3 years, depending on stage at presentation. Current interest in antifibrotic agents.

 Age 55–60, slight male predominance. Insidious dry cough and dyspnea lasting months to years. Clubbing present at diagnosis in 25–50%. Diffuse fine late inspiratory crackles on lung auscultation. Restrictive ventilatory defect and reduced diffusing capacity on pulmonary function tests. ANA and RF positive in ~25% in the absence of documented collagen-vascular disease.

Respiratory bronchiolitis- associated interstitial lung disease (RB-ILD)1

Increased numbers of macrophages evenly dispersed within the alveolar spaces. Rare fibroblast foci, little fibrosis, minimal honeycomb change. In RB-ILD the accumulation of macrophages is localized within the peribronchiolar air spaces; in DIP,1 it is diffuse. Alveolar architecture is preserved.

 

May be indistinguishable from UIP. More often presents with a nodular or reticulonodular pattern. Honeycombing rare. High-resolution CT more likely to reveal diffuse ground-glass opacities and upper lobe emphysema.

Spontaneous remission occurs in up to 20% of patients, so natural history unclear. Smoking cessation is essential. Prognosis clearly better than that of UIP: median survival greater than 10 years. Corticosteroids thought to be effective, but there are no randomized clinical trials to support this view.

 Age 40–45. Presentation similar to that of UIP though in younger patients. Similar results on pulmonary function tests, but less severe abnormalities. Patients with respiratory bronchiolitis are invariably heavy smokers.

Acute interstitial pneumonitis (AIP)

Pathologic changes reflect acute response to injury within days to weeks. Resembles organizing phase of diffuse alveolar damage. Fibrosis and minimal collagen deposition. May appear similar to UIP but more homogeneous and there is no honeycomb change—though this may appear if the process persists for more than a month in a patient on mechanical ventilation.

Diffuse bilateral airspace consolidation with areas of ground-glass attenuation on high-resolution CT scan.

Supportive care (mechanical ventilation) critical but effect of specific therapies unclear. High initial mortality: Fifty to 90 percent die within 2 months after diagnosis. Not progressive if patient survives. Lung function may return to normal or may be permanently impaired.

 Clinically known as Hamman-Rich syndrome. Wide age range, many young patients. Acute onset of dyspnea followed by rapid development of respiratory failure. Half of patients report a viral syndrome preceding lung disease. Clinical course indistinguishable from that of idiopathic ARDS.

Nonspecific interstitial pneumonitis (NSIP)

Nonspecific in that histopathology does not fit into better-established categories. Varying degrees of inflammation and fibrosis, patchy in distribution but uniform in time, suggesting response to single injury. Most have lymphocytic and plasma cell inflammation without fibrosis. Honeycombing present but scant. Some have advocated division into cellular and fibrotic subtypes.

May be indistinguishable from UIP. Most typical picture is bilateral areas of ground-glass attenuation and fibrosis on high-resolution CT. Honeycombing is rare.

Treatment thought to be effective, but no prospective clinical studies have been published. Prognosis overall good but depends on the extent of fibrosis at diagnosis. Median survival greater than 10 years.

 

Cryptogenic organizing pneumonitis (COP, formerly bronchiolitis obliterans organizing pneumonia [BOOP])

Included in the idiopathic interstitial pneumonias on clinical grounds. Buds of loose connective tissue (Masson bodies) and inflammatory cells fill alveoli and distal bronchioles.

Lung volumes normal. Chest radiograph typically shows interstitial and parenchymal disease with discrete, peripheral alveolar and ground-glass infiltrates. Nodular opacities common. high-resolution CT shows subpleural consolidation and bronchial wall thickening and dilation.

Rapid response to corticosteroids in two-thirds of patients. Long-term prognosis generally good for those who respond. Relapses are common.

 Typically age 50–60 but wide variation. Abrupt onset, frequently weeks to a few months following a flu-like illness. Dyspnea and dry cough prominent, but constitutional symptoms are common: fatigue, fever, and weight loss. Pulmonary function tests usually show restriction, but up to 25% show concomitant obstruction.

1Includes desquamative interstitial pneumonia (DIP).

ANA, antinuclear antibody; RF, rheumatoid factor; UIP, usual interstitial pneumonia; ARDS, acute respiratory distress syndrome.

Patients with idiopathic fibrosing interstitial pneumonia may have any of the histologic patterns described in Table 9–14. The first step in evaluation is to identify patients whose disease is truly idiopathic. As indicated in Table 9–13, most identifiable causes of interstitial lung disease are infectious, drug-related, or environmental or occupational agents. Interstitial lung diseases associated with other medical conditions (pulmonary-renal syndromes, collagen-vascular disease) may be identified through a careful medical history. Apart from acute interstitial pneumonia, the clinical presentations of the idiopathic interstitial pneumonias are sufficiently similar to preclude a specific diagnosis. Chest radiographs and high-resolution CT scans are occasionally diagnostic. Ultimately, many patients with apparently idiopathic disease require surgical lung biopsy to make a definitive diagnosis. The importance of accurate diagnosis is twofold. First, it allows the clinician to provide accurate information about the cause and natural history of the illness. Second, accurate diagnosis helps distinguish patients most likely to benefit from therapy. Surgical lung biopsy may spare patients with UIP treatment with potentially morbid therapies.

The diagnosis of UIP can be made on clinical grounds alone in selected patients. A diagnosis of UIP can be made with 90% confidence in patients over 65 years of age who have (1) idiopathic disease by history and who demonstrate inspiratory crackles on physical examination ; (2) restrictive physiology on pulmonary function testing; (3) characteristic radiographic evidence of progressive fibrosis over several years; and (4) diffuse, patchy fibrosis with pleural-based honeycombing on high-resolution CT scan. Such patients do not need surgical lung biopsy. Note that the diagnosis of UIP cannot be confirmed on transbronchial lung biopsy since the histologic diagnosis requires a pattern of changes rather than a single pathognomonic finding. Transbronchial biopsy may exclude UIP by confirming a specific alternative diagnosis.

Audio

 


Recording of a person with pulmonary fibrosis. Note the fine quality of the rales and the timing at the end of inspiration. (Reproduced, with permission, from Raymond L.H. Murphy, Jr., MD: A Simplified Introduction to Lung Sounds [audio tape], 1977.)

Treatment of idiopathic fibrosing interstitial pneumonia is controversial. No randomized study has demonstrated that any treatment improves survival or quality of life compared with no treatment. Clinical experience suggests that patients with DIP or RB-ILD, nonspecific interstitial pneumonia (NSIP), or COP (see Table 9–14) frequently respond to corticosteroids and should be given a trial of therapy—typically prednisone, 1–2 mg/kg/d for a minimum of 2 months. The same therapy is almost uniformly ineffective in patients with UIP. Since this therapy carries significant morbidity, experts do not recommend routine use of corticosteroids in patients with UIP. There are a number of ongoing clinical trials of antifibrotic therapies, such as pirfenidone and interferon gamma-1b, as well as smaller investigations of sildenafil, thalidomide, and biologic modifiers.

Collard HR et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007 Oct 1;176(7):636–43. [PMID: 17585107]

 

Noth I et al. Recent advances in idiopathic pulmonary fibrosis. Chest. 2007 Aug;132(2):637–50. [PMID: 17699135]

 

Ryu JH et al. Diagnosis of interstitial lung diseases. Mayo Clin Proc. 2007 Aug;82(8):976–86. [PMID: 17673067]

 

SARCOIDOSIS

Essentials of Diagnosis

Symptoms related to the lung, skin, eyes, peripheral nerves, liver, kidney, heart, and other tissues.
Demonstration of noncaseating granulomas in a biopsy specimen.
Exclusion of other granulomatous disorders.

General Considerations

Sarcoidosis is a systemic disease of unknown etiology characterized in about 90% of patients by granulomatous inflammation of the lung. The incidence is highest in North American blacks and northern European whites; among blacks, women are more frequently affected than men. Onset of disease is usually in the third or fourth decade.

SYMPTOMS AND SIGNS

Patients may present with malaise, fever, and dyspnea of insidious onset. Symptoms referable to the skin, eyes, peripheral nerves, liver, kidney, or heart may also cause the patient to seek care. Some individuals are asymptomatic and come to medical attention after abnormal findings (typically bilateral hilar and right paratracheal lymphadenopathy) on chest radiographs. Physical findings are atypical of interstitial lung disease: crackles are uncommon on chest examination. Other findings may include erythema nodosum (see photograph), parotid gland enlargement, hepatosplenomegaly, and lymphadenopathy.

Fig.

 

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Erythema nodosum. Nodules on the legs are usually very tender. (Reproduced, with permission, from Orkin M, Maibach HI, Dahl MV [editors]: Dermatology. Originally published by Appleton & Lange. Copyright © 1991 by The McGraw-Hill Companies, Inc.)

LABORATORY FINDINGS

Laboratory tests may show leukopenia, an elevated erythrocyte sedimentation rate, and hypercalcemia (about 5% of patients) or hypercalciuria (20%). Angiotensin-converting enzyme (ACE) levels are elevated in 40–80% of patients with active disease. This finding is neither sensitive nor specific enough to have diagnostic significance. Physiologic testing may reveal evidence of airflow obstruction, but restrictive changes with decreased lung volumes and diffusing capacity are more common. Skin test anergy is present in 70%. ECG may show conduction disturbances and dysrhythmias.

IMAGING

Fig.

 

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SPECIAL EXAMINATIONS

The diagnosis of sarcoidosis generally requires histologic demonstration of noncaseating granulomas in biopsies from a patient with other typical associated manifestations. Other granulomatous diseases (eg, berylliosis, tuberculosis, fungal infections) and lymphoma must be excluded. Biopsy of easily accessible sites (eg, palpable lymph nodes, skin lesions, or salivary glands) is likely to be positive. Transbronchial lung biopsy has a high yield (75–90%) as well, especially in patients with radiographic evidence of parenchymal involvement. Some clinicians believe that tissue biopsy is not necessary when stage I radiographic findings are detected in a clinical situation that strongly favors the diagnosis of sarcoidosis (eg, a young black woman with erythema nodosum). Biopsy is essential whenever clinical and radiographic findings suggest the possibility of an alternative diagnosis such as lymphoma. Bronchoalveolar lavage fluid in sarcoidosis is usually characterized by an increase in lymphocytes and a high CD4/CD8 cell ratio. Bronchoalveolar lavage does not establish a diagnosis but may be useful in following the activity of sarcoidosis in selected patients. All patients require a complete ophthalmologic evaluation.

Treatment

Indications for treatment with oral corticosteroids (prednisone, 0.5–1.0 mg/kg/d) include disabling constitutional symptoms, hypercalcemia, iritis, uveitis, arthritis, central nervous system involvement, cardiac involvement, granulomatous hepatitis, cutaneous lesions other than erythema nodosum, and progressive pulmonary lesions. Long-term therapy is usually required over months to years. Serum ACE levels usually fall with clinical improvement. Immunosuppressive drugs and cyclosporine have been tried, primarily when corticosteroid therapy has been exhausted, but experience with these drugs is limited. Anti-tumor necrosis factor (TNF) therapy with infliximab has shown some promise in extra-pulmonary sarcoidosis.

Prognosis

The outlook is best for patients with hilar adenopathy alone; radiographic involvement of the lung parenchyma is associated with a worse prognosis. Erythema nodosum portends a good outcome. About 20% of patients with lung involvement suffer irreversible lung impairment, characterized by progressive fibrosis, bronchiectasis, and cavitation. Pneumothorax, hemoptysis, mycetoma formation in lung cavities, and respiratory failure often complicate this advanced stage. Myocardial sarcoidosis occurs in about 5% of patients, sometimes leading to restrictive cardiomyopathy, cardiac dysrhythmias, and conduction disturbances. Death from pulmonary insufficiency occurs in about 5% of patients.

Patients require long-term follow-up; at a minimum, yearly physical examination, pulmonary function tests, chemistry panel, ophthalmologic evaluation, chest radiograph, and ECG.

Coker RK. Guidelines for the use of corticosteroids in the treatment of pulmonary sarcoidosis. Drugs. 2007;67(8):1139–47. [PMID: 17521216]

 

Judson MA. Extrapulmonary sarcoidosis. Semin Respir Crit Care Med. 2007 Feb;28(1):83–101. [PMID: 17330194]

 

Lynch JP 3rd et al. Pulmonary sarcoidosis. Semin Respir Crit Care Med. 2007 Feb;28(1):53–74. [PMID: 17330192]

 

PULMONARY ALVEOLAR PROTEINOSIS

Pulmonary alveolar proteinosis is a rare disease in which phospholipids accumulate within alveolar spaces. The condition may be primary (idiopathic) or secondary (occurring in immune deficiency; hematologic malignancies; inhalation of mineral dusts; or following lung infections, including tuberculosis and viral infections). Progressive dyspnea is the usual presenting symptom, and chest radiograph shows bilateral alveolar infiltrates suggestive of pulmonary edema (see x-ray, CT scan). The diagnosis is based on demonstration of characteristic findings on bronchoalveolar lavage (milky appearance and PAS-positive lipoproteinaceous material) in association with typical clinical and radiographic features. In some cases, transbronchial or surgical lung biopsy (revealing amorphous intra-alveolar phospholipid) is necessary.

Fig.

 

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A: Pulmonary alveolar proteinosis (chest radiograph). An ill-defined right perihilar opacity is noted, extending from the hilum to the periphery of the lung. This is typical of pulmonary alveolar proteinosis, though the process is often bilateral and may be more basilar. B: Pulmonary alveolar proteinosis (CT scan). The patient is lying prone. The right and left lungs are replaced by opaque material with multiple small linear and circular lucencies. This pattern of diffuse alveolar infiltration is typical of pulmonary alveolar proteinosis. (Courtesy of H Goldberg.)

 

The course of the disease varies. Some patients experience spontaneous remission; others develop progressive respiratory insufficiency. Pulmonary infection with nocardia (see micrograph) or fungi may occur. Therapy for alveolar proteinosis consists of periodic whole lung lavage.

Fig.

 

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Nocardia asteroides. (Courtesy of Schering Corporation, Kenilworth, New Jersey.)

Ioachimescu OC et al. Pulmonary alveolar proteinosis. Chron Respir Dis. 2006;3(3):149–59. [PMID: 16916009]

 

EOSINOPHILIC PULMONARY SYNDROMES

Eosinophilic pulmonary syndromes are a diverse group of disorders typically characterized by eosinophilic pulmonary infiltrates, dyspnea, and cough. Many patients have constitutional symptoms, including fever. Common causes include exposure to medications (nitrofurantoin, phenytoin, ampicillin, acetaminophen, ranitidine) or infection with helminths (eg, Ascaris, hookworms, Strongyloides) or filariae (eg, Wuchereria bancrofti, Brugia malayi, tropical pulmonary eosinophilia). Löffler syndrome refers to acute eosinophilic pulmonary infiltrates in response to transpulmonary passage of helminth larvae. Pulmonary eosinophilia can also be a feature of other illnesses, including ABPA, Churg-Strauss syndrome, systemic hypereosinophilic syndromes, eosinophilic granuloma of the lung (properly referred to as pulmonary Langerhans cell histiocytosis), neoplasms, and numerous interstitial lung diseases (see x-ray). If an extrinsic cause is identified, therapy consists of removal of the offending drug or treatment of the underlying parasitic infection.

Fig.

 

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A: Eosinophilic pneumonitis. This patient with parasite-induced eosinophilic pneumonitis has ill-defined nodular and fluffy, patchy densities scattered throughout both lungs. B: The lateral film from the same patient shows a better-defined infiltrate at the left lung base. (Courtesy of H Goldberg.)

 

One-third of cases are idiopathic, and there are two common syndromes. Chronic eosinophilic pneumonia is seen predominantly in women and is characterized by fever, night sweats, weight loss, and dyspnea. Asthma is present in half of cases. Chest radiographs often show peripheral infiltrates (see x-ray), the "photographic negative" of pulmonary edema. Bronchoalveolar lavage typically has a marked eosinophilia; peripheral blood eosinophilia is present in greater than 80%. Therapy with oral prednisone (1 mg/kg/d for 1–2 weeks followed by a gradual taper over many months) usually results in dramatic improvement; however, most patients require at least 10–15 mg of prednisone every other day for a year or more (sometimes indefinitely) to prevent relapses. Acute eosinophilic pneumonia is an acute, febrile illness characterized by cough and dyspnea, sometimes rapidly progressing to respiratory failure. The chest radiograph is abnormal but nonspecific. Bronchoalveolar lavage frequently shows eosinophilia but peripheral blood eosinophilia is rare at the onset of symptoms. The response to corticosteroids is usually dramatic.

Fig.

 

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Eosinophilic pneumonia. The pulmonary infiltrate in this case is confined to the lingular portion of the left lung and extends into the upper lobe. There is also a small pleural effusion. This is one of the manifestations of eosinophilic pneumonia. (Courtesy of H Goldberg.)

Alam M et al. Chronic eosinophilic pneumonia: a review. South Med J. 2007 Jan;100(1):49–53. [PMID: 17269525]

 

Allen J. Acute eosinophilic pneumonia. Semin Respir Crit Care Med. 2006 Apr;27(2):142–7. [PMID: 16612765]

 

PULMONARY VENOUS THROMBOEMBOLISM

Predisposition to venous thrombosis, usually of the lower extremities.
One or more of the following: dyspnea, chest pain, hemoptysis, syncope.
Tachypnea and a widened alveolar-arterial Po difference.
Characteristic defects on ventilation-perfusion lung scan, helical CT scan of the chest, or pulmonary angiogram.

General Considerations

Pulmonary venous thromboembolism, often referred to as pulmonary embolism (PE), is a common, serious, and potentially fatal complication of thrombus formation within the deep venous circulation. PE is estimated to cause 200,000 deaths each year in the United States and is the third leading cause of death among hospitalized patients. Despite this prevalence, most cases are not recognized antemortem, and less than 10% of patients with fatal emboli have received specific treatment for the condition. Management demands a vigilant systematic approach to diagnosis and an understanding of risk factors so that appropriate preventive therapy can be given.

Many substances can embolize to the pulmonary circulation, including air (during neurosurgery, from central venous catheters), amniotic fluid (during active labor), fat (long bone fractures), foreign bodies (talc in injection drug users), parasite eggs (schistosomiasis), septic emboli (acute infectious endocarditis), and tumor cells (renal cell carcinoma). The most common embolus is thrombus, which may arise anywhere in the venous circulation or heart but most often originates in the deep veins of the lower extremities. Thrombi confined to the calf rarely embolize to the pulmonary circulation. However, about 20% of calf vein thrombi propagate proximally to the popliteal and ileofemoral veins, at which point they may break off and embolize to the pulmonary circulation. Pulmonary emboli will develop in 50–60% of patients with proximal deep venous thrombosis (DVT); half of these embolic events will be asymptomatic. Approximately 50–70% of patients who have symptomatic pulmonary emboli will have lower extremity DVT when evaluated.

PE and DVT are two manifestations of the same disease. The risk factors for PE are the risk factors for thrombus formation within the venous circulation: venous stasis, injury to the vessel wall, and hypercoagulability (Virchow triad). Venous stasis increases with immobility (bed rest—especially postoperative—obesity, stroke), hyperviscosity (polycythemia), and increased central venous pressures (low cardiac output states, pregnancy). Vessels may be damaged by prior episodes of thrombosis, orthopedic surgery, or trauma. Hypercoagulability can be caused by medications (oral contraceptives, hormonal replacement therapy) or disease (malignancy, surgery) or may be the result of inherited gene defects. The most common inherited cause in white populations is resistance to activated protein C, also known as factor V Leiden. The trait is present in approximately 3% of healthy American men and in 20–40% of patients with idiopathic venous thrombosis. Other major risks for hypercoagulability include the following: deficiencies or dysfunction of protein C, protein S, and antithrombin III; prothrombin gene mutation; and the presence of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody).

PE has multiple physiologic effects. Physical obstruction of the vascular bed and vasoconstriction from neurohumoral reflexes both increase pulmonary vascular resistance. Massive thrombus may cause right ventricular failure. Vascular obstruction increases physiologic dead space (wasted ventilation) and leads to hypoxemia through right-to-left shunting, decreased cardiac output, and surfactant depletion causing atelectasis. Reflex bronchoconstriction promotes wheezing and increased work of breathing.

Clinical Findings

SYMPTOMS AND SIGNS

The clinical diagnosis of PE is notoriously difficult for two reasons. First, the clinical findings depend on both the size of the embolus and the patient's preexisting cardiopulmonary status. Second, common symptoms and signs of pulmonary emboli are not specific to this disorder (Table 9–15).

Table 9–15. Frequency of specific symptoms and signs in patients at risk for pulmonary thromboembolism.

 

 

UPET1 PE+ (n = 327)

 

PIOPED2 PE+ (n = 117)

 

PIOPED2 PE– (n = 248)

 

Symptoms

 

 

 

 Dyspnea

84%

73%

72%

 Respirophasic chest pain

74%

66%

59%

 Cough

53%

37%

36%

 Leg pain

nr

26%

24%

 Hemoptysis

30%

13%

8%

 Palpitations

nr

10%

18%

 Wheezing

nr

9%

11%

 Anginal pain

14%

4%

6%

Signs

 

 

 

 Respiratory rate greaterorequal 16 UPET, greaterorequal

92%

70%

68%

 Crackles (rales)

58%

51%

40%3

 

 Heart rate greaterorequal 100/min

44%

30%

24%

 Fourth heart sound (S4)

 

nr

24%

13%3

 

 Accentuated pulmonary component of second heart sound (S2P)

 

53%

23%

13%3

 

 T greaterorequal 37.5 °C UPET, greaterorequal 38.5 °C PIOPED

43%

7%

12%

 Homans' sign

nr

4%

2%

 Pleural friction rub

nr

3%

2%

3)

 

nr

3%

4%

 Cyanosis

19%

1%

2%

1Data from the Urokinase-Streptokinase Pulmonary Embolism Trial, as reported in Bell WR, Simon TL, DeMets DL. The clinical features of submassive and massive pulmonary emboli. Am J Med. 1977;62:355.

2Data from patients enrolled in the PIOPED I study, as reported in Stein PD et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no preexisting cardiac or pulmonary disease. Chest. 1991;100:598.

3P < .05 comparing patients in the PIOPED I study.

PE+, confirmed diagnosis of pulmonary embolism; PE–, diagnosis of pulmonary embolism ruled out; nr, not reported.

Indeed, no single symptom or sign or combination of clinical findings is specific to PE. Some findings are fairly sensitive: dyspnea and pain on inspiration occur in 75–85% and 65–75% of patients, respectively. Tachypnea is the only sign reliably found in more than half of patients. A common clinical strategy is to use combinations of clinical findings to identify patients at low risk for PE. For example, 97% of patients in the original Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED I) study with angiographically proved pulmonary emboli had one or more of three findings: dyspnea, chest pain with breathing, or tachypnea. Wells and colleagues have published and validated a simple clinical decision rule that quantifies and dichotomizes this clinical risk assessment, allowing diversion of patients deemed unlikely to have PE to a simpler diagnostic algorithm (see Integrated Approach to Diagnosis of Pulmonary Embolism).

LABORATORY FINDINGS

The ECG is abnormal in 70% of patients with PE. However, the most common abnormalities are sinus tachycardia and nonspecific ST and T wave changes, each seen in approximately 40% of patients. Five percent or less of patients in the PIOPED I study had P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block.

Arterial blood gases usually reveal acute respiratory alkalosis due to hyperventilation. The arterial PO2 and the alveolar-arterial oxygen difference (A–a–DO2) are usually abnormal in patients with PE compared with healthy, age-matched controls. However, arterial blood gases are not diagnostic: among patients who were evaluated in the PIOPED I study, neither the PO2 nor the A–a–DO2 differentiated between those with and those without pulmonary emboli. Profound hypoxia with a normal chest radiograph in the absence of preexisting lung disease is highly suspicious for PE.

Plasma levels of D-dimer, a degradation product of cross-linked fibrin, are elevated in the presence of thrombus. Using a D-dimer threshold between 300 and 500 ng/mL, a rapid quantitative enzyme-linked immunosorbent assay (ELISA) has shown a sensitivity for venous thromboembolism of 95–97% and a specificity of 45%. Therefore, a D-dimer < 500 ng/mL using most rapid ELISA provides strong evidence against venous thromboembolism, with a likelihood ratio of 0.11–0.13. Appropriate diagnostic thresholds have not been established for patients in whom D-dimer is elevated.

Serum troponin I, troponin T, and plasma beta-natriuretic peptide (BNP) levels are typically higher in patients with PE compared with those without embolism; the presence and magnitude of the elevation are not useful in diagnosis, but correlate with adverse outcomes, including death, mechanical ventilation and prolonged hospitalization.

IMAGING AND SPECIAL EXAMINATIONS

Chest radiography

The chest radiograph is necessary to exclude other common lung diseases and to permit interpretation of the ventilation-perfusion (vdot/qdot) scan, but it does not establish the diagnosis by itself. The chest radiograph was normal in only 12% of patients with confirmed PE in the PIOPED I study. The most frequent findings were atelectasis, parenchymal infiltrates, and pleural effusions. However, the prevalence of these findings was the same in hospitalized patients without PE. A prominent central pulmonary artery with local oligemia (Westermark sign) or pleural-based areas of increased opacity that represent intraparenchymal hemorrhage (Hampton hump) are uncommon (see x-ray). Paradoxically, the chest radiograph may be most helpful when normal in the setting of hypoxemia.

Fig.

 

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A: Pulmonary embolism (chest radiograph). The heart is significantly enlarged, with prominence of main pulmonary arterial outflow as indicated by fullness in the region of the pulmonary hila. However, there are no other changes in the peripheral lung suggestive of a pulmonary embolus. B: Pulmonary embolism (pulmonary angiogram). A large embolus is present in the right main pulmonary artery at its point of bifurcation between the upper and middle and the lower lobe vessels, resulting in a paucity of perfusion of vessels distal to the embolus. (Courtesy of H Goldberg.)

A perfusion scan is performed by injecting radiolabeled microaggregated albumin into the venous system, allowing the particles to embolize to the pulmonary capillary bed. To perform a ventilation scan, the patient breathes a radioactive gas or aerosol while the distribution of radioactivity in the lungs is recorded.

A defect on perfusion scanning represents diminished blood flow to that region of the lung. This finding is not specific for PE. Defects in the perfusion scan are interpreted in conjunction with the ventilation scan to give a high, low, or intermediate (indeterminate) probability that PE is the cause of the abnormalities. Criteria for the combined interpretation of ventilation and perfusion scans (commonly referred to as a single test, the vdot/qdot scan) are complex, confusing, and not completely standardized. A normal perfusion scan excludes the diagnosis of clinically significant PE (negative predictive value of 91% in the PIOPED I study). A high-probability vdot/qdot scan is most often defined as having two or more segmental perfusion defects in the presence of normal ventilation and is sufficient to make the diagnosis of PE in most instances (positive predictive value of 88% among PIOPED I patients).

vdot/qdot scans are most helpful when they are either normal (see x-ray); (see x-ray) or indicate a high probability of PE. Such readings are reliable—interobserver agreement is best for normal and high-probability scans—and they carry predictive power: The likelihood ratios associated with normal and high-probability scans are 0.10 and 18, respectively, indicating significant and frequently conclusive changes from pretest to posttest probability.

Fig.

 

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Normal lung perfusion. A routine examination may include as many as eight views–anterior, posterior, right and left anterior and posterior obliques, and both right and left laterals (A to H). Some physicians prefer to omit the anterior obliques; others do not include the laterals. There is general agreement that the posterior obliques are the most valuable views. When the patient is injected in the supine position, the radioactive particles are evenly distributed throughout the lungs, with a gently increasing gradient of activity from the upper anterior to the lower posterior lung fields. The cardiac and mediastinal spaces between the lungs have a configuration in the combined anterior and posterior views similar to that of the respective area in the posteroanterior chest radiograph. Cardiomegaly and mediastinal masses will cause distortions that are common to both examinations. An enlarged cardiac space may be caused by cardiomegaly and by effusions or other conditions of the pericardial sac and adjacent pleural cavity. If the patient is rotated, the lung images may override and cause a false defect, which will disappear when the patient is repositioned accurately. However, a true lesion is unlikely if seen in only one view of a complete study. (Reproduced, with permission, from Baum S et al: Atlas of Nuclear Medicine Imaging, 2nd ed. Originally published by Appleton & Lange. Copyright © 1992 by The McGraw-Hill Companies, Inc.)

 

Fig.

 

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Normal lung ventilation with xenon-133. With the patient's single full breath, inhaled radioxenon is evenly distributed to all lung areas, reaching the terminal airways and alveoli in the normal patient (A, posterior view). There is a less noticeable gradient of activity from the upper to the lower lung fields than is seen in perfusion lung images. Fifteen-second images obtained during closed-system rebreathing of a xenon–oxygen mixture show uniform distribution at 120 seconds (B). Serial 15-second frames after switching the patient to room air breathing (C to G) show a homogeneous pattern of washout from all lung areas. This sequence mainly evaluates the posterior lung regions. To better localize gas trapping in specific lung segments or more anterior regions, the acquisition may be modified after the rebreathing phase by rotating the patient into posterior oblique positions. Selected images from a complete study include single breath (H, posterior view), the late phase of rebreathing (I, posterior view), posterior washout (J), left posterior oblique washout (K), and right posterior oblique washout (L). No gas is retained in this patient, which is normal, but in obstructive airway disease gas retention persists and is better localized in the oblique views than in a posterior view alone. A small amount of alveolar xenon normally crosses the alveolar membrane to reach the blood and be distributed throughout the body. Because it is highly soluble in lipids, xenon accumulates in adipose tissue, including the liver, which is faintly seen with prolonged rebreathing. Liver activity should not be mistaken for delayed washout of xenon from the base of the lung. Occasionally, splenic blood pool radioactivity or swallowed xenon in the stomach may also be seen. (SIN BRE = single breath, L REB = late rebreathe, WO = washout.) (Reproduced, with permission, from Baum S et al: Atlas of Nuclear Medicine Imaging, 2nd ed. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)

However, 75% of PIOPED I vdot/qdot scans were nondiagnostic, ie, of low or intermediate probability. At angiography, these patients had an overall incidence of PE of 14% and 30%, respectively.

One of the most important findings of PIOPED I was that the clinical assessment of pretest probability could be used to aid the interpretation of the vdot/qdot scan. For patients with low-probability vdot/qdot scans and a low (20% or less) clinical pretest probability of PE, the diagnosis was confirmed in only 4%. Such patients may reasonably be observed off therapy without angiography. All other patients with nondiagnostic vdot/qdot scans require further testing to determine the presence of venous thromboembolism.

CT

Helical CT pulmonary angiography has essentially supplanted vdot/qdot scanning as the initial diagnostic study in the United States for suspected PE. Helical CT pulmonary angiography requires administration of intravenous radiocontrast dye but is otherwise noninvasive. A high quality study is very sensitive for the detection of thrombus in the proximal pulmonary arteries but less so in more distal arteries where it may miss as many as 75% of subsegmental defects, compared with pulmonary angiography. Comparing helical CT pulmonary angiography to the vdot/qdot scan as the initial test for PE, detection of thrombi is roughly comparable, although more alternative pulmonary diagnoses are made with CT scanning.

Test characteristics of helical CT pulmonary angiography vary widely by study and facility. Factors influencing results include patient size and cooperation, the type and quality of the scanner, the imaging protocol, and the experience of the interpreting radiologist. Early studies comparing single-detector helical CT with standard angiography reported sensitivity of 53–60% and specificity of 81–97% for the diagnosis of PE. The 2006 PIOPED II study, using multidetector (four-row) helical CT and excluding the 6% of patients whose studies were "inconclusive," reported sensitivity of 83% and specificity of 96%.

A 15–20% false-negative rate is high for a screening test, and raises the practical question whether it is safe to withhold anticoagulation in patients with a negative helical CT. Research data provide two complementary answers. The insight of PIOPED I, that the clinical assessment of pretest probability improves the performance of the vdot/qdot scan, was confirmed with helical CT pulmonary angiography in PIOPED II, where positive and negative predictive values were highest in patients with concordant clinical assessments but poor with conflicting assessments: The negative predictive value of a normal helical CT in patients with a high pretest probability was only 60%. Therefore, a normal helical CT alone does not exclude PE in high-risk patients, and either empiric therapy or further testing is indicated.

A large, prospective trial called the Christopher Study incorporated objective, validated pretest clinical assessment into diagnostic algorithms using D-dimer measurement. In this study, patients with a high pretest probability and a negative helical CT pulmonary angiogram who were not receiving anticoagulation had a low (< 2%) 3-month incidence of subsequent PE. This low rate of complications supports the contention that many false-negative studies represent clinically insignificant, small distal thrombi and provides support for monitoring most patients with a high-quality negative helical CT pulmonary angiogram off therapy (see Integrated Approach to Diagnosis of Pulmonary Embolism below). The rate of false-positive helical CT pulmonary angiograms and overtreatment of PE has not been as well studied to date.

Venous thrombosis studies

Seventy percent of patients with PE will have DVT on evaluation, and approximately half of patients with DVT will have PE on angiography. Since the history and physical examination are neither sensitive nor specific for PE and since the results of vdotqdot scanning are frequently equivocal, documentation of DVT in a patient with suspected PE establishes the need for treatment and may preclude further testing.

Commonly available diagnostic techniques include venous ultrasonography, impedance plethysmography, and contrast venography. In most centers, venous ultrasonography is the test of choice to detect proximal DVT (see echocardiogram). Inability to compress the common femoral or popliteal veins in symptomatic patients is diagnostic of first-episode DVT (positive predictive value of 97%); full compressibility of both sites excludes proximal DVT (negative predictive value of 98%). The test is less accurate in distal thrombi, recurrent thrombi, or in asymptomatic patients. Impedance plethysmography relies on changes in electrical impedance between patent and obstructed veins to determine the presence of thrombus. Accuracy is comparable though not quite as high as ultrasonography. Both ultrasonography and impedance plethysmography are useful in the serial examination of patients with high clinical suspicion of venous thromboembolism but negative leg studies. In patients with suspected first-episode DVT and a negative ultrasound or impedance plethysmography examination, multiple studies have confirmed the safety of withholding anticoagulation while conducting two sequential studies on days 1–3 and 7–10. Similarly, patients with nondiagnostic vdot/qdot scans and an initial negative venous ultrasound or impedance plethysmography examination may be monitored off therapy with serial leg studies over 2 weeks. When serial examinations are negative for proximal DVT, the risk of subsequent venous thromboembolism over the following 6 months is less than 2%.

Fig.

 

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Deep venous thrombosis. Aged thrombus (T) presents with various degrees of echogenicity. A: Common femoral vein (C). B: Popliteal vein (P). (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL: Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)

 

Contrast venography remains the reference standard for the diagnosis of DVT (see venogram). An intraluminal filling defect is diagnostic of venous thrombosis. However, venography has significant shortcomings and has been replaced by venous ultrasound as the diagnostic procedure of choice. Venography may be useful in complex situations where there is discrepancy between clinical suspicion and noninvasive testing.

Fig.

 

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Venography of deep venous thrombosis. Venography demonstrates (A) a filling defect (arrow) and (B) the "railroad sign" (arrowheadUltrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)

Pulmonary angiography

Pulmonary angiography remains the reference standard for the diagnosis of PE. An intraluminal filling defect in more than one projection establishes a definitive diagnosis. Secondary findings highly suggestive of PE include abrupt arterial cutoff, asymmetry of blood flow—especially segmental oligemia—or a prolonged arterial phase with slow filling. Pulmonary angiography was performed in 755 patients in the PIOPED I study. A definitive diagnosis was established in 97%; in 3% the studies were nondiagnostic. Four patients (0.8%) with negative angiograms subsequently had pulmonary thromboemboli at autopsy. Serial angiography has demonstrated minimal resolution of thrombus prior to day 7 following presentation. Thus, negative angiography within 7 days of presentation excludes the diagnosis.

Pulmonary angiography is a safe but invasive procedure with well-defined morbidity and mortality data. Minor complications occur in approximately 5% of patients. Most are allergic contrast reactions, transient renal dysfunction, or related to percutaneous catheter insertion; cardiac perforation and arrhythmias are reported but rare. Among the PIOPED I patients who underwent angiography, there were five deaths (0.7%) directly related to the procedure.

The appropriate role of pulmonary angiography in the diagnosis of PE remains a subject of ongoing debate. There is wide agreement that angiography is indicated in any patient in whom the diagnosis is in doubt when there is a high clinical pretest probability of PE or when the diagnosis of PE must be established with certainty, as when anticoagulation is contraindicated or placement of an inferior vena cava filter is contemplated.

MRI has sensitivity and specificity equivalent to contrast venography in the diagnosis of DVT. It has improved sensitivity when compared with venous ultrasound in the diagnosis of DVT, without loss of specificity. The test is noninvasive and avoids the use of potentially nephrotoxic radiocontrast dye. However, it remains expensive and not widely available. Artifacts introduced by respiratory and cardiac motion have limited the use of MRI in the diagnosis of PE. New techniques have improved sensitivity and specificity to levels comparable with helical CT, but MRI remains primarily a research tool for PE.

Integrated Approach to Diagnosis of Pulmonary Embolism

An integrated approach to diagnosis of PE uses the clinical likelihood of venous thromboembolism derived from a clinical prediction rule (Table 9–16) along with the results of diagnostic tests to come to one of three decision points: to establish venous thromboembolism (PE or DVT) as the diagnosis, to exclude venous thromboembolism with sufficient confidence to follow the patient off anticoagulation, or to refer the patient for additional testing. An ideal diagnostic algorithm would proceed in a cost-effective, stepwise fashion to come to these decision points at minimal risk to the patient. The standard vdot/qdot scan based algorithm (Table 9–17) has been replaced in most North American centers by a rapid D-dimer and helical CT pulmonary angiography based diagnostic algorithm Figure 9–5: illustration. The vdot/qdot

Table 9–16. Clinical prediction rule for pulmonary embolism (PE).

 

Variable

 

Clinical symptoms and signs of deep venous thrombosis (DVT) (leg swelling and pain with palpation of deep veins)

3.0

Alternative diagnosis less likely than PE

3.0

Heart rate > 100 beats/min

1.5

Immobilization for more than 3 days or surgery in previous 4 weeks

1.5

Previous PE or DVT

1.5

Hemoptysis

1.0

Cancer (with treatment within past 6 months or palliative care)

1.0

Three-tiered clinical probability assessment

Score

 High

> 6.0

 Moderate

2.0 to 6.0

 Low

< 2.0

Dichotomous clinical probability assessment

Score

 PE likely

> 4.0

 PE unlikely

< or = 4.0

Data from Wells PS et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000 Mar;83(3):416–20.

Table 9–17. Pulmonary ventilation-perfusion scan based diagnostic algorithm for PE.

 

Clinical concern for PE:

1. Analyze by three-tiered clinical probability assessment

2. Obtain vdot/qdot scan

3. Match results in the following table

Clinical suspicion for PE by clinical probability assessment

 

 

HIGH

MODERATE

LOW

vdot/qdot scan Results

High probability

STOP.

Diagnosis established.

Treat for PE.

STOP.

Diagnosis established.

Treat for PE.

Diagnosis likely (56% in PIOPED I, but small number of patients).

Treat for PE or evaluate further with LE US or CT-PA.

Indeterminate

Diagnosis highly likely (66% in PIOPED I).

Treat for PE or evaluate further with LE US or CT-PA.

Uncertain diagnosis

Evaluate further with LE US or CT-PA.

Uncertain diagnosis.

Evaluate further with LE US or CT-PA.

Low probability

Uncertain diagnosis.

Evaluate further with LE US or CT-PA.

Uncertain diagnosis.

Evaluate further with LE US or CT-PA.

STOP.

Diagnosis excluded; monitor off anticoagulation.

Consider alternative diagnoses.

Normal

STOP.

Diagnosis excluded; monitor off anticoagulation.

Consider alternative diagnoses.

STOP.

Diagnosis excluded; monitor off anticoagulation.

Consider alternative diagnoses.

STOP.

Diagnosis excluded; monitor off anticoagulation.

Consider alternative diagnoses.

Adapted from: The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990 May 23–30;263(20):2753–9.

PE, pulmonary embolism; LE US, lower extremity venous ultrasound for DVT; CT-PA, helical CT pulmonary angiography.

Figure 9–5.

 

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D-dimer and helical CT-PA based diagnostic algorithm for PE. CT-PA, CT pulmonary angiogram; PE, pulmonary embolism; ELISA, enzyme-linked immunosorbent assay; VTE, venous thromboembolic disease; LE US, lower extremity venous ultrasound for deep venous thrombosis; PA, pulmonary angiogram.

(Reproduced, with permission, from van Belle A et al: Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295:172.)

Prevention

Venous thromboembolism is often clinically silent until it presents with significant morbidity or mortality. It is a prevalent disease, clearly associated with identifiable risk factors. For example, the incidence of proximal DVT, PE, and fatal PE in untreated patients undergoing hip fracture surgery is reported to be 10–20%, 4–10%, and 0.2–5%, respectively. There is unambiguous evidence of the efficacy of prophylactic therapy in this and other clinical situations, yet it remains underused. Only about 50% of surgical deaths from PE had received any form of preventive therapy. A discussion of strategies for the prevention of venous thromboembolism can be found in Chapter 14: Disorders of Hemostasis & Antithrombotic Therapy.

Treatment

ANTICOAGULATION

A discussion of anticoagulation options and strategies for the treatment of venous thromboembolism can be found in Chapter 14: Disorders of Hemostasis & Antithrombotic Therapy.

THROMBOLYTIC THERAPY

Streptokinase, urokinase, and recombinant tissue plasminogen activator (rt-PA; alteplase) increase plasmin levels and thereby directly lyse intravascular thrombi. In patients with established PE, thrombolytic therapy accelerates resolution of emboli within the first 24 hours compared with standard heparin therapy. This is a consistent finding using angiography, vdot/qdot scanning, echocardiography, and direct measurement of pulmonary artery pressures. However, at 1 week and 1 month after diagnosis, these agents show no difference in outcome compared with heparin and warfarin. There is no evidence that thrombolytic therapy improves mortality. Subtle improvements in pulmonary function, including improved single-breath diffusing capacity and a lower incidence of exercise-induced pulmonary hypertension, have been observed. The reliability and clinical importance of these findings is unclear. The major disadvantages of thrombolytic therapy compared with heparin are its greater cost and a significant increase in major hemorrhagic complications. The incidence of intracranial hemorrhage in patients with PE treated with alteplase is 2.1% compared with 0.2% in patients treated with heparin.

Current evidence supports thrombolytic therapy for PE in patients at high risk for death in whom the more rapid resolution of thrombus may be lifesaving. Such patients are usually hemodynamically unstable despite heparin therapy. Absolute contraindications to thrombolytic therapy include active internal bleeding and stroke within the past 2 months. Major contraindications include uncontrolled hypertension and surgery or trauma within the past 6 weeks. The role of thrombolysis in patients who are hemodynamically stable but with echocardiographic evidence of right heart strain is unclear and is subject to considerable practice variation.

ADDITIONAL MEASURES

Interruption of the inferior vena cava may be indicated in patients with a major contraindication to anticoagulation who have or are at high risk for development of proximal DVT or PE. Placement of an inferior vena cava filter is also recommended for recurrent thromboembolism despite adequate anticoagulation, for chronic recurrent embolism with a compromised pulmonary vascular bed (eg, in pulmonary hypertension), and with the concurrent performance of surgical pulmonary embolectomy or pulmonary thromboendarterectomy. Percutaneous transjugular placement of a mechanical filter is the preferred mode of inferior vena cava interruption. These devices reduce the short-term incidence of PE in patients presenting with proximal lower extremity DVT. However, they are associated with a twofold increased risk of recurrent DVT in the first 2 years following placement.

Prognosis

PE is estimated to cause more than 50,000 deaths annually. In the majority of deaths, PE is not recognized antemortem or death occurs before specific treatment can be initiated. These statistics highlight the importance of preventive therapy in high-risk patients (Chapter 14: Disorders of Hemostasis & Antithrombotic Therapy). The outlook for patients with diagnosed and appropriately treated PE is generally good. Overall prognosis depends on the underlying disease rather than the PE itself. Death from recurrent thromboemboli is uncommon, occurring in less than 3% of cases. Perfusion defects resolve in most survivors. Chronic thromboembolic pulmonary hypertension develops in approximately 1% of patients. Selected patients may benefit from pulmonary endarterectomy.

Hull RD. Revisiting the past strengthens the present: an evidence-based medicine approach for the diagnosis of deep venous thrombosis. Ann Intern Med. 2005 Apr 5;142(7):583–5. [PMID: 15809468]

 

Perrier A et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med. 2005 Apr 28; 352(17):1760–8. [PMID: 15858185]

 

Quiroz R et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systematic review. JAMA. 2005 Apr 27;293(16):2012–7. [PMID: 15855435]

 

Roy PM et al. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ. 2005 Jul 30;331(7511):259. [PMID: 16052017]

 

Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008 Mar 6;358(10):1037–52. [PMID: 18322285]

 

van Belle A et al; Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006 Jan 11;295(2):172–9. [PMID: 16403929]

 

PULMONARY HYPERTENSION

Essentials of Diagnosis

Dyspnea, fatigue, chest pain, and syncope on exertion.
Narrow splitting of second heart sound with loud pulmonary component; findings of right ventricular hypertrophy and cardiac failure in advanced disease.
Hypoxemia and increased wasted ventilation on pulmonary function tests.
Electrocardiographic evidence of right ventricular strain or hypertrophy and right atrial enlargement.
Enlarged central pulmonary arteries on chest radiograph.

General Considerations

The pulmonary circulation is unique because of its high blood flow, low pressure (normally 25/8 mm Hg, mean 12), and low resistance (normally 200–250 dynes/sec/cm–5). It can accommodate large increases in blood flow during exercise with only modest increases in pressure because of its ability to recruit and distend lung blood vessels. Contraction of smooth muscle in the walls of pulmonary arteriolar resistance vessels becomes an important factor in numerous pathologic states. Pulmonary hypertension is present when pulmonary artery pressure rises to a level inappropriate for a given cardiac output. Once present, pulmonary hypertension is self-perpetuating. It introduces secondary structural abnormalities in pulmonary vessels, including smooth muscle hypertrophy and intimal proliferation, and these may eventually stimulate atheromatous changes and in situ thrombosis, leading to further narrowing of the arterial bed.

Selected mechanisms responsible for secondary pulmonary hypertension and examples of corresponding clinical conditions are set forth in Table 9–18. Pulmonary arteriolar vasoconstriction due to chronic hypoxemia may complicate any chronic lung disease and compound the effects of loss of pulmonary blood vessels (as seen with disorders such as emphysema and pulmonary fibrosis) and obstruction of the pulmonary vascular bed (as seen with disorders such as chronic pulmonary thromboembolic disease). Sustained increases in pulmonary venous pressure from left ventricular failure (systolic, diastolic, or both), mitral stenosis, and pulmonary veno-occlusive disease may cause "postcapillary" pulmonary hypertension. Increased pulmonary blood flow due to intracardiac shunts and increased blood viscosity due to polycythemia can also cause pulmonary hypertension. Pulmonary hypertension has also been associated with hepatic cirrhosis and portal hypertension.

 

Reduction in cross-sectional area of pulmonary arterial bed

 Vasoconstriction

   Hypoxemia from any cause (chronic lung disease, sleep-disordered breathing, etc)

   Acidosis

 Loss of vessels

 

   Emphysema

   Vasculitis

   Interstitial lung disease

   Collagen-vascular disease

 Obstruction of vessels

 

   In situ thrombosis

   Schistosomiasis

   Sickle cell disease

 Narrowing of vessels

 

Increased pulmonary venous pressure

 Constrictive pericarditis

 Left ventricular failure or reduced compliance

 Mitral stenosis

 Left atrial myxoma

 Pulmonary veno-occlusive disease

 Mediastinal diseases compressing pulmonary veins

Increased pulmonary blood flow

 Congenital left-to-right intracardiac shunts

Increased blood viscosity

 

Miscellaneous

 Pulmonary hypertension occurring in association with hepatic cirrhosis and portal hypertension

 HIV infection

 

Idiopathic (formerly primary) pulmonary hypertension (see Chapter 10: Heart Disease) is pulmonary arterial hypertension that occurs in the absence of the identified cardiopulmonary disorders above or significant connective tissue disease. It occurs with hepatic cirrhosis and portal hypertension, HIV infection, use of anorectic drugs and sporadically in young and middle-aged women, some of whom have a familial form. Untreated, it is characterized by progressive dyspnea, a rapid downhill course, and an invariably fatal outcome. This condition is also called plexogenic pulmonary arteriopathy, in reference to the characteristic histopathologic plexiform lesion found in muscular pulmonary arteries.

Pulmonary veno-occlusive disease is a rare cause of postcapillary pulmonary hypertension occurring in children and young adults. The cause is unknown, but associations with various conditions such as viral infection, bone marrow transplantation, chemotherapy, and malignancy have been described. The disease is characterized by progressive fibrotic occlusion of pulmonary veins and venules, along with secondary hypertensive changes in the pulmonary arterioles and muscular pulmonary arteries. Nodular areas of pulmonary congestion, edema, hemorrhage, and hemosiderosis are found. Chest radiography reveals prominent, symmetric interstitial markings, Kerley B lines, pulmonary artery dilation, and normally sized left atrium and left ventricle. Antemortem diagnosis is often difficult but is occasionally established by open lung biopsy. There is no effective therapy, and most patients die within 2 years as a result of progressive pulmonary hypertension.

Clinical Findings

SYMPTOMS AND SIGNS

Secondary pulmonary hypertension is difficult to recognize clinically in the early stages, when symptoms and signs are primarily those of the underlying disease. Pulmonary hypertension may cause or contribute to dyspnea, present initially on exertion and later at rest. Dull, retrosternal chest pain resembling angina pectoris may be present. Fatigue and syncope on exertion also occur, presumably a result of reduced cardiac output related to elevated pulmonary artery pressures or bradycardia.

The signs of pulmonary hypertension include narrow splitting of the second heart sound, accentuation of the pulmonary component of the second heart sound, and a systolic ejection click. In advanced cases, tricuspid and pulmonary valve insufficiency and signs of right ventricular failure and cor pulmonale are found.

LABORATORY FINDINGS

Polycythemia is found in many cases of pulmonary hypertension that are associated with chronic hypoxemia. Electrocardiographic changes are those of right axis deviation, right ventricular hypertrophy, right ventricular strain, or right atrial enlargement (see ECG).

Fig.

 

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ECG from a patient with primary pulmonary hypertension, showing severe right ventricular hypertrophy. Note the monophasic tall R preceded by a small Q in V6. The P wave in V1 is upright and directed anteriorly, indicating right atrial hypertrophy, and there is also right axis deviation with a deep S in lead I and a tall R in lead III. (Reproduced, with permission, from Cheitlin MD, Sokolow M, McIlroy MB: Clinical Cardiology, 6th ed. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)

IMAGING AND SPECIAL EXAMINATIONS

Radiographs and high-resolution CT scans of the chest can assist in the diagnosis of pulmonary hypertension and determination of the cause. In chronic disease, dilation of the right and left main and lobar pulmonary arteries and enlargement of the pulmonary outflow tract are seen; in advanced disease, right ventricular and right atrial enlargement are seen (see x-ray). Peripheral "pruning" of large pulmonary arteries is characteristic of pulmonary hypertension in severe emphysema.

Echocardiography is helpful in evaluating patients thought to have mitral stenosis, left atrial myxoma, and pulmonary valvular disease and may also reveal right ventricular enlargement and paradoxical motion of the interventricular septum (see Video). Doppler ultrasonography is a reliable noninvasive means of estimating pulmonary artery systolic pressure. However, precise hemodynamic measurements can only be obtained with right heart catheterization, which is helpful when postcapillary pulmonary hypertension, intracardiac shunting, or thromboembolic disease is considered as part of the differential diagnosis.

Video 9-1

 


Paradoxical septal motion. (Courtesy of E Foster.)

The diagnosis of pulmonary hypertension cannot be made on routine pulmonary function tests. Some results may help identify the cause; eg, diminution of the pulmonary capillary bed may cause reduction in the single breath diffusing capacity.

The following studies may be useful to exclude causes of secondary pulmonary hypertension: liver function tests, HIV test, collagen-vascular serologic studies, polysomnography, vdot/qdot lung scanning, pulmonary angiography, and surgical lung biopsy. vdot/qdot lung scanning is very helpful in identifying patients with pulmonary hypertension caused by recurrent pulmonary thromboemboli (see x-ray), a condition that is often difficult to recognize clinically.

Fig.

 

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Recurrence of pulmonary embolism over a long time. There are multiple segmental perfusion defects (A to D) that are normal on ventilation (E to F, posterior views), introducing a high probability of pulmonary embolism. Thirteen days later, the perfusion study shows virtually complete resolution (G to J). The patient returned 28 months later with bilateral perfusion defects (K to N), with normal ventilation and a normal chest radiograph (not shown), which is compatible with recurrent pulmonary embolism. Extensive defects are again seen 51/2 years later (O to R), with only minor trapping of xenon in the lung bases (S to ), indicating recurrent pulmonary embolism. Partial resolution is seen 9 days later (W to Z). (REB = rebreathe, WO = washout, SIN BRE = single breath.) (Reproduced, with permission, from Baum S et al: Atlas of Nuclear Medicine Imaging, 2nd ed. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)

Treatment

Treatment of idiopathic (primary) pulmonary hypertension is discussed in Chapter 10: Heart Disease. Treatment of secondary pulmonary hypertension consists mainly of treating the underlying disorder. Early recognition of pulmonary hypertension is crucial to interrupt the self-perpetuating cycle responsible for rapid clinical progression. By the time most patients present with symptoms and signs of pulmonary hypertension, however, the condition is far advanced. If hypoxemia or acidosis is detected, corrective measures should be started immediately. Supplemental oxygen administered for at least 15 hours per day has been demonstrated to slow the progression of pulmonary hypertension in patients with hypoxemic COPD.

Permanent anticoagulation is indicated in primary pulmonary hypertension but should be given only to those patients with secondary pulmonary hypertension at high risk for thromboembolism. Vasodilator therapy using various pharmacologic agents (eg, calcium antagonists, hydralazine, isoproterenol, diazoxide, nitroglycerin) has shown disappointing results in secondary pulmonary hypertension. Patients most likely to benefit from long-term pulmonary vasodilator therapy are those who respond favorably to a vasodilator challenge at right heart catheterization. It is clear that long-term oral vasodilator therapy should be used only if hemodynamic benefit is documented. Complications of pulmonary vasodilator therapy include systemic hypotension, hypoxemia, and even death.

Continuous long-term intravenous infusion (using a portable pump) of prostacyclin (PGI2; epoprostenol), a potent pulmonary vasodilator, has been shown to confer hemodynamic and symptomatic benefits in selected patients with idiopathic (primary) pulmonary hypertension. This is the first therapy to demonstrate improved survival of patients with idiopathic (primary) pulmonary hypertension. Limitations of continuous infusion prostacyclin are difficulties in titration, technical problems with portable delivery systems, and the high cost of the drug. Newer agents in research trials include subcutaneous (treprostinil), inhaled (iloprost), and oral (beraprost) prostacyclin analogues, endothelin receptor antagonists (bosentan), and phosphodiesterase inhibitors (sildenafil). Some of these agents have shown improvement in functional status but, so far, there is no evidence for improved outcomes. Combination therapies is an area of active research.

Patients with marked polycythemia (hematocrit > 60%) should undergo repeated phlebotomy in an attempt to reduce blood viscosity. Cor pulmonale complicating pulmonary hypertension is treated by managing the underlying pulmonary disease and by using diuretics, salt restriction, and, in appropriate patients, supplemental oxygen. The use of digitalis in cor pulmonale remains controversial. Pulmonary thromboendarterectomy may benefit selected patients with pulmonary hypertension secondary to chronic thrombotic obstructions of major pulmonary arteries.

Single or double lung transplantation may be performed on patients with end-stage idiopathic (primary) pulmonary hypertension. The 2-year survival rate is 50%.

Prognosis

The prognosis in secondary pulmonary hypertension depends on the course of the underlying disease. Patients with pulmonary hypertension due to fixed obliteration of the pulmonary vascular bed generally respond poorly to therapy; development of cor pulmonale in these cases implies a poor prognosis. The prognosis is favorable when pulmonary hypertension is detected early and the conditions leading to it are readily reversed.

Doyle RL et al. American College of Chest Physicians. Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004 Jul;126(1 Suppl):63S–71S. [PMID: 15249495]

 

Farber HW et al. Pulmonary arterial hypertension. N Engl J Med. 2004 Oct 14;351(16):1655–65. [PMID: 15483284]

 

Rubin LJ et al. Evaluation and management of the patient with pulmonary arterial hypertension. Ann Intern Med. 2005 Aug 16;143(4):282–92. [PMID: 16103472]

 

PULMONARY VASCULITIS

Wegener granulomatosis is an idiopathic disease manifested by a combination of glomerulonephritis, necrotizing granulomatous vasculitis of the upper and lower respiratory tracts, and varying degrees of small vessel vasculitis. Chronic sinusitis, arthralgias, fever, skin rash, and weight loss are frequent presenting symptoms. Specific pulmonary complaints occur less often. The most common sign of lung disease is nodular pulmonary infiltrates, often with cavitation, seen on chest radiography. Tracheal stenosis and endobronchial disease are sometimes seen. The diagnosis is most often based on serologic testing and biopsy of lung, sinus tissue, or kidney with demonstration of necrotizing granulomatous vasculitis. See Chapter 19: Musculoskeletal & Immunologic Disorders.

Allergic angiitis and granulomatosis (Churg-Strauss syndrome) is an idiopathic multisystem vasculitis of small and medium-sized arteries that occurs in patients with asthma. Histologic features include fibrinoid necrotizing epithelioid and eosinophilic granulomas. The skin and lungs are most often involved, but other organs, including the heart, gastrointestinal tract, liver, and peripheral nerves, may also be affected. Marked peripheral eosinophilia is the rule. Abnormalities on chest radiographs range from transient infiltrates to multiple nodules. This illness may be part of a spectrum that includes polyarteritis nodosa.

Treatment of pulmonary vasculitis usually requires corticosteroids and cyclophosphamide. Oral prednisone (1 mg/kg ideal body weight per day initially, tapering slowly to alternate-day therapy over 3–6 months) is the corticosteroid of choice; in Wegener granulomatosis, some clinicians may use cyclophosphamide alone. For fulminant vasculitis, therapy may be initiated with intravenous methylprednisolone (up to 1 g intravenously per day) for several days. Cyclophosphamide (1–2 mg/kg ideal body weight per day initially, with dosage adjustments to avoid neutropenia) is given daily by mouth until complete remission is obtained and then is slowly tapered, and often replaced with methotrexate or azathioprine for maintenance therapy.

Five-year survival rates in patients with these vasculitis syndromes have been improved by the combination therapy. Complete remissions can be achieved in over 90% of patients with Wegener granulomatosis. The addition of trimethoprim-sulfamethoxazole (one double-strength tablet by mouth twice daily) to standard therapy may help prevent relapses.

Brown KK. Pulmonary vasculitis. Proc Am Thorac Soc. 2006;3 (1):48–57. [PMID: 16493151]

 

Langford CA. Update on Wegener granulomatosis. Cleve Clin J Med. 2005 Aug;72(8):689–90. [PMID: 16122054]

 

Noth I et al. Churg-Strauss syndrome. Lancet. 2003 Feb 15; 361(9357):587–94. [PMID: 12598156]

 

ALVEOLAR HEMORRHAGE SYNDROMES

Diffuse alveolar hemorrhage may occur in a variety of immune and nonimmune disorders. Hemoptysis, alveolar infiltrates on chest radiograph, anemia, dyspnea, and occasionally fever are characteristic. Rapid clearing of diffuse lung infiltrates within 2 days is a clue to the diagnosis of diffuse alveolar hemorrhage. Pulmonary hemorrhage can be associated with an increased DLCO.

Causes of immune alveolar hemorrhage have been classified as anti-basement membrane antibody disease (Goodpasture syndrome), vasculitis and collagen vascular disease (systemic lupus erythematosus, Wegener granulomatosis, systemic necrotizing vasculitis, and others), and pulmonary capillaritis associated with idiopathic rapidly progressive glomerulonephritis. Nonimmune causes of diffuse hemorrhage include coagulopathy, mitral stenosis, necrotizing pulmonary infection, drugs (penicillamine), toxins (trimellitic anhydride), and idiopathic pulmonary hemosiderosis.

Goodpasture syndrome is idiopathic recurrent alveolar hemorrhage and rapidly progressive glomerulonephritis. The disease is mediated by anti-glomerular basement membrane antibodies. Goodpasture syndrome occurs mainly in men who are in their 30s and 40s. Hemoptysis is the usual presenting symptom, but pulmonary hemorrhage may be occult. Dyspnea, cough, hypoxemia, and diffuse bilateral alveolar infiltrates are typical features. Iron deficiency anemia and microscopic hematuria are usually present. The diagnosis is based on characteristic linear IgG deposits in glomeruli or alveoli by immunofluorescence and on the presence of anti-glomerular basement membrane antibody in serum. Combinations of immunosuppressive drugs (initially methylprednisolone, 30 mg/kg intravenously over 20 minutes every other day for three doses, followed by daily oral prednisone, 1 mg/kg/d; with cyclophosphamide, 2 mg/kg by mouth per day) and plasmapheresis have yielded excellent results.

is a disease of children or young adults characterized by recurrent pulmonary hemorrhage; in contrast to Goodpasture syndrome, renal involvement and anti-glomerular basement membrane antibodies are absent, but iron deficiency is typical. Treatment of acute episodes of hemorrhage with corticosteroids may be useful. Recurrent episodes of pulmonary hemorrhage may result in interstitial fibrosis and pulmonary failure.

Collard HR et al. Diffuse alveolar hemorrhage. Clin Chest Med. 2004 Sep;25(3):583–92. [PMID: 15331194]

 

SMOKE INHALATION

The inhalation of products of combustion may cause serious respiratory complications. As many as one-third of patients admitted to burn treatment units have pulmonary injury from smoke inhalation. Morbidity and mortality due to smoke inhalation exceed those attributed to the burns themselves. The death rate of patients with both severe burns and smoke inhalation exceeds 50%.

All patients suspected of having significant smoke inhalation must be assessed for three consequences of smoke inhalation: impaired tissue oxygenation, thermal injury to the upper airway, and chemical injury to the lung. Impaired tissue oxygenation results from inhalation of carbon monoxide or cyanide and is an immediate threat to life. The management of patients with carbon monoxide and cyanide poisoning is discussed in Chapter 38: Poisoning. The clinician must recognize that patients with carbon monoxide poisoning display a normal partial pressure of oxygen in arterial blood (Pa2) but have a low measured (ie, not oximetric) hemoglobin saturation (SaO2). Immediate treatment with 100% oxygen is essential and should be continued until the measured carboxyhemoglobin level falls to less than 10% and concomitant metabolic acidosis has resolved.

Thermal injury to the mucosal surfaces of the upper airway occurs from inhalation of hot gases. Complications become evident by 18–24 hours. These include edema, impaired ability to clear oral secretions, and upper airway obstruction, producing inspiratory stridor. Respiratory failure occurs in severe cases. Early management (see also Chapter 37: Environmental Disorders) includes the use of a high-humidity face mask with supplemental oxygen, gentle suctioning to evacuate oral secretions, elevation of the head 30 degrees to promote clearing of secretions, and topical epinephrine to reduce edema of the oropharyngeal mucous membrane. Helium-oxygen gas mixtures (Heliox) may reduce labored breathing due to upper airway narrowing. Close monitoring with arterial blood gases and later with oximetry is important. Examination of the upper airway with a fiberoptic laryngoscope or bronchoscope is superior to routine physical examination (see bronchoscopy). Endotracheal intubation is often necessary to establish airway patency and is likely to be necessary in patients with deep facial burns or oropharyngeal or laryngeal edema. Tracheotomy should be avoided if possible because of an increased risk of pneumonia and death from sepsis.

Fig.

 

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These are the findings–48 hours after the event–of the middle lobe bronchus of a 19-year-old male, a paint thinner addict, who attempted suicide by igniting inhaled paint thinner. At the bifurcation, blackening can be seen as well as whitish necrosis and edematous swelling. The widening of the bifurcation due to swelling is characteristic of the initial period following severe airway burns. (Reproduced, with permission, from Oho K, Amemiya R: Practical Fiberoptic Bronchoscopy. Igaku-Shoin, 1980.)

Chemical injury to the lung results from inhalation of toxic gases and products of combustion, including aldehydes and organic acids. The site of lung injury depends on the solubility of the gases inhaled, the duration of exposure, and the size of inhaled particles that transport noxious gases to distal lung units. Bronchorrhea and bronchospasm are seen early after exposure along with dyspnea, tachypnea, and tachycardia. Labored breathing and cyanosis may follow. Physical examination at this stage reveals diffuse wheezing and rhonchi. Bronchiolar and alveolar edema (eg, ARDS) may develop within 1–2 days after exposure. Sloughing of the bronchiolar mucosa may occur within 2–3 days, leading to airway obstruction, atelectasis, and worsening hypoxemia. Bacterial colonization and pneumonia are common by 5–7 days after the exposure.

Treatment of smoke inhalation consists of supplemental oxygen, bronchodilators, suctioning of mucosal debris and mucopurulent secretions via an indwelling endotracheal tube, chest physical therapy to aid clearance of secretions, and adequate humidification of inspired gases. Positive end-expiratory pressure (PEEP) has been advocated to treat bronchiolar edema. Judicious fluid management and close monitoring for secondary bacterial infection with daily sputum Gram stains round out the management protocol.

The routine use of corticosteroids for chemical lung injury from smoke inhalation has been shown to be ineffective and may even be harmful. Routine or prophylactic use of antibiotics is not recommended.

Patients who survive should be watched for the late development of bronchiolitis obliterans.

Mlcak RP et al. Respiratory management of inhalation injury. Burns. 2007 Feb;33(1):2–13. [PMID: 17223484]

 

PULMONARY ASPIRATION SYNDROMES

Aspiration of foreign material into the tracheobronchial tree results from various disorders that impair normal deglutition, especially disturbances of consciousness and esophageal dysfunction.

Aspiration of Inert Material

Aspiration of inert material may cause asphyxia if the amount aspirated is massive and if cough is impaired, in which case immediate tracheobronchial suctioning is necessary. Most patients suffer no serious sequelae from aspiration of inert material.

Aspiration of Toxic Material

Aspiration of toxic material into the lung usually results in clinically evident pneumonia. Hydrocarbon pneumonitis is caused by aspiration of ingested petroleum distillates, eg, gasoline, kerosene, furniture polish, and other household petroleum products. Lung injury results mainly from vomiting and secondary aspiration. Therapy is supportive. The lung should be protected from repeated aspiration with a cuffed endotracheal tube if necessary. Lipoid pneumonia is a chronic syndrome related to the repeated aspiration of oily materials, eg, mineral oil, cod liver oil, and oily nose drops; it often occurs in elderly patients with impaired swallowing. Patchy infiltrates in dependent lung zones and lipid-laden macrophages in expectorated sputum are characteristic findings.

"Café Coronary"

Acute obstruction of the upper airway by food is associated with difficulty swallowing, old age, dental problems that impair chewing, and use of alcohol and sedative drugs. The Heimlich procedure is lifesaving in many cases.

Retention of an aspirated foreign body in the tracheobronchial tree may produce both acute and chronic conditions, including recurrent pneumonia, bronchiectasis, lung abscess, atelectasis, and postobstructive hyperinflation. Occasionally, a misdiagnosis of asthma, COPD, or lung cancer is made in adult patients who have aspirated a foreign body. The plain chest radiograph usually suggests the site of the foreign body. In some cases, an expiratory film, demonstrating regional hyperinflation due to a check-valve effect, is helpful. Bronchoscopy is usually necessary to establish the diagnosis and attempt removal of the foreign body.

Chronic Aspiration of Gastric Contents

Chronic aspiration of gastric contents may result from primary disorders of the larynx or the esophagus, such as achalasia, esophageal stricture, systemic sclerosis (scleroderma), esophageal carcinoma, esophagitis, and gastroesophageal reflux. In the last condition, relaxation of the tone of the lower esophageal sphincter allows reflux of gastric contents into the esophagus and predisposes to chronic pulmonary aspiration, especially at night. Cigarette smoking, consumption of alcohol, and use of theophylline are known to relax the lower esophageal sphincter. Pulmonary disorders linked to gastroesophageal reflux and chronic aspiration include bronchial asthma, pulmonary fibrosis, and bronchiectasis. Even in the absence of aspiration, acid in the esophagus may trigger bronchospasm through reflex mechanisms.

The diagnosis of chronic aspiration is difficult. Ambulatory monitoring of esophageal pH for 24 hours detects esophageal reflux. Esophagogastroscopy and barium swallow are sometimes necessary to rule out esophageal disease. Management consists of elevation of the head of the bed, cessation of smoking, weight reduction, and antacids, H2-receptor antagonists (eg, cimetidine, 300–400 mg), or proton pump inhibitors (eg, omeprazole, 20 mg) at night. Metoclopramide (10–15 mg orally four times daily or 20 mg at bedtime), or bethanechol (10–25 mg at bedtime) may also be helpful in some patients with gastroesophageal reflux.

Acute Aspiration of Gastric Contents (Mendelson Syndrome)

Acute aspiration of gastric contents is often catastrophic. The pulmonary response depends on the characteristics and amount of the gastric contents aspirated. The more acidic the material, the greater the degree of chemical pneumonitis. Aspiration of pure gastric acid (pH < 2.5) causes extensive desquamation of the bronchial epithelium, bronchiolitis, hemorrhage, and pulmonary edema. Acute gastric aspiration is one of the most common causes of ARDS. The clinical picture is one of abrupt onset of respiratory distress, with cough, wheezing, fever, and tachypnea. Crackles are audible at the bases of the lungs. Hypoxemia may be noted immediately after aspiration occurs. Radiographic abnormalities, consisting of patchy alveolar infiltrates in dependent lung zones, appear within a few hours. If particulate food matter has been aspirated along with gastric acid, radiographic features of bronchial obstruction may be observed. Fever and leukocytosis are common even in the absence of superinfection.

Treatment of acute aspiration of gastric contents consists of supplemental oxygen, measures to maintain the airway, and the usual measures for treatment of acute respiratory failure. There is no evidence to support the routine use of corticosteroids or prophylactic antibiotics after gastric aspiration has occurred. Secondary pulmonary infection, which occurs in about one-fourth of patients, typically appears 2–3 days after aspiration. Management of this complication depends on the observed flora of the tracheobronchial tree. Hypotension secondary to alveolocapillary membrane injury and intravascular volume depletion is common and is managed with the judicious administration of intravenous fluids.

Paintal HS et al. Aspiration syndromes: 10 clinical pearls every physician should know. Int J Clin Pract. 2007 May;61(5):846–52. [PMID: 17493092]

 

 

Many acute and chronic pulmonary diseases are directly related to inhalation of noxious substances encountered in the workplace. Disorders that are due to chemical agents may be classified as follows: (1) pneumoconioses, (2) hypersensitivity pneumonitis, (3) obstructive airway disorders, (4) toxic lung injury, (5) lung cancer, (6) pleural diseases, and (7) miscellaneous disorders.

Pneumoconioses

Table 9–19. Selected pneumoconioses.

 

Disease

Agent

Occupations

Metal dusts

 Siderosis

Metallic iron or iron oxide

Mining, welding, foundry work

 Stannosis

Tin, tin oxide

Mining, tin-working, smelting

 Baritosis

Barium salts

Glass and insecticide manufacturing

Coal dust

 Coal worker's pneumoconiosis

Coal dust

Coal mining

Inorganic dusts

 Silicosis

Free silica (silicon dioxide)

Rock mining, quarrying, stone cutting, tunneling, sandblasting, pottery, diatomaceous earth

Silicate dusts

 Asbestosis

Asbestos

Mining, insulation, construction, shipbuilding

 Talcosis

Magnesium silicate

Mining, insulation, construction, shipbuilding

 Kaolin pneumoconiosis

Sand, mica, aluminum silicate

Mining of china clay; pottery and cement work

 Shaver disease

Aluminum powder

Manufacture of corundum

 

COAL WORKER'S PNEUMOCONIOSIS

In coal worker's pneumoconiosis, ingestion of inhaled coal dust by alveolar macrophages leads to the formation of coal macules, usually 2–5 mm in diameter, which appear on chest radiograph as diffuse small opacities that are especially prominent in the upper lung. Simple coal worker's pneumoconiosis is usually asymptomatic; pulmonary function abnormalities are unimpressive. Cigarette smoking does not increase the prevalence of coal worker's pneumoconiosis but may have an additive detrimental effect on ventilatory function. In complicated coal worker's pneumoconiosis ("progressive massive fibrosis"), conglomeration and contraction in the upper lung zones occur, with radiographic features resembling complicated silicosis. Caplan syndrome is a rare condition characterized by the presence of necrobiotic rheumatoid nodules (1–5 cm in diameter) in the periphery of the lung in coal workers with rheumatoid arthritis.

SILICOSIS

In silicosis, extensive or prolonged inhalation of free silica (silicon dioxide) particles in the respirable range (0.3–5 mcm) causes the formation of small rounded opacities (silicotic nodules) throughout the lung (see x-ray). Calcification of the periphery of hilar lymph nodes ("eggshell" calcification) is an unusual radiographic finding that strongly suggests silicosis. Simple silicosis is usually asymptomatic and has no effect on routine pulmonary function tests; in complicated silicosis, large conglomerate densities appear in the upper lung and are accompanied by dyspnea and obstructive and restrictive pulmonary dysfunction. The incidence of pulmonary tuberculosis is increased in patients with silicosis. All patients with silicosis should have a tuberculin skin test and a current chest radiograph. If old, healed pulmonary tuberculosis is suspected, multidrug treatment for tuberculosis (not single-agent preventive therapy) should be instituted.

Fig.

 

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Pulmonary silicosis. (Courtesy of H Goldberg.)

ASBESTOSIS

Asbestosis is a nodular interstitial fibrosis occurring in workers exposed to asbestos fibers (shipyard and construction workers, pipe fitters, insulators) over many years (typically 10–20 years). Patients with asbestosis usually seek medical attention at least 15 years after exposure with the following symptoms and signs: progressive dyspnea, inspiratory crackles, and in some cases, clubbing and cyanosis. The radiographic features of asbestosis include linear streaking at the lung bases, opacities of various shapes and sizes, and honeycomb changes in advanced cases (see x-ray). The presence of pleural calcifications may be a clue to diagnosis. High-resolution CT scanning is the best imaging method for asbestosis because of its ability to detect parenchymal fibrosis and define the presence of coexisting pleural plaques. Cigarette smoking in asbestos workers increases the prevalence of radiographic pleural and parenchymal changes and markedly increases the incidence of lung carcinoma. It may also interfere with the clearance of short asbestos fibers from the lung. Pulmonary function studies show restrictive dysfunction and reduced diffusing capacity. The presence of a ferruginous body in tissue suggests significant asbestos exposure; however, other histologic features must be present for diagnosis. There is no specific treatment.

Fig.

 

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Asbestosis. Calcified pleural plaques at both lung bases are typical. (Courtesy of H Goldberg.)

O'Reilly KM et al. Asbestos-related lung disease. Am Fam Physician. 2007 Mar 1;75(5):683–8. [PMID: 17375514]

 

Scarisbrick D. Silicosis and coal workers' pneumoconiosis. Practitioner. 2002 Feb;246(1631):114, 117–9. [PMID: 11852619]

 

Hypersensitivity pneumonitis (extrinsic allergic alveolitis) is a nonatopic, nonasthmatic allergic pulmonary disease. It is manifested mainly as an occupational disease (Table 9–20), in which exposure to inhaled organic agents leads to acute and eventually chronic pulmonary disease. Acute illness is characterized by sudden onset of malaise, chills, fever, cough, dyspnea, and nausea 4–8 hours after exposure to the offending agent. This may occur after the patient has left work or even at night and thus may mimic paroxysmal nocturnal dyspnea. Bibasilar crackles, tachypnea, tachycardia, and (occasionally) cyanosis are noted. Small nodular densities sparing the apices and bases of the lungs are noted on chest radiograph. Pulmonary function studies reveal restrictive dysfunction and reduced diffusing capacity. Laboratory studies reveal an increase in the white blood cell count with a shift to the left, hypoxemia, and the presence of precipitating antibodies to the offending agent in serum. Hypersensitivity pneumonitis antibody panels against common offending antigens are available; positive results, while supportive, do not establish a definitive diagnosis.

Table 9–20. Selected causes of hypersensitivity pneumonitis.

 

Disease

Antigen

Source

Farmer's lung

Micropolyspora faeni, Thermoactinomyces vulgaris

Moldy hay

"Humidifier" lung

Thermophilic actinomycetes

Contaminated humidifiers, heating systems, or air conditioners

Bird fancier's lung ("pigeon- breeder's disease")

Avian proteins

Bird serum and excreta

Bagassosis

Thermoactinomyces sacchari and

Moldy sugar cane fiber (bagasse)

Sequoiosis

Graphium, Aureo basidium, and other fungi

Moldy redwood sawdust

Maple bark stripper's disease

Cryptostroma (Coniosporium) corticale

Rotting maple tree logs or bark

Mushroom picker's disease

Same as farmer's lung

 

Suberosis

Penicillium frequentans

 

Detergent worker's lung

Bacillus subtilis enzyme

Enzyme additives

 

Acute hypersensitivity pneumonitis is characterized by interstitial infiltrates of lymphocytes and plasma cells, with noncaseating granulomas in the interstitium and air spaces. A subacute hypersensitivity pneumonitis syndrome (15% of cases) has been described that is characterized by the insidious onset of chronic cough and slowly progressive dyspnea, anorexia, and weight loss. Chronic respiratory insufficiency and the appearance of pulmonary fibrosis on radiographs may occur after repeated exposure to the offending agent. Surgical lung biopsy is occasionally necessary for diagnosis. Diffuse fibrosis is the hallmark of the subacute and chronic phases.

Treatment of hypersensitivity pneumonitis consists of identification of the offending agent, avoidance of further exposure, and, in severe acute or protracted cases, oral corticosteroids (prednisone, 0.5 mg/kg daily as a single morning dose, tapered to nil over 4–6 weeks). Change in occupation is often unavoidable.

Ismail T et al. Extrinsic allergic alveolitis. Respirology. 2006 May;11(3):262–8. [PMID: 16635083]

 

Obstructive Airway Disorders

Occupational pulmonary diseases manifested as obstructive airway disorders include occupational asthma, industrial bronchitis, and byssinosis.

It has been estimated that from 2% to 5% of all cases of asthma are related to occupation. Offending agents in the workplace are numerous; they include grain dust, wood dust, tobacco, pollens, enzymes, gum arabic, synthetic dyes, isocyanates (particularly toluene diisocyanate), rosin (soldering flux), inorganic chemicals (salts of nickel, platinum, and chromium), trimellitic anhydride, phthalic anhydride, formaldehyde, and various pharmaceutical agents. Diagnosis of occupational asthma depends on a high index of suspicion, an appropriate history, spirometric studies before and after exposure to the offending substance, and peak flow rate measurements in the workplace. Bronchial provocation testing may be helpful in some cases. Treatment consists of avoidance of further exposure to the offending agent and bronchodilators, but symptoms may persist for years after workplace exposure has been terminated.

INDUSTRIAL BRONCHITIS

Industrial bronchitis is chronic bronchitis found in coal miners and others exposed to cotton, flax, or hemp dust. Chronic disability from industrial bronchitis is infrequent.

BYSSINOSIS

Byssinosis is an asthma-like disorder in textile workers caused by inhalation of cotton dust. The pathogenesis is obscure. Chest tightness, cough, and dyspnea are characteristically worse on Mondays or the first day back at work, with symptoms subsiding later in the week. Repeated exposure leads to chronic bronchitis.

Toxic Lung Injury

Silo-filler's disease is acute toxic high-permeability pulmonary edema caused by inhalation of nitrogen dioxide encountered in recently filled silos. Bronchiolitis obliterans is a common late complication, which may be prevented by early treatment of the acute reaction with corticosteroids. Extensive exposure to silage gas may be fatal.

Lung Cancer

Many industrial pulmonary carcinogens have been identified, including asbestos, radon gas, arsenic, iron, chromium, nickel, coal tar fumes, petroleum oil mists, isopropyl oil, mustard gas, and printing ink. Cigarette smoking acts as a cocarcinogen with asbestos and radon gas to cause bronchogenic carcinoma. Asbestos alone causes malignant mesothelioma. Almost all histologic types of lung cancer have been associated with these carcinogens. Chloromethyl methyl ether specifically causes small cell carcinoma of the lung.

Pleural Diseases

Occupational diseases of the pleura may result from exposure to asbestos (see above) or talc. Inhalation of talc causes pleural plaques that are similar to those caused by asbestos. Benign asbestos pleural effusion occurs in some asbestos workers and may cause chronic blunting of the costophrenic angle on chest radiograph.

Other Occupational Pulmonary Diseases

Occupational agents are also responsible for other pulmonary disorders. These include berylliosis, an acute or chronic pulmonary disorder related to exposure to beryllium, which is absorbed through the lungs or skin and widely disseminated throughout the body. Acute berylliosis is a toxic, ulcerative tracheobronchitis and chemical pneumonitis following intense and severe exposure to beryllium. Chronic berylliosis, a systemic disease closely resembling sarcoidosis, is more common. Chronic pulmonary beryllium disease is thought to be an alveolitis mediated by the proliferation of beryllium-specific helper-inducer T cells in the lung. Exposure to beryllium now occurs in machining and handling of beryllium products and alloys. Beryllium miners are not at risk for berylliosis. Beryllium is no longer used in fluorescent lamp production, which was a source of exposure before 1950.

Beach J et al. A systematic review of the diagnosis of occupational asthma. Chest. 2007 Feb;131(2):569–78. [PMID: 17296663]

 

Mapp CE et al. Occupational asthma. Am J Respir Crit Care Med. 2005 Aug 1;172(3):280–305. [PMID: 15860754]

 

DRUG-INDUCED LUNG DISEASE

Typical patterns of pulmonary response to drugs implicated in drug-induced respiratory disease are summarized in Table 9–21. Pulmonary injury due to drugs occurs as a result of allergic reactions, idiosyncratic reactions, overdose, or undesirable side effects. In most patients, the mechanism of pulmonary injury is unknown.

Table 9–21. Pulmonary manifestations of selected drug toxicities.

 

Asthma

Pulmonary edema

betalower-Blockers

 Noncardiogenic

 Aspirin

   Aspirin

 Nonsteroidal anti-inflammatory drugs

   Chlordiazepoxide

   Cocaine

 Histamine

    Ethchlorvynol

 Methacholine

   Heroin

 Acetylcysteine

 Cardiogenic

 Aerosolized pentamidine

  betalower-Blockers

 Any nebulized medication

Pleural effusion

Chronic cough

 Bromocriptine

 Angiotensin-converting enzyme inhibitors

 Nitrofurantoin

 

Pulmonary infiltration

 Without eosinophilia

  Methysergide

   Amitriptyline

 Chemotherapeutic agents

   Azathioprine

Mediastinal widening

   Amiodarone

 Phenytoin

 With eosinophilia

  Corticosteroids

    Sulfonamides

 Methotrexate

  L-Tryptophan

Respiratory failure

   Nitrofurantoin

 Neuromuscular blockade

   Penicillin

    Aminoglycosides

   Methotrexate

   Succinylcholine

   Crack cocaine

   Gallamine

Drug-induced systemic lupus erythematosus

 

 Hydralazine

 Central nervous system depression

 Procainamide

    Sedatives

 Isoniazid

   Hypnotics

 Chlorpromazine

   Opioids

 Phenytoin