Mark S. Chesnutt, MD
Thomas J. Prendergast, MD
DISORDERS OF THE AIRWAYS
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
Acute upper airway obstruction can be immediately life-threatening and must be relieved promptly to avoid asphyxia. Causes of acute upper airway obstruction include trauma to the larynx or pharynx, foreign body aspiration, laryngospasm, laryngeal edema from thermal injury or angioedema, infections (acute epiglottitis, Ludwig angina, pharyngeal or retropharyngeal abscess), 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 after 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 characterized by paradoxical vocal fold adduction, resulting in both acute and chronic upper airway obstruction. It can cause dyspnea and wheezing that may be distinguished from asthma or exercise-induced 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.
Gimenez LM et al. Vocal cord dysfunction: an update. Ann Allergy Asthma Immunol. 2011 Apr;106(4):267–75. [PMID: 21457874]
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. Tracheomalacia, foreign body aspiration, and retained secretions may cause variable tracheal obstruction.
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.
Bronchial obstruction may be caused by retained pulmonary secretions, aspiration, foreign bodies, bronchomalacia, 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 exact location of obstruction of the central bronchi. MRI may be superior to CT for delineating the extent of 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.
Brigger MT et al. Management of tracheal stenosis. Curr Opin Otolaryngol Head Neck Surg. 2012 Dec;20(6):491–6. [PMID: 22929114]
ESSENTIALS OF DIAGNOSIS
Episodic or chronic symptoms of airflow obstruction.
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.
Asthma is a common disease, affecting approximately 7–10% of the population. It is slightly more common in male children (< 14 years old) and in female adults. There is a genetic predisposition to asthma. Prevalence, hospitalizations, and fatal asthma have all increased in the United States over the past 20 years. Each year, approximately 500,000 hospital admissions and 4500 deaths in the United States are attributed to asthma. Hospitalization rates have been highest among blacks and children, and death rates 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 and airflow limitation.
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, rhinosinusitis, postnasal drip, aspiration, gastroesophageal reflux, changes in the weather, and stress. Exposure toproducts of combustion (eg, tobacco smoke, crack cocaine, methamphetamines, and other agents) increases asthma symptoms and the need for medications and reduces lung function. Air pollution(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. Other medications may precipitate asthma symptoms (see Table 9–23). 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 decompensated heart failure.
Symptoms and signs vary widely between patients as well as individually over time. General clinical findings in stable asthma patients are listed in Figure 9–1 and Table 9–1; Table 9–2 lists findings seen during asthma exacerbations.
Figure 9–1. 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. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.)
Table 9–1. Assessing asthma control.
Table 9–2. Evaluation and classification of severity of asthma exacerbations.
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 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, secretion increases, and polyps are often seen in patients with allergic asthma. Eczema, atopic dermatitis, or other allergic skin disorders may also be present. Wheezing or a prolonged expiratory phase during normal breathing 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.
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.
Clinicians are able to identify airflow obstruction on examination, but they have limited ability to assess its severity or to predict whether it is reversible. The evaluation for asthma should therefore includespirometry (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], FEV1/FVC) before and after the administration of a short-acting bronchodilator. 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 ≥ 12% and 200 mL in FEV1 or ≥ 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 may mimic a restrictive ventilatory defect.
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 FEV1is less than 65% of predicted. A positive methacholine test is defined as a ≥ 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.
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 patient and 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.
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, severe or refractory asthma symptoms.
Complications of asthma include exhaustion, dehydration, airway infection, and tussive syncope. Pneumothorax occurs but is rare. Acute hypercapnic and hypoxemic respiratory failure occurs in severe disease.
Patients who have atypical symptoms or poor response to therapy may have a condition that mimics asthma. 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 (eg, angioedema or inhalation injury). Lower airway disorders include nonasthmatic chronic obstructive pulmonary disease (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 (“functional” asthma), emotional laryngeal wheezing, vocal fold dysfunction, or episodic laryngeal dyskinesis. Rarely, Münchausen syndrome or malingering may explain a patient’s complaints.
NAEPP 3 Diagnosis & Management Guidelines
The third Expert Panel Report of 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), provides guidelines for diagnosis and management of asthma (NAEPP 3) (Figure 9–2). 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.
Figure 9–2. 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.)
All patients, but particularly those with poorly controlled symptoms or 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.
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. Proper inhaler technique and the use of an inhalation chamber with metered-dose inhalers (MDIs) decrease oropharyngeal deposition and improve drug delivery to the lung. Nebulizer therapy is reserved for acutely ill patients and those who cannot use inhalers because of difficulties with coordination, understanding, or cooperation.
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 satisfying patients’ and families’ expectations of asthma care. NAEPP 3 recommendations emphasize daily anti-inflammatory therapy with inhaled corticosteroids as the cornerstone of treatment of persistent asthma.
Anti-inflammatory agents, long-acting bronchodilators, and leukotriene modifiers comprise the important long-term control medications (Tables 9–3 and 3–4). Other classes of agents are mentioned briefly below as well.
Table 9–3. Long-term control medications for asthma.
Table 9–4. Estimated comparative daily dosages for inhaled corticosteroids for asthma.
Inhaled corticosteroids are preferred, first-line agents for all patients with persistent asthma. Patients with persistent symptoms or asthma exacerbations who are not taking an inhaled corticosteroid should be started on one. 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 (“spacer”) coupled with mouth washing after inhaled corticosteroid use decreases local side effects (cough, dysphonia, oropharyngeal candidiasis) and systemic absorption. Dry powder inhalers (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. Concurrent treatment with calcium supplements and vitamin D should be initiated to prevent corticosteroid-induced bone mineral loss in long-term administration. Bone mineral density testing after 3 or more months of systemic corticosteroid lifetime use can guide the use of bisphosphonates for treatment of steroid-induced osteoporosis. Rapid discontinuation of systemic corticosteroids after long-term use may precipitate adrenal insufficiency.
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. At therapeutic doses, potential adverse effects include insomnia, aggravation of dyspepsia and gastroesophageal reflux, and urination difficulties in men with prostatic hyperplasia. Dose-related toxicities include nausea, vomiting, tachyarrhythmias, headache, seizures, hyperglycemia, and hypokalemia.
Short-acting bronchodilators and systemic corticosteroids are the important quick-relief medications (Table 9–5).
Table 9–5. Quick-relief medications for asthma.
Inhaled beta-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. One or two inhalations of a short-acting inhaled beta-2-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 nebulization does not offer more effective delivery than MDIs used correctly but does provide higher doses. With most beta-2-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 beta-2-agonists is not recommended. Increased use (more than one canister a month) or lack of expected effect indicates diminished asthma control and indicates the need for additional long-term control 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). More severe exacerbations require evaluation and management in an urgent care or emergency department setting (Figure 9–4).
Figure 9–3. 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.)
Figure 9–4. 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 asthma exacerbations are characterized by only minor changes in airway function (PEF > 80%) and minimal symptoms and signs of airway dysfunction (see Table 9–2). Many such patients respond quickly and fully to an inhaled short-acting beta-2-agonist alone. However, an inhaled short-acting beta-2-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, initiating one should be considered during the mild exacerbation. 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.
The principal goals of treatment of moderate asthma exacerbations are correction of hypoxemia, reversal of airflow obstruction, and reduction of the likelihood of recurrence of obstruction. Early intervention may lessen the severity and shorten the duration of an exacerbation. Of paramount importance is correction of hypoxemia through the use of supplemental oxygen. Airflow obstruction is treated with continuous administration of an inhaled short-acting beta-2-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 the severity of the asthma exacerbation. Serial measurement of airflow in the emergency department may reduce the rate of hospital admissions for asthma exacerbations. The post-exacerbation care plan is important. 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 an action plan for managing recurrence.
Severe exacerbations of asthma can be life-threatening, so treatment should be started immediately. All patients with a severe exacerbation should immediately receive oxygen, high doses of an inhaled short-acting beta-2-agonist, and systemic corticosteroids. A brief history pertinent to the exacerbation can be completed while such treatment is being initiated. More detailed assessments, including laboratory studies, usually add little early on and so should be postponed until after therapy is instituted.
Oxygen therapy is very important because asphyxia is a common cause of asthma deaths. Supplemental oxygen should be given to maintain an Sao2 > 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 beta-2-agonist is indicated and usually well tolerated in severe airway obstruction. Some studies suggest that continuous therapy is more effective 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 symptoms and the occurrence of side effects. Ipratropium bromide reduces the rate of hospital admissions when added to inhaled short-acting beta-2-agonists in patients with moderate to severe asthma exacerbations.
Systemic corticosteroids are administered as detailed above. Intravenous magnesium sulfate (2 g intravenously over 20 minutes) produces a detectable improvement in airflow and may reduce hospitalization rates in acute severe asthma (FEV1 < 25% of predicted on presentation, or failure to respond to initial treatment).
Mucolytic agents (eg, acetylcysteine, potassium iodide) may worsen cough or airflow obstruction. Anxiolytic and hypnotic drugs are generally contraindicated in severe asthma exacerbations because of their respiratory depressant effects.
In the emergency department setting, repeat assessment of patients with severe exacerbations should be done after the initial dose of inhaled bronchodilator and again 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, arterial blood gas results (if available), 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 ≥ 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.
In the intensive care setting, a small subset of patients will not respond to treatment and will progress to impending respiratory failure due to a combination of worsening airflow obstruction and respiratory muscle fatigue (see Table 9–2). Since such patients can deteriorate rapidly, they must 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, the patient’s intravascular volume should be closely monitored because hypotension commonly follows the administration of sedative medications and the initiation of positive-pressure ventilation; these patients are often dehydrated due to poor recent oral intake and high insensible losses.
The main goals of mechanical ventilation are to ensure adequate oxygenation and to avoid barotrauma. Controlled hypoventilation with permissive hypercapnia is often required to limit airway pressures. Frequent high-dose delivery of inhaled short-acting beta-2-agonists should be continued along with anti-inflammatory agents as discussed above. Many questions remain regarding the optimal delivery of inhaled beta-2-agonists to intubated, mechanically ventilated patients.
When to Refer
Barnes PJ. Severe asthma: advances in current management and future therapy. J Allergy Clin Immunol. 2012 Jan;129(1): 48–59. [PMID: 22196524]
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National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and B lood Institute, 2007. (NIH publication No. 08-4051). http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
ESSENTIALS OF DIAGNOSIS
History of cigarette smoking
Chronic cough, dyspnea, and sputum production.
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.
The American Thoracic Society defines COPD as a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible. The NHLBI estimates that 14 million Americans have been diagnosed with COPD; an equal number are thought to be afflicted but remain undiagnosed. Grouped together, COPD and asthma now represent the fourth leading cause of death in the United States, with over 130,000 deaths reported annually. The death rate from COPD is increasing rapidly, especially among elderly men.
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.
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. Approximately 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 alpha-1-antiprotease[alpha-1-antitrypsin]) have been implicated. Atopy and the tendency for bronchoconstriction to develop in response to nonspecific airway stimuli may be important risks.
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. As the disease progresses, two symptom patterns tend to emerge, historically referred to as “pink puffers” and “blue bloaters” (Table 9–6). Most COPD patients have pathologic evidence of both disorders, and their clinical course may involve other factors such as central control of ventilation and concomitant sleep-disordered breathing.
Table 9–6. Patterns of disease in advanced COPD.
Pneumonia, pulmonary hypertension, cor pulmonale, and chronic respiratory failure characterize the late stage of COPD. A hallmark of COPD is the periodic exacerbation of symptoms beyond normal day-to-day variation, often including increased dyspnea, an increased frequency or severity of cough, increased sputum volume or change in sputum character. These exacerbations are commonly precipitated by infection (more often viral than bacterial) or environmental factors. Exacerbations of COPD vary widely in severity but typically require a change in regular therapy.
Spirometry provides objective information about pulmonary function and assesses the response to 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) (Table 9–6) 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.
Arterial blood gas measurements characteristically show no abnormalities early in COPD other than an increased a–a–Do2. Indeed, measurement is 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. Supraventricular arrhythmias (multifocal atrial tachycardia, atrial flutter, and atrial fibrillation) and ventricular irritability also occur.
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. CT of the chest, particularly using high-resolution CT, is more sensitive and specific than plain radiographs for its diagnosis. In advanced disease, pulmonary hypertension may be suggested by enlargement of central pulmonary arteries on radiographs and Doppler echocardiography provides an estimate of pulmonary artery pressure.
Clinical, imaging, and laboratory findings should enable the clinician to distinguish COPD from other obstructive pulmonary disorders such as asthma, bronchiectasis, cystic fibrosis, bronchopulmonary mycosis, and central airflow obstruction. Asthma is characterized by complete or near-complete reversibility of airflow obstruction. Bronchiectasis is distinguished from COPD by recurrent pneumonia and hemoptysis, digital clubbing, and characteristic imaging abnormalities. Patients with severe alpha-1-antitrypsin deficiency have a family history of the disorder and the finding of panacinar bibasilar emphysema early in life, usually in the third or fourth decade; hepatic cirrhosis and hepatocellular carcinoma may develop. Cystic fibrosis occurs in children, adolescents and young adults. Mechanical obstruction of the central airways can be distinguished from COPD by flow-volume loops.
Acute bronchitis, pneumonia, pulmonary thromboembolism, atrial dysrhythmias (such as atrial fibrillation, atrial flutter, and multifocal atrial tachycardia), 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.
COPD is largely preventable through elimination of long-term exposure to tobacco smoke or other inhaled toxins. Smokers with early evidence of airflow limitation can significantly alter their disease by smoking cessation. Smoking cessation slows the decline in FEV1 in middle-aged smokers with mild airways obstruction. Vaccination against seasonal and epidemic influenza A (H1N1) and pneumococcal infection may also be of benefit.
The treatment of COPD is guided by the severity of symptoms or the presence of an exacerbation of stable symptoms. Standards for the management of patients with stable COPD and COPD exacerbations from the American Thoracic Society and the Global Initiative for Obstructive Lung Disease (GOLD), a joint expert committee of the NHLBI and the WHO, are incorporated in the recommendations below. See Chapter 37 for a discussion of air travel in patients with lung disease.
Table 9–7. Home oxygen therapy: Requirements for Medicare coverage.1
Home oxygen may be supplied by liquid oxygen systems, 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 to $500 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.
The most commonly prescribed short-acting bronchodilators are the anticholinergic ipratropium bromide and beta-2-agonists (eg, albuterol, metaproterenol), delivered by MDI or as an inhalation solution by nebulizer. Ipratropium bromide is generally preferred to the short-acting beta-2-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. Short-acting beta-2-agonists are less expensive and have a more rapid onset of action, commonly leading to greater patient satisfaction. At maximal doses, beta-2-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 beta-2-agonists compared with as-needed administration. Use of both short-acting beta-2-agonists and anticholinergics at submaximal doses leads to improved bronchodilation compared with either agent alone but does not improve dyspnea.
Long-acting beta-2-agonists (eg, formoterol, salmeterol, indacaterol, arformoterol) and anticholinergics (tiotropium) appear to achieve bronchodilation that is equivalent or superior to what is experienced with ipratropium, in addition to similar improvements in health status. Although more expensive than short-acting agents, long-acting bronchodilators may have superior clinical efficacy in persons with advanced disease. One RCT of long-term administration of tiotropium added to standard therapy reported fewer exacerbations or hospitalizations, and improved dyspnea scores, in the tiotropium group. Tiotropium had no effect on long-term decline in lung function, however. Another RCT comparing the effects of tiotropium with those of salmeterol-fluticasone over 2 years reported no difference in the risk of COPD exacerbation. The incidence of pneumonia was higher in the salmeterol-fluticasone group, yet dyspnea scores were lower and there was a mortality benefit compared with tiotropium. This last finding awaits confirmation in further studies.
The symptomatic benefits of long-acting bronchodilators are firmly established. Increased exacerbations and mortality in patients treated with salmeterol have not been observed in COPD patients, and several studies report a trend toward lower mortality in patients treated with salmeterol alone, compared with placebo. In addition, a 4-year tiotropium trial reported fewer cardiovascular events in the intervention group. Subsequent meta-analyses that include the 4-year tiotropium trial did not find an increase in cardiovascular events in treated patients and most practitioners believe that the documented benefits of anticholinergic therapy outweigh any potential risks.
However, combination therapy with an inhaled corticosteroid and a long-acting beta-2-agonist reduces the frequency of exacerbations and improves self-reported functional status in COPD patients, compared with placebo or with sole use of inhaled corticosteroids, long-acting beta-2-agonists, or anticholinergics. In one RCT, addition of an inhaled corticosteroid/long-acting beta-2-agonist to tiotropium therapy in COPD patients did not reduce the frequency of exacerbations but did improve hospitalization rates and functional status.
Apart from acute exacerbations, COPD is not generally responsive to oral corticosteroid therapy. Compared with patients receiving placebo, only 10–20% of stable outpatients with COPD given oral corticosteroids will have a > 20% increase in FEV1. 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. If an empiric trial of oral corticosteroid is conducted, a baseline FEV1 should be documented when the patient is stable (ie, not measured during an exacerbation), on maximal long-term bronchodilator therapy, and obtained immediately after a bronchodilator administration. After a 3- to 4-week trial of 0.25–0.5 mg/kg oral prednisone, the corticosteroid should only be continued if there is a 20% or greater increase in FEV1 over this baseline value. Responders to oral corticosteroids are usually switched to inhaled agents, but there are few data to guide this practice. Oral corticosteroids have well-recognized adverse effects, so it is prudent to minimize cumulative exposure. It is rare for a patient to be truly “corticosteroid-dependent” when all other available therapies are optimized.
Human alpha-1-antitrypsin is available for replacement therapy in emphysema due to congenital deficiency (PiZZ or null genotype) of alpha-1-antiprotease (alpha-1-antitrypsin). Patients over 18 years of age with airflow obstruction by spirometry and serum levels less than 11 mcmol/L (˜50 mg/dL) are potential candidates for replacement therapy. Alpha-1-antitrypsin is administered intravenously in a dose of 60 mg/kg body weight once weekly. There is no evidence that replacement therapy is beneficial to heterozygotes (eg, PiMZ) with low-normal serum levels, although such patients may be at slightly increased risk for emphysema, especially in the setting of tobacco smoke exposure. Severe dyspnea in spite of optimal medical management may warrant a clinical trial of an opioid (eg, morphine 5–10 mg orally every 3–4 hours, oxycodone 5–10 mg orally every 4–6 hours, sustained-release morphine 10 mg orally once daily). Sedative-hypnotic drugs (eg, diazepam, 5 mg three times daily) marginally improve intractable dyspnea but cause significant drowsiness; they may benefit very anxious patients. Transnasal positive-pressure ventilation at home to rest the respiratory muscles is an approach 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.
Management of the hospitalized patient with an acute exacerbation of COPD includes (1) supplemental oxygen (titrated to maintain Sao2 between 90% and 94% or Pao2 between 60 mm Hg and 70 mm Hg), (2) inhaled ipratropium bromide (500 mcg by nebulizer, or 36 mcg by MDI with spacer, every 4 hours as needed) plus beta-2-agonists (eg, albuterol 2.5 mg diluted with saline to a total of 3 mL by nebulizer, or MDI, 90 mcg per puff, four to eight puffs via spacer, every 1–4 hours as needed), (3) corticosteroids (prednisone 30–40 mg orally per day for 7–10 days is usually sufficient, even 5 days may be adequate), (4) broad-spectrum antibiotics and, (5) in selected cases, chest physiotherapy.
For patients without risk factors for Pseudomonas, management options include a fluoroquinolone (eg, levofloxacin 750 mg orally or intravenously per day, or moxifloxacin 400 mg orally or intravenously every 24 hours) or a third-generation cephalosporin (eg, ceftriaxone 1 g intravenously per day, or cefotaxime 1 g intravenously every 8 hours).
For patients with risk factors for Pseudomonas, therapeutic options include piperacillin-tazobactam (4.5 g intravenously every 6 hours), ceftazidime (1 g intravenously every 8 hours), cefepime (1 g intravenously every 12 hours), or levofloxacin (750 mg orally or intravenously per day for 3–7 days).
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 dysrhythmias, 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 nosocomial 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 acute respiratory distress syndrome (ARDS).
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.
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 FEV1 ≤ 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. As patients near the end of life, meticulous attention to palliative care is essential to effectively manage dyspnea (see Chapter 5).
When to Refer
When to Admit
Leuppi JD et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013 Jun 5;309(21):2223–31. [PMID: 23695200]
Littner MR. In the clinic. Chronic obstructive pulmonary disease. Ann Intern Med. 2011 Apr 5;154(7):ITC4–15. [PMID: 21464346]
Miles MC et al. Optimum bronchodilator combinations in chronic obstructive pulmonary disease: what is the current evidence? Drugs. 2012 Feb 12;72(3):301–8. [PMID: 22316346]
Qaseem A et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011 Aug 2;155(3):179–91. [PMID: 21810710]
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]
Torpy JM et al. JAMA patient page. Chronic obstructive pulmonary disease. JAMA. 2012 Sep 26;308 (12):1281. [PMID: 23011720]
ESSENTIALS OF DIAGNOSIS
Chronic productive cough with dyspnea and wheezing.
Radiographic findings of dilated, thickened airways and scattered, irregular opacities.
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, alpha-1-antiprotease [alpha-1-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 kidney and liver diseases. Most patients with bronchiectasis have panhypergammaglobulinemia, however, 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.
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 (see Figure 6–41). Copious, foul-smelling, purulent sputum is characteristic. Obstructive pulmonary dysfunction with hypoxemia is seen in moderate or severe disease.
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.
Haemophilus influenzae is the most common organism recovered from non–cystic fibrosis patients with bronchiectasis. P aeruginosa, S pneumoniae, and Staphylococcus aureus are commonly identified. Nontuberculous mycobacteria are seen less commonly. Patients with Pseudomonas infection experience an accelerated course, with more frequent exacerbations and more rapid decline in lung function.
Treatment of acute exacerbations consists of antibiotics, 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. Antibiotic therapy should be guided by sputum smears and cultures. If a specific bacterial pathogen cannot be isolated, then empiric oral antibiotic therapy for 10–14 days is appropriate. Common regimens include amoxicillin or amoxicillin-clavulanate (500 mg every 8 hours), ampicillin or tetracycline (250–500 mg four times daily), trimethoprim-sulfamethoxazole (160/800 mg every 12 hours), or ciprofloxacin (500–750 mg twice daily). It is important to screen patients for infection with nontuberculous mycobacteria because these organisms may underlie a lack of treatment response. Preventive or suppressive treatment is sometimes given to stable outpatients with bronchiectasis who have copious purulent sputum. Prolonged macrolide therapy (azithromycin 500 mg three times a week for 6 months or 250 mg daily for 12 months) has been found to decrease the frequency of exacerbations compared to placebo. High-dose amoxicillin (3 g/d) or alternating cycles of the antibiotics listed above given orally for 2–4 weeks are also used, although this practice is not supported by clinical trial data. In patients with underlying cystic fibrosis, inhaled aerosolized aminoglycosides reduce colonization by Pseudomonas species, improve FEV1 and reduce hospitalizations; in non–cystic fibrosis bronchiectasis, adding inhaled tobramycin to oral ciprofloxacin for acute exacerbations due to Pseudomonas decreases microbial sputum burden but without apparent clinical benefit. 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.
Altenburg J et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non–cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013 Mar27;309(12):1251–9. [PMID: 23532241]
Feldman C. Bronchiectasis: new approaches to diagnosis and management. Clin Chest Med. 2011 Sep;32(3):535–46. [PMID: 21867821]
Wong C et al. Azithromycin for prevention of exacerbations in non–cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Aug18;380(9842):660–7. [PMID: 22901887]
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 three times a day with food for 3 days followed by twice daily for at least 16 weeks) without added toxicity. Bronchodilators (Table 9–5) are also helpful. Complications include hemoptysis, severe bronchiectasis, and pulmonary fibrosis.
Bains SN et al. Allergic bronchopulmonary aspergillosis. Clin Chest Med. 2012 Jun;33(2):265–81. [PMID: 22640845]
Mahdavinia M et al. Management of allergic bronchopulmonary aspergillosis: a review and update. Ther Adv Respir Dis. 2012 Jun;6(3):173–87. [PMID: 22547692]
ESSENTIALS OF DIAGNOSIS
Chronic or recurrent productive cough, dyspnea, and wheezing.
Recurrent airway infections or chronic colonization of the airways with H influenzae, P aeruginosa, S aureus, or Burkholderia cepacia. Bronchiectasis and scarring on chest radiographs.
Airflow obstruction on spirometry.
Pancreatic insufficiency, recurrent pancreatitis, distal intestinal obstruction syndrome, chronic hepatic disease, nutritional deficiencies, or male urogenital abnormalities.
Sweat chloride concentration > 60 mEq/L on two occasions or gene mutation known to cause cystic fibrosis.
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 1 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 and leads to tissue damage. In the respiratory tract, inadequate hydration of the tracheobronchial epithelium impairs mucociliary function. High concentration of extracellular DNA in airway secretions (due to chronic airway inflammation and autolysis of neutrophils) increases sputum viscosity.
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. Patients with cystic fibrosis have an increased risk of malignancies of the gastrointestinal tract, osteopenia, and arthropathies.
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 chronic rhinosinusitis symptoms, steatorrhea, diarrhea, and abdominal pain. Patients with cystic fibrosis are often malnourished with low body mass index. Digital clubbing, 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. Nearly all men with cystic fibrosis have congenital bilateral absence of the vas deferens with azoospermia. Biliary cirrhosis and gallstones may occur.
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.
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 are common findings. Pneumothorax can also be seen. Thin-section CT scanning often confirms the presence of bronchiectasis.
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 performed in experienced laboratories are required for accurate diagnosis. A normal sweat chloride test does not exclude the diagnosis in which case genotyping or other alternative diagnostic studies (such as measurement of nasal membrane potential difference, semen analysis, or assessment of pancreatic function) should be pursued, especially if 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.
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. Inhaled recombinant human deoxyribonuclease (rhDNase, dornase alpha) cleaves extracellular DNA in sputum, decreasing sputum viscosity; 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. Inhalation of hypertonic saline twice daily has been associated with small improvements in pulmonary function and fewer pulmonary exacerbations. The beneficial effects of hypertonic saline 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 ofP aeruginosa are commonly present. H influenzae, Stenotrophomonas maltophilia, and B cepacia (a highly drug-resistant organism) are occasionally isolated. Long-term antibiotic therapy is helpful in slowing disease progression and reducing exacerbations in patients with sputum cultures positive for P aeruginosa. These antibiotics include azithromycin 500 mg orally three times a week, which has immunomodulatory properties, and various inhaled antibiotics (eg, tobramycin, aztreonam, colistin, and levofloxacin) taken two to three times a day. The length of therapy depends on the persistent presence of P aeruginosa in the sputum. The incidence of atypical mycobacterial colonization is higher in cystic fibrosis patients and directed antibiotic treatment is recommended for frequent exacerbations, progressive decline in lung function, or failure to thrive. Yearly screening with sputum acid-fast bacilli cultures is advised.
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. An inhaled corticosteroid should be added to the treatment regimen for patients who have cystic fibrosis with persistent asthma or allergic bronchopulmonary mycosis.
Ivacaftor is an oral drug, available for the 5% of cystic fibrosis patients with a G551D mutation. Ivacaftor is a potentiator of the CFTR channel that works by increasing the time the channel remains open after being activated; it has been found to improve lung function by 10% within 2 weeks of treatment, decrease pulmonary exacerbations by 55%, and decrease sweat chloride into the indeterminate range. CFTR corrector therapy for the most common mutation (DeltaF508) is currently under trial.
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%.
Vaccination against pneumococcal infection and annual influenza vaccination are advised. Screening of family members and genetic counseling are suggested.
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.
Braun AT et al. Cystic fibrosis lung transplantation. Curr Opin Pulm Med. 2011 Nov;17(6):467–72. [PMID: 21897255]
Cohen-Cymberknoh M et al. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med. 2011 Jun1;183(11):1463–71. [PMID: 21330455]
Flume PA et al; Cystic Fibrosis Foundation Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009 Nov1;180(9):802–8. [PMID: 19729669]
Flume PA et al; Cystic Fibrosis Foundation Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010 Aug1;182(3):298–306. [PMID: 20675678]
ESSENTIALS OF DIAGNOSIS
Insidious onset of cough and dyspnea.
Irreversible airflow obstruction on pulmonary function testing.
Minimal findings on chest radiograph.
Relevant exposure or risk factor: toxic fumes, viral infections, organ transplantation, connective tissue disease.
Bronchiolitis is a generic term applied to varied inflammatory processes that affect the bronchioles, which are small conducting 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 less common but is encountered in multiple clinical settings. Disorders associated with bronchiolitis include organ transplantation, connective tissue diseases, and hypersensitivity pneumonitis. Inhalational injuries as well as postinfectious and drug-induced causes are identified by association with a known exposure or illness prior to the onset of symptoms. Idiopathic cases are characterized by the insidious onset of dyspnea or cough and include cryptogenic organizing pneumonitis (COP).
The clinical approach to bronchiolitis divides patients into groups based on etiology, but different clinical syndromes may have identical histopathological findings. As a result, no single classification scheme has been widely accepted, and there is an overlapping array of terms to describe these disorders from the viewpoints of the clinician, the pathologist, and the radiologist.
Acute bronchiolitis is most commonly seen following viral infection in children.
Constrictive bronchiolitis (also referred to as obliterative bronchiolitis, or bronchiolitis obliterans) is relatively infrequent although it is the most common finding following inhalation injury. It may also be seen in rheumatoid arthritis; drug reactions; and chronic rejection following heart-lung, lung, or bone marrow transplant. Patients with constrictive bronchiolitis have airflow obstruction on spirometry; minimal radiographic abnormalities; and a progressive, deteriorating clinical course.
Proliferative bronchiolitis is associated with diverse pulmonary disorders including infection, aspiration, ARDS, hypersensitivity pneumonitis, connective tissue diseases, and organ transplantation. Compared with constrictive bronchiolitis, proliferative bronchiolitis is more likely to have an abnormal chest radiograph.
Cryptogenic organizing pneumonitis (COP) formally referred to as bronchiolitis obliterans with organizing pneumonia (BOOP) (see Table 9–17) affects men and women between the ages of 50 and 70 years, typically with a dry cough, dyspnea, and constitutional symptoms that may be present for weeks to months prior to seeking medical attention. A history of a preceding viral illness is present in half of cases. Pulmonary function testing typically reveals a restrictive ventilatory defect and impaired oxygenation. The chest radiograph frequently shows bilateral patchy, ground-glass or alveolar infiltrates, although other patterns have been described (see Table 9–17).
Follicular bronchiolitis is most commonly associated with connective tissue disease, especially rheumatoid arthritis, and with immunodeficiency states.
Respiratory bronchiolitis usually occurs without symptoms or physiologic evidence of lung impairment.
Diffuse panbronchiolitis is most 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. Patients complain of dyspnea, cough, and sputum production, 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.
Constrictive bronchiolitis is relatively unresponsive to corticosteroids and is frequently progressive. Corticosteroids are effective in two-thirds of patients with proliferative bronchiolitis, and improvement can be prompt. Therapy is initiated with prednisone at 1 mg/kg/d orally 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. Most patients with COP recover following corticosteroid treatment.
Drakopanagiotakis F et al. Cryptogenic and secondary organizing pneumonia: clinical presentation, radiographic findings, treatment response, and prognosis. Chest. 2011 Apr;139(4):893–900. [PMID: 20724743]
Nakaseko C et al. Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation. Int J Hematol. 2011 Mar;93(3):375–82. [PMID: 21424350]
This section sets forth the evaluation and management of pulmonary infiltrates in immunocompetent persons separately from the approach to immunocompromised persons—defined as those with HIV disease, absolute neutrophil counts < 1000/mcL (1.0 × 109/L), current or recent exposure to myelosuppressive or immunosuppressive drugs, or those currently taking prednisone in a dosage > 5 mg/d.
ESSENTIALS OF DIAGNOSIS
Fever or hypothermia, tachypnea, cough with or without sputum, dyspnea, chest discomfort, sweats or rigors (or both).
Bronchial breath sounds or inspiratory crackles on chest auscultation.
Parenchymal opacity on chest radiograph.
Occurs outside of the hospital or within 48 hours of hospital admission in a patient not residing in a long-term care facility.
Community-acquired pneumonia (CAP) is a common disorder, with approximately 4–5 million cases diagnosed each year in the United States, 25% of which require hospitalization. It is the most deadly infectious disease in the United States and the eighth leading cause of death. Mortality in milder cases treated as outpatients is < 1%. Among patients hospitalized for CAP, in-hospital mortality is approximately 10–12% and 1-year mortality (in those over age 65) is > 40%. Risk factors for the development of CAP include advanced age; alcoholism; tobacco use; comorbid medical conditions, especially asthma or COPD; and immunosuppression.
The patient’s history, physical examination, and imaging studies are essential to establishing a diagnosis of CAP. None of these efforts identifies a specific microbiologic cause, however. Sputum examination may be helpful in selected patients but 40% of patients cannot produce an evaluable sputum sample and Gram stain and culture lack sensitivity for the most common causes of pneumonia. Since patient outcomes improve when the initial antibiotic choice is appropriate for the infecting organism, the American Thoracic Society and Infectious Disease Society of America recommend empiric treatment based on epidemiologic data (see Table 9–8). Such treatment improves initial antibiotic coverage, reduces unnecessary hospitalization, and appears to improve 30-day survival.
Table 9–8. Recommended empiric antibiotics for community-acquired pneumonia.
Decisions regarding hospitalization and ICU care should be based on prognostic criteria (see below).
Definition & Pathogenesis
CAP is diagnosed outside of the hospital in ambulatory patients who are not residents of nursing homes or other long-term care facilities. It may also be diagnosed in a previously ambulatory patient within 48 hours after admission to the hospital.
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. CAP occurs when there is a defect in one or more of these normal defense mechanisms or when a large infectious inoculum or a virulent pathogen overwhelms the immune response.
Prospective studies fail to identify the cause of CAP 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 CAP 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 Legionella species. Common viral causes of CAP 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 uncommon causes: Chlamydophila psittaci(psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), endemic fungi (Blastomyces, Coccidioides, Histoplasma), and sin nombre virus (hantavirus pulmonary syndrome).
Most patients with CAP experience an acute or subacute onset of fever, cough with or without sputum production, and dyspnea. Other common symptoms include sweats, chills, rigors, chest discomfort, pleurisy, hemoptysis, fatigue, myalgias, anorexia, headache, and abdominal pain.
Common physical findings include fever or hypothermia, tachypnea, tachycardia, and arterial oxygen desaturation. Many patients appear acutely ill. Chest examination often reveals inspiratory crackles and bronchial breath sounds. Dullness to percussion may be observed if lobar consolidation or a parapneumonic pleural effusion is present. The clinical evaluation is < 50% sensitive compared to chest imaging for the diagnosis of CAP (see Imaging section below). In most patients, therefore, a chest radiograph is essential to the evaluation of suspected CAP.
Diagnostic testing for a specific infectious cause of CAP is not generally indicated in ambulatory patients treated as outpatients because empiric antibiotic therapy is almost always effective in this population. In ambulatory outpatients whose presentation (travel history, exposure) suggests an etiology not covered by standard therapy (eg, Coccidioides) or public health concerns (eg, Mycobacterium tuberculosis, influenza), diagnostic testing is appropriate. Diagnostic testing is recommended in hospitalized CAP patients for multiple reasons: the likelihood of an infectious cause unresponsive to standard therapy is higher in more severe illness, the inpatient setting allows narrowing of antibiotic coverage as specific diagnostic information is available, and the yield of testing is improved in more acutely ill patients.
Diagnostic testing results are used to guide initial antibiotic therapy, permit adjustment of empirically chosen therapy to a specific infectious cause or resistance pattern, and facilitate epidemiologic analysis. There are three widely available, rapid point-of-care diagnostic tests that may guide initial therapy: the sputum Gram stain, urinary antigen tests for S pneumonia and Legionella species, and rapid antigen detection tests for influenza. Sputum Gram stain is neither sensitive nor specific for S pneumonia, the most common cause of CAP. The usefulness of a sputum Gram stain lies in broadening initial coverage in patients to be hospitalized for CAP, most commonly to cover S aureus (including community-acquired methicillin-resistant strains, CA-MRSA) or gram-negative rods. Urinary antigen assays for Legionella pneumophilia and S pneumoniae are at least as sensitive and specific as sputum Gram stain and culture. Results are available immediately and are not affected by early initiation of antibiotic therapy. Positive tests may allow narrowing of initial antibiotic coverage. Urinary antigen assay for S pneumoniae should be ordered for patients with leukopenia, asplenia, active alcohol use, chronic severe liver disease, pleural effusion, and those requiring ICU admission. Urinary antigen assay for L pneumophilia should be ordered for patients with active alcohol use, travel within 2 weeks, pleural effusion and those requiring ICU admission. Rapid influenza testing has intermediate sensitivity but high specificity. Positive tests may reduce unnecessary antibacterial use and direct isolation of hospitalized patients.
Additional microbiologic testing including pre-antibiotic sputum and blood cultures (at least two sets with needle sticks at separate sites) has been standard practice for patients with CAP who require hospitalization. The yield of blood and sputum cultures is low. However, false-positive results are common, and the impact of culture results on patient outcomes is small. As a result, targeted testing based on specific indications is recommended. Culture results are not available prior to initiation of antibiotic therapy. Their role is to allow narrowing of initial empiric antibiotic coverage, adjustment of coverage based on specific antibiotic resistance patterns, to identify unsuspected pathogens not covered by initial therapy, and to provide information for epidemiologic analysis.
Apart from microbiologic testing, hospitalized patients should undergo complete blood count with differential and a chemistry panel (including serum glucose, electrolytes, urea nitrogen, creatinine, bilirubin, and liver enzymes). Hypoxemic patients should have arterial blood gases sampled. Test results help assess severity of illness and guide evaluation and management. HIV testing should be considered in all adult patients, and performed in those with risk factors.
A pulmonary opacity on chest radiography or CT scan is required to establish a diagnosis of CAP. Radiographic findings range from patchy airspace opacities to lobar consolidation with air bronchograms to diffuse alveolar or interstitial opacities. Additional findings can include pleural effusions and cavitation. Chest imaging cannot identify a specific microbiologic cause of CAP, however. There is no pattern of radiographic abnormalities pathognomonic of any infectious cause.
Chest imaging may help assess severity and response to therapy over time. Progression of pulmonary opacities 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 opacities in patients with CAP can take 6 weeks or longer. Clearance is usually quickest in younger patients, nonsmokers, and those with only single lobe involvement.
Patients with CAP who have significant pleural fluid collections may require diagnostic thoracentesis (glucose, lactate dehydrogenase [LD], and total protein levels; leukocyte count with differential; pH determination) with pleural fluid Gram stain and culture. Positive pleural cultures indicate the need for tube thoracostomy drainage.
Patients with cavitary opacities should have sputum fungal and mycobacterial cultures.
Sputum induction and fiberoptic bronchoscopy to obtain samples of lower respiratory secretions are indicated in patients who cannot provide expectorated sputum samples or who may havePneumocystis jirovecii or M tuberculosis pneumonia.
Serologic assays, polymerase chain reaction tests, specialized culture tests, and other diagnostic tests for organisms such as viruses, Legionella, M pneumoniae, and C pneumoniae may be performed when these diagnoses are suspected.
The differential diagnosis of lower respiratory tract infection is extensive and includes upper respiratory tract infections, reactive airway diseases, heart failure, cryptogenic organizing pneumonitis, lung cancer, pulmonary vasculitis, pulmonary thromboembolic disease, and atelectasis.
Two general principles guide antibiotic therapy once the diagnosis of CAP is established: prompt initiation of a drug to which the etiologic pathogen is susceptible.
In patients who require specific diagnostic evaluation, sputum and culture specimens should be obtained prior to initiation of antibiotics. Since early administration of antibiotics to acutely ill patients is associated with improved outcomes, obtaining diagnostic specimens or test results should not delay the initial dose of antibiotics by more than 6 hours from presentation.
Optimal antibiotic therapy would be pathogen directed, but a definitive microbiologic diagnosis is rarely available on or within 6 hours of presentation. A syndromic approach to therapy, based on clinical presentation and chest imaging, does not reliably predict the microbiology of CAP. Therefore, initial antibiotic choices are typically empiric, based on acuity (treatment as an outpatient, inpatient, or in the ICU), patient risk factors for specific pathogens, and local antibiotic resistance patterns (Table 9–8).
Since S pneumoniae remains a common cause of CAP in all patient groups, local prevalence of drug-resistant S pneumoniae significantly affects initial antibiotic choice. Prior treatment with one antibiotic in a pharmacologic class (eg, beta-lactam, macrolide, fluoroquinolone) predisposes the emergence of drug-resistant S pneumoniae, with resistance developing against that class of antibiotics to which the pathogen was previously exposed. Definitions of resistance have shifted based on observations of continued clinical efficacy at achievable serum levels. In CAP, for parenteral penicillin G or oral amoxicillin, susceptible strains have a minimum inhibitory concentration (MIC) ≤ 2 mcg/mL; intermediate resistance is defined as an MIC between 2 mcg/mL and 4 mcg/mL because treatment failures are uncommon with MIC ≤ 4 mcg/mL. Macrolide resistance has increased; approximately one-third of S pneumoniae isolates now show in vitro resistance to macrolides. Treatment failures have been reported but remain rare compared to the number of patients treated; current in vivo efficacy appears to justify maintaining macrolides as first-line therapy except in areas where there is a high prevalence of resistant strains. S pneumoniae resistant to fluoroquinolones is rare in the United States (1% to levofloxacin, 2% to ciprofloxacin) but is increasing.
Community-acquired methicillin-resistant S aureus (CA-MRSA) is genetically and phenotypically different from hospital-acquired MRSA strains. CA-MRSA is a rare cause of necrotizing pneumonia, empyema, respiratory failure, and shock; it appears to be associated with prior influenza infection. Linezolid may be preferred to vancomycin in treatment of CA-MRSA pulmonary infection. For expanded discussions of specific antibiotics, see Chapter 30.
See Table 9–8 for specific drug dosages. The most common etiologies of CAP in outpatients who do not require hospitalization are S pneumoniae; M pneumoniae; C pneumoniae; and respiratory viruses, including influenza. For previously healthy patients with no recent (90 days) use of antibiotics, the recommended treatment is a macrolide (clarithromycin or azithromycin) or doxycycline.
In patients at risk for drug resistance (antibiotic therapy within the past 90 days, age > 65 years, comorbid illness, immunosuppression, exposure to a child in daycare), the recommended treatment is a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin) or a macrolide plus a beta-lactam (high-dose amoxicillin and amoxicillin-clavulanate are preferred to cefpodoxime and cefuroxime).
In regions where there is a high incidence of macrolide-resistant S pneumoniae, initial therapy in patients with no comorbidities may include a respiratory fluoroquinolone or the combination of a beta-lactam added to a macrolide.
There are limited data to guide recommendations for duration of treatment. The decision should be influenced by the severity of illness, etiologic pathogen, response to therapy, other medical problems, and complications. Most experts recommend administering a minimum of 5 days of therapy and continuing antibiotics until the patient is afebrile for 48–72 hours. There appears to be no advantage to routinely extending antibiotic therapy beyond 3 days following clinical improvement with defervescence.
The most common etiologies of CAP in patients who require hospitalization but not intensive care are S pneumoniae, M pneumoniae, C pneumoniae, H influenza, Legionella species, and respiratory viruses. Some patients have aspiration as an immediate precipitant to the CAP without a specific bacterial etiology. First-line therapy in hospitalized patients is a respiratory fluoroquinolone (eg, moxifloxacin, gemifloxacin, or levofloxacin) or the combination of a macrolide (clarithromycin or azithromycin) plus a beta-lactam (cefotaxime, ceftriaxone, or ampicillin) (see Table 9–8).
Almost all patients admitted to a hospital for treatment of CAP receive intravenous antibiotics. However, no studies in hospitalized patients demonstrated superior outcomes with intravenous antibiotics compared with oral antibiotics, as long as patients were able to tolerate the oral therapy and the drug was well absorbed. Duration of inpatient antibiotic treatment is the same as for outpatients.
The most common etiologies of CAP in patients who require admission to intensive care are S pneumoniae, Legionella species, H influenza, Enterobacteriaceae species, S aureus, and Pseudomonas species. First-line therapy in ICU patients with CAP is either azithromycin or a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin) combined with an antipneumococcal beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam). In patients at risk for Pseudomonas infection, one of two following regimens can be used: an antipneumococcal, antipseudomonal beta-lactam (piperacillin-tazobactam, cefepime, imipenem, meropenem) plus ciprofloxacin or levofloxacin or the above antipneumococcal beta-lactam plus an aminoglycoside (gentamicin, tobramycin, amikacin) plus either azithromycin or a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin).
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 age ≥ 65 years or any chronic illness that increases the risk of CAP (see Chapter 30). Immunocompromised patients and those at highest risk for 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.
The seasonal influenza vaccine is effective in preventing severe disease due to influenza virus with a resulting positive impact on both primary influenza pneumonia and secondary bacterial pneumonias. The seasonal influenza vaccine is administered annually to persons at risk for complications of influenza infection (age ≥ 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 may be administered as soon as the patient has stabilized.
When to Admit
Once a diagnosis of CAP is made, the first management decision is to determine the site of care: Is it safe to treat the patient at home or does he or she require hospital or intensive care admission? There are two widely used clinical prediction rules available to guide admission and triage decisions, the Pneumonia Severity Index (PSI) and the CURB-65.
The PSI is a validated prediction model that uses 20 items from demographics, medical history, physical examination, laboratory and imaging to stratify patients into five risk groups. The PSI is weighted toward discrimination at low predicted mortality. In conjunction with clinical judgment, it facilitates safe decisions to treat CAP in the outpatient setting. An on-line PSI risk calculator is available athttp://pda.ahrq.gov/clinic/psi/psicalc.asp. The CURB-65 assesses five simple, independent predictors of increased mortality (confusion, uremia, respiratory rate, blood pressure, and age > 65) to calculate a 30-day predicted mortality (http://www.mdcalc.com/curb-65-severity-score-community-acquired-pneumonia/). Compared with the PSI, the simpler CURB-65 is less discriminating at low mortality but excellent at identifying patients with high mortality who may benefit from ICU level care. A modified version (CRB-65) dispenses with serum blood urea nitrogen and eliminates the need for laboratory testing. Both have the advantage of simplicity: Patients with zero CRB-65 predictors have a low predicted mortality (< 1%) and usually do not need hospitalization; hospitalization should be considered for those with one or two predictors, since they have an increased risk of death; and urgent hospitalization (with consideration of ICU admission) is required for those with three or four predictors.
Expert opinion has defined major and minor criteria to identify patients at high risk for death. Major criteria are septic shock with need for vasopressor support and respiratory failure with need for mechanical ventilation. Minor criteria are respiratory rate ≥ 30 breaths per minute, hypoxemia (defined as Pao2/Fio2 ≤ 250), hypothermia (core temperature < 36.0°C), hypotension requiring aggressive fluid resuscitation, confusion/disorientation, multilobar pulmonary opacities, leukopenia due to infection with WBC < 4000/mcL (< 4.0 × 109/L), thrombocytopenia with platelet count < 100,000/mcL (< 100 × 109/L), uremia with blood urea nitrogen ≥ 20 mg/dL (> 7.1 mmol/L), metabolic acidosis, or elevated lactate level. Either one major criterion or three or more minor criteria of illness severity generally require ICU level care.
In addition to pneumonia-specific issues, good clinical practice always makes an admission decision in light of the whole patient. Additional factors suggesting need for inpatient hospitalization include the following:
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 Mar1;44(Suppl 2):S27–72. [PMID: 17278083]
Richards G et al. CURB-65, PSI, and APACHE II to assess mortality risk in patients with severe sepsis and community acquired pneumonia in PROWESS. J Intensive Care Med. 2011 Jan–Feb;26(1):34–40. [PMID: 21341394]
Waterer GW et al. Management of community-acquired pneumonia in adults. Am J Respir Crit Care Med. 2011 Jan15;183(2):157–64. [PMID: 20693379]
Watkins RR et al. Diagnosis and management of community-acquired pneumonia in adults. Am Fam Physician. 2011 Jun1;83(11):1299–306. [PMID: 21661712]
ESSENTIALS OF DIAGNOSIS
Hospital-acquired pneumonia (HAP) occurs > 48 hours after admission to the hospital or other health care facility and excludes any infection present at the time of admission.
Health care–associated pneumonia (HCAP) occurs in community members whose extensive contact with healthcare has changed their risk for virulent and drug resistant organisms.
Ventilator-associated pneumonia (VAP) develops following endotracheal intubation and mechanical ventilation.
At least two of the following: fever, leukocytosis, purulent sputum.
New or progressive parenchymal opacity on chest radiograph.
Especially common in patients requiring intensive care or mechanical ventilation.
Hospitalized patients carry different flora with different resistance patterns than healthy patients in the community, and their health status may place them at higher risk for more severe infection. The diagnostic approach and antibiotic treatment of patients with hospital-acquired pneumonia (HAP) is, therefore, different from patients with CAP. Similarly, management of patients in whom pneumonia develops following endotracheal intubation and mechanical ventilation (ventilator-associated pneumonia or VAP) should address issues specific to this group of patients. Some community members have extensive contact with the healthcare system and carry flora that more closely resemble hospitalized patients than healthy community residents. When pneumonia develops in these persons, the infection is referred to as health care–associated pneumonia (HCAP). Initial management and antibiotic therapy should be targeted to the common flora and specific risk factors for severe disease.
Considered together, these nosocomial pneumonias (HAP/VAP/HCAP) represent an important cause of morbidity and mortality despite widespread use of preventive measures, advances in diagnostic testing, and potent new antimicrobial agents. HAP is the second most common cause of infection among hospital inpatients and is the leading cause of death due to infection with mortality rates ranging from 20% to 50%. While a minority of cases occurs in ICU patients, the highest-risk patients are those in ICUs or who are being mechanically ventilated; these patients also experience higher morbidity and mortality from HAP. As management of more chronic illnesses shifts to the outpatient setting, more cases of HCAP are caused by unusual organisms, and there is a high frequency of drug resistance. Definitive identification of the infectious cause of a lower respiratory infection is rarely available on presentation, thus, rather than pathogen-directed antibiotic treatment, the choice of empiric therapy is informed by epidemiologic and patient data.
Definition & Pathogenesis
HAP develops more than 48 hours after admission to the hospital and VAP develops in a mechanically ventilated patient more than 48 hours after endotracheal intubation. HCAP is defined as pneumonia that occurs in a nonhospitalized patient with extensive healthcare contact (see Table 9–9).
Table 9–9. Risk factors for health care–associated pneumonia.
Three factors distinguish nosocomial pneumonia from CAP: (1) different infectious causes; (2) different antibiotic susceptibility patterns, specifically, a higher incidence of drug resistance; and (3) poorer underlying health status of patients putting them at risk for more severe infections. Since access to the lower respiratory tract occurs primarily through microaspiration, nosocomial pneumonia starts with a change in upper respiratory tract flora. Colonization of the pharynx and possibly the stomach with bacteria is the most important step in the pathogenesis of nosocomial pneumonia. Pharyngeal colonization is promoted by exogenous factors (eg, instrumentation of the upper airway with nasogastric and endotracheal tubes; contamination by dirty hands, equipment, and contaminated aerosols; and treatment with broad-spectrum antibiotics that promote the emergence of drug-resistant organisms) and patient factors (eg, malnutrition, advanced age, altered consciousness, swallowing disorders, and underlying pulmonary and systemic diseases). Within 48 hours of admission, 75% of seriously ill hospitalized patients have their upper airway colonized with organisms from the hospital environment.
Impaired cellular and mechanical defense mechanisms in the lungs of hospitalized patients raise the risk of infection after aspiration has occurred.
Gastric acid may play a role in protection against nosocomial pneumonias. Observational studies have suggested that elevation of gastric pH due to antacids, H2-receptor antagonists, proton pump inhibitors (PPIs), or enteral feeding is associated with gastric microbial overgrowth, tracheobronchial colonization, and HAP/VAP. Sucralfate, a cytoprotective agent that does not alter gastric pH, is associated with a trend toward a lower incidence of VAP. The Infectious Disease Society of America and other professional organizations recommend that acid suppressive medications (H2-receptor antagonists and PPIs) only be given to patients at high risk for stress gastritis.
The microbiology of the nosocomial pneumonias differs from CAP but is substantially the same among HAP, VAP, and HCAP (Table 9–10). The most common organisms responsible for HAP include S aureus (both methicillin-sensitive S aureus and MRSA), P aeruginosa, gram-negative rods including non-extended spectrum beta-lactamase (non-ESBL)–producing and ESBL-producing (Enterobacterspecies, K pneumoniae, and Escherichia coli) organisms. VAP patients may be infected with Acinetobacter species and Stenotrophomonas maltophilia. HCAP patients may have common organisms (S pneumoniae, H influenzae) that are more likely to be drug-resistant, or flora that resembles HAP. 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 nosocomial pneumonias.
Table 9–10. Organisms prevalent in nosocomial pneumonias.1
The symptoms and signs associated with nosocomial pneumonias are nonspecific; however, two or more clinical findings (fever, leukocytosis, purulent sputum) in the setting of a new or progressive pulmonary opacity on chest radiograph were approximately 70% sensitive and 75% specific for the diagnosis of VAP in one study. Other findings include those listed above for CAP.
The differential diagnosis of new lower respiratory tract symptoms and signs in hospitalized patients includes heart failure, atelectasis, aspiration, ARDS, pulmonary thromboembolism, pulmonary hemorrhage, and drug reactions.
Diagnostic evaluation for suspected nosocomial pneumonia includes blood cultures from two different sites. Blood cultures can identify the pathogen in up to 20% of all patients with nosocomial pneumonias; positivity is associated with increased risk of complications and other sites of infection. Blood counts and clinical chemistry tests do not establish a specific diagnosis of HCAP; however, they help define the severity of illness and identify complications. The assessment of oxygenation by an arterial blood gas or pulse oximetry determination helps define the severity of illness and determines the need for assisted ventilation. Thoracentesis for pleural fluid analysis should be considered in patients with pleural effusions.
Examination of sputum is attended by the same disadvantages as in CAP. Gram stains and cultures of sputum are neither sensitive nor specific in the diagnosis of nosocomial pneumonias. 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 bacterial antibiotic sensitivity patterns and as a guide to adjusting empiric therapy.
Radiographic findings in HAP/VAP are nonspecific and often confounded by other processes that led initially to hospitalization or ICU admission. (See CAP above.)
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 VAP. Endotracheal aspiration cultures have significant negative predictive value but limited positive predictive value in the diagnosis of specific infectious causes of HAP/VAP. An invasive diagnostic approach using quantitative culture of bronchoalveolar lavage samples or protected specimen brush samples in patients in whom VAP is suspected leads to significantly less antibiotic use, earlier attenuation of organ dysfunction, and fewer deaths at 14 days.
Treatment of the nosocomial pneumonias, like treatment of CAP, is usually empiric (Table 9–11). Because of the high mortality rate, therapy should be started as soon as pneumonia is suspected. There is no consensus on the best regimens because this patient population is heterogeneous and local flora and resistance patterns must be taken into account.
Table 9–11. Recommended empirical antibiotics for nosocomial pneumonias.1
After results of sputum, blood, and pleural fluid cultures are available, it may be possible to de-escalate initially broad therapy. Duration of antibiotic therapy should be individualized based on the pathogen, severity of illness, response to therapy, and comorbid conditions. Data from one large trial assessing treatment outcomes in VAP suggested that 8 days of antibiotics is as effective as 15 days, except in cases caused by P aeruginosa.
For expanded discussions of specific antibiotics, see Chapter 30.
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Labelle A et al. Healthcare-associated pneumonia: approach to management. Clin Chest Med. 2011 Sep;32(3):507–15. [PMID: 21867819]
Zilberberg MD et al. Healthcare-associated pneumonia: the state of evidence to date. Curr Opin Pulm Med. 2011 May;17(3):142–7. [PMID: 21252678]
ESSENTIALS OF DIAGNOSIS
History of or predisposition to aspiration.
Indolent symptoms, including fever, weight loss, malaise.
Foul-smelling purulent sputum (in many patients).
Infiltrate in dependent lung zone, with single or multiple areas of cavitation or pleural effusion.
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.
In most cases of aspiration and necrotizing pneumonia, lung abscess, and empyema, multiple species of anaerobic bacteria are causing the infection. Most of the remaining cases are caused by infection with both anaerobic and aerobic bacteria. Prevotella melaninogenica, Peptostreptococcus, Fusobacterium nucleatum, and Bacteroides species are commonly isolated anaerobic bacteria.
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.
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.
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. An air-fluid level is usually present. Other causes of cavitary lung disease (tuberculosis, mycosis, cancer, infarction, granulomatosis with polyangiitis [formerly 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. Ultrasonography is of value in locating fluid and may also reveal pleural loculations.
Drugs of choice are clindamycin (600 mg intravenously every 8 hours until improvement, then 300 mg orally every 6 hours) or amoxicillin-clavulanate (875 mg/125 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. Penicillin alone is inadequate treatment for anaerobic pleuropulmonary infections because an increasing number of anaerobic organisms produce beta-lactamases, and up to 20% of patients do not respond to penicillins. Antibiotic therapy for anaerobic pneumonia 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.
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PULMONARY INFILTRATES IN THE IMMUNOCOMPROMISED HOST
Pulmonary infiltrates in immunocompromised patients (patients with HIV disease, absolute neutrophil counts < 1000/mcL (< 1.0 × 109/L), current or recent exposure to myelosuppressive or immunosuppressive drugs, or those currently taking > 5 mg/d of prednisone) 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 an immunocompromised 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 timecourse 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 jirovecii, viruses (eg, cytomegalovirus), and fungi (eg, 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 jirovecii 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 jirovecii 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 before proceeding 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 P jirovecii pneumonia in patients with AIDS when induced sputum analysis is negative. Surgical lung biopsy, now often performed by video-assisted thoracoscopy, provides the definitive option for diagnosis of pulmonary infiltrates in the immunocompromised host. However, a specific diagnosis is obtained in only about two-thirds of cases, and the information obtained rarely affects the outcome.
Corti M et al. Respiratory infections in immunocompromised patients. Curr Opin Pulm Med. 2009 May;15(3):209–17. [PMID: 19276812]
Crothers K et al. HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era. Am J Respir Crit Care Med. 2011 Feb1;183(3):388–95. [PMID: 20851926]
Limper AH et al. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan1;183(1):96–128. [PMID: 21193785]
Marom EM et al. Imaging studies for diagnosing invasive fungal pneumonia in immunocompromised patients. Curr Opin Infect Dis. 2011 Aug;24(4):309–14. [PMID: 21673574]
ESSENTIALS OF DIAGNOSIS
Fatigue, weight loss, fever, night sweats, and productive cough.
Risk factors for acquisition of infection: household exposure, incarceration, drug use, travel to an endemic area.
Chest radiograph: pulmonary opacities, most often apical.
Acid-fast bacilli on smear of sputum or sputum culture positive for M tuberculosis.
Tuberculosis is one of the world’s most widespread and deadly illnesses. M tuberculosis, the organism that causes tuberculosis infection and disease, infects one-third of the world’s population. In 2012, there were 8.6 million new cases of tuberculosis worldwide with 1.3 million people dying of the disease. In the United States, an estimated 11 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 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 6% of individuals with latent tuberculosis infection who are not given preventive therapy; half of these cases occur in the 2 years following primary infection. Diverse conditions such as gastrectomy, silicosis, diabetes mellitus, and an impaired immune response (eg, HIV infection; therapy with corticosteroids, tumor necrosis factor inhibitors or other immunosuppressive drugs) are associated with an increased risk of reactivation.
In approximately 5% of cases, the immune response is inadequate to contain the primary infection and progressive primary tuberculosis develops, accompanied by both pulmonary and constitutional symptoms as described below. The clinical presentation does not definitively distinguish primary disease from reactivation of latent tuberculosis infection. Standard teaching has held that 90% of tuberculosis in adults represents activation of latent disease. However, DNA fingerprinting of the bacillus suggests that as many as one-third of new cases of tuberculosis in urban populations are primary infections resulting from person-to-person transmission.
The prevalence of drug-resistant strains is increasing worldwide; however, in the United States, the rate of drug-resistant isolates has fallen to < 1%. Risk factors for drug resistance include immigration from countries with a high prevalence of drug-resistant tuberculosis, close and prolonged contact with individuals with drug-resistant tuberculosis, unsuccessful previous therapy, and nonadherence to treatment. Drug resistance may be single or multiple. Drug-resistant tuberculosis is resistant to one first-line antituberculous drug, either isoniazid or rifampin. Multidrug-resistant tuberculosis is resistant to isoniazid and rifampin, and possibly additional agents. Extensively drug-resistant tuberculosis is resistant to isoniazid, rifampin, fluoroquinolones, and either aminoglycosides or capreomycin or both. Outcomes of drug-resistant tuberculosis treatment are worse than when the isolate is drug-sensitive, but outcomes appear to vary with HIV status. In a review of extensively drug-resistant tuberculosis cases in the United States, mortality was 10% and 68% in HIV-negative and HIV-positive patients, respectively.
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.
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. 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 establish a diagnosis of M tuberculosis, since nontuberculous mycobacteria may colonize the airways and are increasingly recognized to cause clinical illness in patients with underlying structural lung disease.
In patients thought to have tuberculosis who cannot produce satisfactory specimens or when the smear of the spontaneously expectorated sputum is negative for acid-fast bacilli, sputum induction with 3% hypertonic saline should be performed. Flexible bronchoscopy with bronchial washings has similar diagnostic yield to induced sputum; transbronchial lung biopsies do not significantly increase the diagnostic yield but may lead to earlier diagnosis by identifying tissue granulomas. Post-bronchoscopy expectorated sputum specimens should be collected. Early morning aspiration of gastric contents after an overnight fast 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. Positive blood cultures forM tuberculosis are uncommon in patients with normal CD4 cell counts but the organism may be cultured from blood in up to 50% of HIV-seropositive patients with tuberculosis whose CD4 cell counts are < 100/mcL (< 0.1 × 109/L).
Traditional light-microscopic examination of stained sputum for acid-fast bacilli and culture of sputum specimens remain the mainstay of tuberculosis diagnosis. The slow rate of mycobacterial growth, the urgency to provide early, appropriate treatment to patients to improve their outcomes and limit community spread, and concerns about potential drug toxicities in patients treated empirically who do not have tuberculosis infection, have fostered interest in rapid diagnostic techniques (see Table 9–12). Molecular diagnostics offer multiple options and many advantages at significantly increased expense. Nucleic acid amplication testing not only detects M tuberculosis (NAAT-TB) but it also identifies resistance markers (NAAT-R). NAAT-TB can identify M tuberculosis within hours of sputum processing, allowing early isolation and treatment, but the negative predictive value is low in smear-negative patients. NAAT-R allows rapid identification of primary drug resistance and is indicated in the following patients: (1) those treated previously for tuberculosis, (2) those born (or who lived for > 1 year) in a country with moderate tuberculosis incidence or a high incidence of multiple drug-resistant isolates, (3) contacts of patients with multidrug-resistant tuberculosis, or (4) those who are HIV seropositive. Clinical suspicion remains the critical factor in interpreting all these studies. Standard 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.
Table 9–12. Essential laboratory tests for the detection of Mycobacterium tuberculosis.1
Needle biopsy of the pleura reveals granulomatous inflammation in approximately 60% of patients with pleural effusions caused by M tuberculosis. Pleural fluid cultures are positive for M tuberculosisin less than 23–58% 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. Tests for pleural fluid adenosine deaminase (approximately 90% sensitivity and specificity for pleural tuberculosis at levels > 70 units/L) and interferon-gamma (89% sensitivity, 97% specificity in a recent meta-analysis) can be extremely helpful diagnostic aids, particularly in making decisions to pursue invasive testing in complex cases.
Contrary to traditional teaching, molecular analysis demonstrates that radiographic abnormalities in pulmonary tuberculosis do not distinguish primary disease from reactivation of latent tuberculosis (Figure 9–5). The only independent predictor of an atypical pattern on chest radiograph—that is, not associated with upper lobe or cavitary disease—is an impaired host immune response. In elderly patients, lower lobe infiltrates with or without pleural effusion are frequently encountered. Lower lung tuberculosis may masquerade as pneumonia or lung cancer. A “miliary” pattern (diffuse small nodular densities) can be seen with hematologic or lymphatic dissemination of the organism. Immunocompromised patients—particularly those with late-stage HIV infection—often display lower lung zone, diffuse, or miliary infiltrates; pleural effusions; and involvement of hilar and, in particular, mediastinal lymph nodes.
Figure 9–5. Pulmonary tuberculosis. Chest CT scan showing biapical noncavitary consolidation consistent with pulmonary tuberculosis and associated right axillary lymphadenopathy.
Resolution of active tuberculosis leaves characteristic radiographic findings. Dense nodules in the pulmonary hila, with or without obvious calcification, upper lobe fibronodular scarring, and bronchiectasis with volume loss are common findings. Ghon (calcified primary focus) and Ranke (calcified primary focus and calcified hilar lymph node) complexes are seen in a minority of patients.
Testing for latent tuberculosis infection is used to evaluate an asymptomatic person in whom M tuberculosis infection is suspected (eg, following contact exposure) or to establish the prevalence of tuberculosis infection in a population. Testing may be used in a person with symptoms of active tuberculosis, but a positive test does not distinguish between active and latent infection. Routine testing of individuals at low risk for tuberculosis is not recommended.
The traditional approach to latent tuberculosis infection is the tuberculin skin test. 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 is measured after 48–72 hours. To optimize test performance, criteria for determining a positive reaction vary depending on the likelihood of infection. Table 9–13 summarizes the criteria established by the Centers for Disease Control and Prevention (CDC) for interpretation of the Mantoux tuberculin skin test. Sensitivity and specificity of the tuberculin skin test are high: 77% and 97%, respectively. Specificity falls to 59% in populations previously vaccinated with bacillus Calmette-Guérin (BCG, an extract of Mycobacterium bovis). False-negative tuberculin skin test reactions may result from improper testing technique; concurrent infections, including fulminant tuberculosis; malnutrition; advanced age; immunologic disorders; malignancy; corticosteroid therapy; chronic kidney disease; and HIV infection. Some individuals with latent tuberculosis infection may have a negative tuberculin skin test when tested many years after exposure. 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.
Table 9–13. Classification of positive tuberculin skin test reactions.1
Interferon gamma release assays are in vitro assays of CD4+ T-cell–mediated interferon gamma release in response to stimulation by specific M tuberculosis antigens. The antigens are absent from all BCG strains and most nontuberculous mycobacteria; therefore, in whole blood, the specificity of interferon gamma release assays is superior to the tuberculin skin test in BGC-vaccinated individuals. Sensitivity is comparable to the tuberculin skin test: 60–90% depending on the specific assay and study population. Sensitivity is reduced by HIV infection, particularly in patients with low CD4 counts. Specificity is high, > 95%. Potential advantages of interferon gamma release assay testing include fewer false-positive results from prior BCG vaccination, better discrimination of positive responses due to nontuberculous mycobacteria, and the requirement for only one patient contact (ie, no need for the patient to return to have the tuberculin skin test read 48–72 hours later). Disadvantages include the need for specialized laboratory equipment and personnel, and the substantially increased cost compared to the tuberculin skin test.
In endemic areas, interferon gamma release assays are no more sensitive than the tuberculin skin test in active tuberculosis (20–40% false-negative rate) and cannot distinguish active from latent disease. Interferon gamma release assays should not be used to exclude active tuberculosis.
Guidelines established by the CDC allow interferon gamma release assays to be used interchangeably with the tuberculin skin testing in the diagnosis of latent tuberculosis infection. Interferon gamma release assays are preferred in patients with prior BCG vaccination; the tuberculin skin test is preferred in children under 5 years old. Routine use of both tests is not recommended. In individuals with a positive tuberculin skin test but a low prior probability of latent tuberculosis infection and low risk for progression to active disease, the interferon gamma release assay may be helpful as a confirmatory test to exclude a false-positive tuberculin skin test.
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 clinicians 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.
Characteristics of antituberculous drugs are provided in Table 9–14. Additional treatment considerations can be found in Chapter 33. More complete information can be obtained from the CDC’s Division of Tuberculosis Elimination Web site at http://www.cdc.gov/tb/.
Table 9–14. Characteristics of antituberculous drugs.
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 M tuberculosis. 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 a week 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) Isoniazid, rifampin, pyrazinamide, and ethambutol three times a week 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 9–15. 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 9–15. Recommended dosages for the initial treatment of tuberculosis.
Management of tuberculosis is 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 (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 http://www.cdc.gov/tb/). DOT should be used for all HIV-positive tuberculosis patients. Pyridoxine (vitamin B6), 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.
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 and extensively drug-resistant tuberculosis call for an individualized daily DOT plan under the supervision of an experienced clinician. Treatment regimens are based on the patient’s overall status and the results of susceptibility studies. Most drug-resistant 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 continued for at least another 12 months. Some experts recommend at least 18–24 months of a three-drug regimen.
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 constrictive pericarditis from tuberculous pericarditis and to reduce neurologic complications from tuberculous meningitis (see Chapter 33).
Tuberculosis in pregnancy is usually treated with isoniazid, rifampin, and ethambutol for 2 months, followed by isoniazid and rifampin for an additional 7 months. Ethambutol can be stopped after the first month if isoniazid and rifampin susceptibility is confirmed. 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. First-line therapy is not known to be harmful to nursing newborns at these concentrations. Therefore, breastfeeding is not contraindicated while receiving first-line antituberculous therapy. Lactating women receiving other agents should consult a tuberculosis expert.
Adults should have measurements of a complete blood count (including platelets) and serum bilirubin, hepatic enzymes, urea nitrogen, and creatinine before starting therapy 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.
Routine monitoring of laboratory tests for evidence of drug toxicity during therapy is not recommended, unless baseline results are abnormal or liver disease is suspected. Monthly questioning for symptoms of drug toxicity is advised. Patients should be educated about common side effects of antituberculous medications and instructed to seek medical attention should these symptoms occur. Monthly follow-up of outpatients is recommended, including sputum smear and culture for 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 drug-resistant isolates 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 nonadherence to the regimen and for drug-resistant organisms. 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 tuberculous infection is essential to controlling and eliminating tuberculosis. Treatment of latent tuberculous infection substantially reduces the risk that infection will progress to active disease. Targeted testing with the tuberculin skin test or interferon gamma release assays is used to identify persons who are at high risk for tuberculosis and who stand to benefit from treatment of latent infection. Table 9–13 gives the tuberculin skin test criteria for treatment of latent tuberculous infection. In general, patients with a positive tuberculin skin test or interferon gamma release assay 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.
Some close contacts of persons with active tuberculosis should be evaluated for treatment of latent tuberculous infection despite a negative tuberculin skin test reaction (< 5 mm induration). These include immunosuppressed persons and those who may develop disease quickly after tuberculous infection. Close contacts who have a negative tuberculin skin test reaction on initial testing should be retested 10–12 weeks later.
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 oral 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 oral 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. This regimen has been associated with significant hepatotoxicity, so careful laboratory monitoring is required. (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 receiving protease inhibitors or NNRTIs who are given rifampin 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 drug-resistant tuberculosis should receive two drugs to which the infecting organism has demonstrated susceptibility. Contacts in whom the tuberculin skin test or interferon gamma release assay is negative and contacts who are HIV seronegative may be observed without treatment or treated for 6 months. HIV-positive contacts should be treated for 12 months. All contacts of persons with multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis should have 2 years of follow-up regardless of treatment.
Persons with a positive tuberculin skin test (≥ 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 in prophylaxis of pulmonary tuberculosis. BCG vaccination in the United States should only be undertaken after consultation with local health officials and tuberculosis experts. 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.
Almost all properly treated immunocompetent 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.
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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 opacities on chest radiograph, often with thin-walled cavities, that spread contiguously and often involve overlying pleura.
Isolation of nontuberculous mycobacteria in a sputum culture.
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.)
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.
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; the list of more unusual etiologic NTM species is long. Most NTM cause a chronic pulmonary infection that resembles tuberculosis but tends to progress more slowly. Disseminated disease is rare in immunocompetent hosts; however, disseminated MAC disease is common in patients with AIDS.
NTM infection among immunocompetent hosts frequently presents in one of three prototypical patterns: cavitary, upper lobe lesions in older male smokers that may mimic M tuberculosis; nodular bronchiectasis affecting the mid lung zones in middle-aged women with chronic cough; and hypersensitivity pneumonitis following environmental exposure. 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 (COPD, bronchiectasis, previous mycobacterial disease, cystic fibrosis, and pneumoconiosis) may confound the evaluation. In patients with bronchiectasis, coinfection with NTM and Aspergillus is a negative prognostic factor. New or worsening infiltrates as well as adenopathy or pleural effusion (or both) are described in HIV-positive patients with NTM infection as part of the immune reconstitution inflammatory syndrome following institution of highly active antiretroviral therapy.
The diagnosis of NTM infection rests on recovery of the pathogen from cultures. Sputum cultures positive for atypical mycobacteria do not 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 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 immunosuppression. HIV-infected patients may show significant MAC growth on culture of bronchial washings without clinical infection; therefore, HIV patients being evaluated for MAC infection must be considered individually.
Drug susceptibility testing on cultures of NTM is recommended for the following NTM: (1) Mycobacterium avium intracellulare to macrolides only (clarithromycin and azithromycin); (2) M kansasii to rifampin; and (3) rapid growers (such as Mycobacterium fortuitum, Mycobacterium chelonae, M abscessus) to amikacin, doxycycline, imipenem, fluoroquinolones, clarithromycin, cefoxitin, and sulfonamides.
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.
Establishing NTM infection does not mandate treatment in all cases, for two reasons. First, clinical disease may never develop in some patients, particularly asymptomatic patients with few organisms isolated from single specimens. Second, the spectrum of clinical disease severity is very wide; in patients with mild or slowly progressive symptoms, traditional chemotherapeutic regimens using a combination of agents may lead to drug-induced side effects worse than the disease itself.
Specific treatment regimens and responses to therapy vary with the species of NTM. HIV-seronegative patients with MAC pulmonary disease usually receive a combination of daily clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol (Table 9–15). For patients with severe fibrocavitary disease, streptomycin or amikacin is added for the first 2 months. 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 do not 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. 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. Rapidly growing mycobacteria (M abscessus, M fortuitum, M chelonae) are generally resistant to standard antituberculous therapy.
When to Refer
Patients with rapidly growing mycobacteria infection should be referred for expert management.
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Esteban J et al. Current treatment of nontuberculous mycobacteriosis: an update. Expert Opin Pharmacother. 2012 May;13(7):967–86. [PMID: 22519767]
Griffith DE et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb15;175(4):367–416. [PMID: 17277290]
Iseman MD. Mycobacterial infections in the era of modern biologic agents. Am J Med Sci. 2011 Apr;341(4):278–80. [PMID: 21378550]
See Chapter 39 for discussions of Lung Cancer, Secondary Lung Cancer, and Mesothelioma.
SCREENING FOR LUNG CANCER
Two large RCTs reported findings in 2011 that clarify the utility of lung cancer screening. The Prostate, Lung, Colorectal and Ovarian Randomized Trial (PLCO) randomized 154,901 adults (52% current or former smokers) between the ages of 55 and 74 years to receive either no screening or annual posterior-anterior chest radiographs for 4 consecutive years. The investigators monitored the participants after screening for an average of 12 years. Results showed no mortality benefit from four annual chest radiographs either in the whole cohort or in a subset of heavy smokers who met the entry criteria for the other major trial, the National Lung Screening Trial (NLST). The NLST enrolled 53,454 current or former smokers (minimum 30-pack year exposure history) between the ages of 55 and 74 years who were randomly assigned to one of two screening modalities: three annual posterior-anterior chest radiographs or three annual low-dose chest CT scans. They were monitored for an additional 6.5 years after screening. Compared with chest radiography, low-dose chest CT detected more early-stage lung cancers and fewer advanced-stage lung cancers, indicating that CT screening systematically shifted the time of diagnosis to earlier stages, thereby providing more persons the opportunity for effective treatment. Furthermore, compared with chest radiographs, the cohort that received three annual CT scans had a statistically significant mortality benefit, with reductions in both lung cancer deaths (20.0%) and all-cause mortality (6.7%). This is the first time that evidence from a RCT demonstrated that lung cancer screening reduces all-cause mortality.
Additional information from PLCO, the NLST, and multiple other ongoing randomized trials is available. Salient issues that temper enthusiasm for widespread screening at this time include the following: (1) Generalizability to community practice: NLST-participating institutions demonstrated a high level of expertise in imaging interpretation and diagnostic evaluation. Ninety-six percent of findings on CT were false positives but the vast majority of patients were monitored with serial imaging. Invasive diagnostic evaluations were uncommon and were associated with a low complication rate (1.4%). (2) Duration of screening: The rate of detection of new lung cancers did not fall with each subsequent annual screening over 3 years. Since each year lung cancers first become detectable during that screening interval, the optimal number of annual CT scans is unknown as is the optimal screening interval. (3) Overdiagnosis: After 6.4 years of post-screening observation, there were more lung cancers in the NLST CT cohort than the chest radiography cohort (1089 and 969, respectively). Since the groups were randomized and well matched, lung cancer incidence should have been identical. Therefore, 18.5% of the lung cancers detected by CT remained clinically silent and invisible on chest radiograph for 6.4 years. Many, perhaps most, of these lung cancers will never cause clinical disease and represent overdiagnosis. (4) Cost effectiveness: The number needed to screen with three annual chest CT scans to prevent one death from lung cancer was 320.
Clear evidence exists showing the benefit of screening with low-dose chest CT in high-risk individuals and, since late 2013, screening has been recommended by the US Preventive Services Task Force. There is no evidence of benefit in a mixed population screened with chest radiography.
Aberle DR et al; National Lung Screening Trial Research Team. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med. 2013 Sep5;369(10):920–31. [PMID: 24004119]
Field JK et al. Prospects for population screening and diagnosis of lung cancer. Lancet. 2013 Aug24;382(9893):732–41. [PMID: 23972816]
Humphrey LL et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive services task force recommendation. Ann Intern Med. 2013 Sep17;159(6):411–20. [PMID: 23897166]
Kovalchik SA et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med. 2013 Jul18;369(3):245–54. [PMID: 23863051]
Moyer VA. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013 Dec31. [Epub ahead of print] [PMID: 24378917]
National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug4;365(5):395–409. [PMID: 21714641]
Oken MM et al. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and O varian (PLCO) randomized trial. JAMA. 2011 Nov2;306(17):1865–73. [PMID: 22031728]
Patz EF Jret al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med. 2013 Dec9. [Epub ahead of print] [PMID: 24322569]
SOLITARY PULMONARY NODULE
A solitary pulmonary nodule, sometimes referred to as a “coin lesion,” is a < 3 cm isolated, rounded opacity on chest imaging 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. Benign neoplasms 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 will 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 imaging data can be used to assess the probability of malignancy. 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 imaging evaluation is to review old imaging studies. 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 while long-term stability (doubling time greater than 465 days) suggests benignity. Certain radiographic features help in estimating the probability of malignancy. Size is correlated with malignancy. A 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. Chest CT is indicated in any suspicious solitary pulmonary nodule.
Based on clinical and radiologic data, the clinician should assign a specific probability of malignancy to the lesion. The decision whether to recommend a biopsy or surgical excision 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 identify growth suggestive of 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 CT 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.
Some centers recommend video-assisted thoracoscopic surgery (VATS) resection of all solitary pulmonary nodules with intermediate probability of malignancy. In some cases, the surgeon will remove the nodule and evaluate it in the operating room with frozen section. If the nodule is malignant, he or she will proceed to lobectomy and lymph node sampling, either thoracoscopically or through conversion to standard thoracotomy. This approach is less common when PET scanning is available.
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.
Ost DE et al. Decision making in patients with pulmonary nodules. Am J Respir Crit Care Med. 2012 Feb15;185(4):363–72. [PMID: 21980032]
Wang Memoli JS et al. Meta-analysis of guided bronchoscopy for the evaluation of the pulmonary nodule. Chest. 2012 Aug;142(2):385–93. [PMID: 21980059]
RIGHT MIDDLE LOBE SYNDROME
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.
Gudbjartsson T et al. Middle lobe syndrome: a review of clinicopathological features, diagnosis and treatment. Respiration. 2012;84(1):80–6. [PMID: 22377566]
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 (see Chapter 39).
Aydin E et al. Long-term outcomes and prognostic factors of patients with surgically treated pulmonary carcinoid: our institutional experience with 104 patients. Eur J Cardiothorac Surg. 2011 Apr;39(4):549–54. [PMID: 21282063]
Cakir M et al. The molecular pathogenesis and management of bronchial carcinoids. Expert Opin Ther Targets. 2011 Apr;15(4):457–91. [PMID: 21275849]
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 hiatal 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.
Fujii Y. Published guidelines for management of thymoma. Thorac Surg Clin. 2011 Feb;21(1):125–9. [PMID: 21070994]
Gubens MA. Treatment updates in advanced thymoma and thymic carcinoma. Curr Treat Options Oncol. 2012 Dec;13 (4):527–34. [PMID: 22961051]
Mikhail M et al. Thymic neoplasms: a clinical update. Curr Oncol Rep. 2012 Aug;14(4):350–8. [PMID: 22639107]
Nakazono T et al. MRI findings of mediastinal neurogenic tumors. AJR Am J Roentgenol. 2011 Oct;197(4):W643–52. [PMID: 21940535]
INTERSTITIAL LUNG DISEASE (DIFFUSE PARENCHYMAL LUNG DISEASE)
ESSENTIALS OF DIAGNOSIS
Insidious onset of progressive dyspnea and nonproductive chronic cough; extrapulmonary findings may accompany specific diagnoses.
Tachypnea, small lung volumes, bibasilar dry rales; digital clubbing and right heart failure with advanced disease.
Chest radiographs with low lung volumes and patchy distribution of ground glass, reticular, nodular, reticulonodular, or cystic opacities.
Reduced lung volumes, pulmonary diffusing capacity and 6-minute walk distance; hypoxemia with exercise.
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 (alveolitis). 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 9–16 outlines a selected list of differential diagnoses of interstitial lung disease. In most patients, no specific cause can be identified. In the remainder, medications 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.
Table 9–16. Differential diagnosis of interstitial lung disease.
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.
Known causes of interstitial lung disease are dealt with in their specific sections. The important idiopathic forms are discussed below.
IDIOPATHIC INTERSTITIAL PNEUMONIAS
ESSENTIALS OF DIAGNOSIS
Important to identify specific fibrosing disorders.
Idiopathic disease may require biopsy for diagnosis.
Accurate diagnosis identifies patients most likely to benefit from therapy.
The most common diagnosis among patients with interstitial lung disease is idiopathic interstitial pneumonia. 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 interstitial pneumonia. These distinct histopathologic features are now recognized as being associated with different natural histories and responses to therapy (see Table 9–17). Therefore, in the evaluation of patients with interstitial lung disease, clinicians should attempt to identify specific disorders.
Table 9–17. Idiopathic interstitial pneumonias.
Patients with idiopathic interstitial pneumonia may have any of the histologic patterns described in Table 9–17. The first step in evaluation is to identify patients whose disease is truly idiopathic. As indicated in Table 9–16, most identifiable causes of interstitial lung disease are infectious, medication-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.
The diagnosis of usual interstitial pneumonia (UIP) can be made on clinical grounds alone in selected patients (Table 9–17). 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 (Figure 9–6). Such patients do not need surgical lung biopsy.
Figure 9–6. Idiopathic pulmonary fibrosis. CT scan of the lungs showing the typical radiographic pattern of idiopathic pulmonary fibrosis, with a predominantly basilar, peripheral pattern of traction bronchiectasis, reticulation, and early honeycombing.
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 jirovecii 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, or 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. 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. Transbronchial biopsy also 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.
Treatment of idiopathic 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 RB-ILD, nonspecific interstitial pneumonia (NSIP), or COP (see Table 9–17) 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. A number of antifibrotic (pirfenidone, interferon gamma 1b) and immunomodulator/immunosuppressant (cyclosporine A, azathioprine, etanercept) agents have been investigated and none of them are recommended for the treatment of UIP, either in monotherapy or combination therapy. The only definitive treatment for UIP is lung transplantation, with a 5-year survival rate estimated at 50%.
Ferguson EC et al. Lung CT: part 2, the interstitial pneumonias—clinical, histologic, and CT manifestations. AJR Am J Roentgenol. 2012 Oct;199(4):W464–76. [PMID: 22997396]
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Raghu G et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011 Mar15;183(6):788–824. [PMID: 21471066]
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.
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.
Patients may have malaise, fever, and dyspnea of insidious onset. Symptoms from skin involvement (erythema, lupus pernio [Figure 9–7]), iritis, peripheral neuropathy, arthritis (see Chapter 20), or cardiomyopathy 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 in that crackles are uncommon on chest examination. Other symptoms and findings may include parotid gland enlargement, hepatosplenomegaly, and lymphadenopathy.
Figure 9–7. Skin involvement in sarcoidosis (lupus pernio), here involving the nasal rim. (From Richard P. Usatine, MD; reproduced with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)
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.
Radiographic findings are variable and include bilateral hilar adenopathy alone (radiographic stage I), hilar adenopathy and parenchymal involvement (radiographic stage II), or parenchymal involvement alone (radiographic stage III). Parenchymal involvement is usually manifested radiographically by diffuse reticular infiltrates, but focal infiltrates, acinar shadows, nodules and, rarely, cavitation may be seen. Pleural effusion is noted in less than 10% of patients.
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.
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.
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 respiratory 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.
Baughman RP et al. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med. 2011 Mar1;183(5):573–81. [PMID: 21037016]
Iannuzzi MC et al. Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics. JAMA. 2011 Jan26;305(4):391–9. [PMID: 21266686]
Morgenthau AS et al. Recent advances in sarcoidosis. Chest. 2011 Jan;139(1):174–82. [PMID: 21208877]
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 immunodeficiency; 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. 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.
The course of the disease varies. Some patients experience spontaneous remission; others develop progressive respiratory insufficiency. Pulmonary infection with Nocardia or fungi may occur. Therapy for alveolar proteinosis consists of periodic whole lung lavage.
Borie R et al. Pulmonary alveolar proteinosis. Eur Respir Rev. 2011 Jun;20(120):98–107. [PMID: 21632797]
Patel SM et al. Pulmonary alveolar proteinosis. Can Respir J. 2012 Jul–Aug;19(4):243–5. [PMID: 22891182]
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 allergic bronchopulmonary mycosis, 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. If an extrinsic cause is identified, therapy consists of removal of the offending drug or treatment of the underlying parasitic infection.
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, 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.
Cottin V et al. Eosinophilic lung diseases. Immunol Allergy Clin North Am. 2012 Nov;32(4):557–86. [PMID: 23102066]
Rose DM et al. Primary eosinophilic lung diseases. Allergy Asthma Proc. 2013 Jan–Feb;34(1):19–25. [PMID: 23406932]
DISORDERS OF THE PULMONARY CIRCULATION
PULMONARY VENOUS THROMBOEMBOLISM
ESSENTIALS OF DIAGNOSIS
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 Po2 difference.
Elevated rapid D-dimer and characteristic defects on CT arteriogram of the chest, ventilation-perfusion lung scan, or pulmonary angiogram.
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 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; prothrombin gene mutation; hyperhomocysteinemia 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.
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 9–18).
Table 9–18. Frequency of specific symptoms and signs in patients at risk for pulmonary thromboembolism.
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’ 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).
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 (300 and 500 mcg/L), 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 (< 500 mcg/L) using a rapid quantitative 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 B-type 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 mechanical ventilation, prolonged hospitalization, and death.
Figure 9–8. Pulmonary emboli. Pulmonary CT angiogram demonstrating multiple segmental and subsegmental pulmonary emboli (arrows) in the right lung in a patient with a spontaneous upper extremity deep venous thrombosis.
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. 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 (/) 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, 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.
However, 75% of PIOPED I (/) 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 (/) scan. For patients with low-probability (/) 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 (/) scans require further testing to determine the presence of venous thromboembolism.
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. 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 (/) 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%.
Contrast venography remains the reference standard for the diagnosis of DVT. 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.
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 kidney injury, or percutaneous catheter–related injuries; 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.
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 9–19) 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. Most North American centers use a rapid D-dimer and helical CT pulmonary angiography based diagnostic algorithm (Figure 9–9). The standard (/) scan based algorithm (Table 9–20) remains useful in many patients, especially those who are not able to undergo CT pulmonary angiography (eg, those with advanced chronic kidney disease). In the rigorously conducted Christopher Study, the incidence of venous thromboembolism was only 1.3% and fatal PE occurred in just 0.5% of persons monitored for 3 months off anticoagulation therapy after objective, validated tools for clinical assessment, quantitative rapid D-dimer assays and a negative helical CT pulmonary angiography. The incidence of PE following a negative evaluation by these three means is comparable to that seen following negative pulmonary angiography.
Table 9–19. Clinical prediction rule for pulmonary embolism (PE).
Figure 9–9. 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 Jan 11;295(2):172–9.)
Table 9–20. Pulmonary ventilation-perfusion scan based diagnostic algorithm for PE.
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. Discussion of strategies for the prevention of venous thromboembolism can be found in Chapter 14.
Anticoagulation is not definitive therapy but a form of secondary prevention. Heparin binds to and accelerates the ability of antithrombin to inactivate thrombin, factor Xa, and factor IXa. It thus retards additional thrombus formation, allowing endogenous fibrinolytic mechanisms to lyse existing clot. The standard regimen of heparin followed by 6 months of oral warfarin results in an 80–90% reduction in the risk of both recurrent venous thrombosis and death from PE. LMWHs are as effective as unfractionated heparin in the treatment of venous thromboembolism (see Tables 14–15, 14–18, 14–19).
The optimal duration of anticoagulation therapy for venous thromboembolism is unknown. There appears to be a protective benefit to continued anticoagulation in first-episode venous thromboembolism (twice the rate of recurrence in 6 weeks compared with 6 months of therapy) and recurrent disease (eightfold risk of recurrence in 6 months compared with 4 years of therapy). These studies do not distinguish patients with reversible risk factors, such as surgery or transient immobility, from patients who have a nonreversible hypercoagulable state such as factor V Leiden, inhibitor deficiency, antiphospholipid syndrome, or malignancy. An RCT of low-dose warfarin (INR 1.5–2.0) versus no therapy following 6 months of standard therapy in patients with idiopathic DVT was stopped early. The protective benefits of continued anticoagulation include fewer DVTs in addition to a trend toward lower mortality despite more hemorrhage in the warfarin group. Risk reductions were consistent across groups with and without inherited thrombophilia.
For many patients, venous thrombosis is a recurrent disease, and continued therapy results in a lower rate of recurrence at the cost of an increased risk of hemorrhage. Therefore, the appropriate duration of therapy needs to take into consideration the patient’s age, potentially reversible risk factors, likelihood and potential consequences of hemorrhage, and preferences for continued therapy. The current American College of Chest Physician Guidelines recommend 3 months of anticoagulation after a first episode provoked by a surgery or a transient nonsurgical risk factor. Extended therapy (6–12 months) is recommended for unprovoked or recurrrent episode with a low to moderate risk of bleeding. For patients with cancer, extended therapy is recommended regardless of bleeding risk and LMWH is preferred over vitamin K antagonists. It is reasonable to continue therapy for 6 months after a first episode when there is a reversible risk factor, 12 months after a first-episode of idiopathic thrombosis, and 6–12 months to indefinitely in patients with nonreversible risk factors or recurrent disease. D-dimer testing has been suggested to identify those who may benefit from continued anticoagulation after 3 months of therapy but clinical data have not supported its utility in this regard.
The major complication of anticoagulation is hemorrhage. Risk factors for hemorrhage include the intensity of the anticoagulation; duration of therapy; concomitant administration of drugs such as aspirin that interfere with platelet function; and patient characteristics, particularly increased age, previous gastrointestinal hemorrhage, and coexistent chronic kidney disease.
The reported incidence of major hemorrhage following intravenous administration of unfractionated heparin is nil to 7%; that of fatal hemorrhage is nil to 2%. The incidence with LMWHs is not statistically different. There is no information comparing hemorrhage rates at different doses of heparin. The risk of death from another pulmonary embolism during subtherapeutic heparin administration in the first 24–48 hours after diagnosis is significant; it appears to outweigh the risk of short-term supratherapeutic heparin levels. The incidence of hemorrhage during therapy with warfarin is reported to be between 3% and 4% per patient year. The frequency varies with the target INR and is consistently higher when the INR exceeds 4.0. There is no apparent additional antithrombotic benefit in venous thromboembolism with a target INR above 2.0–3.0 (see Chapter 14).
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, (/) 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 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 from acute pulmonary embolism is unclear and is subject to considerable practice variation.
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 so plans must be usually made for their subsequent removal.
In rare critically ill patients for whom thrombolytic therapy is contraindicated or unsuccessful, mechanical or surgical extraction of thrombus may be indicated. Pulmonary embolectomy is an emergency procedure of last resort with a very high mortality rate. It is performed only in a few specialized centers. Several catheter devices to fragment and extract thrombus through a transvenous approach have been reported in small numbers of patients. Comparative outcomes with surgery, thrombolytic therapy, or heparin have not been studied.
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 (see Chapter 14). 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.
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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 heart failure in advanced disease.
Electrocardiographic evidence of right ventricular strain or hypertrophy and right atrial enlargement.
Enlarged central pulmonary arteries on chest radiograph.
Elevated right ventricular systolic pressure on two-dimensional echocardiography with Doppler flow studies.
Pulmonary hypertension is a complex problem characterized by pathologic elevation in pulmonary arterial pressure. Normal pulmonary artery systolic pressure at rest is 15–30 mm Hg, with a mean pressure between 10 mm Hg and 18 mm Hg. The pulmonary circulation is a low pressure, low resistance system due to its large cross-sectional area and it can accommodate significant increase in blood flow during exercise. The primary pathologic mechanism in pulmonary hypertension is an increase in pulmonary vascular resistance that leads to an increase in the pulmonary systolic pressure > 30 mm Hg or the mean pressure > 20 mm Hg.
The World Health Organization currently classifies pulmonary hypertension based on similarities in pathologic mechanisms and includes the following five groups.
Group 1 (pulmonary arterial hypertension secondary to various disorders): This group gathers diseases that localize directly to the pulmonary arteries leading to structural changes, smooth muscle hypertrophy, and endothelial dysfunction. This group includes idiopathic (formerly primary) pulmonary arterial hypertension, heritable pulmonary arterial hypertension, HIV infection, portal hypertension, drugs and toxins, connective tissue disorders, congenital heart disease, schistosomiasis, chronic hemolytic anemia, primary veno-occlusive disease, and pulmonary capillary hemangiomatosis.
Group 2 (pulmonary venous hypertension secondary to left heart disease): Often referred to as pulmonary venous hypertension or “post-capillary” pulmonary hypertension, this group includes left ventricular systolic or diastolic dysfunction and valvular heart disease.
Group 3 (pulmonary hypertension secondary to lung disease or hypoxemia): This group is caused by advanced obstructive and restrictive lung disease including COPD, interstitial lung disease, pulmonary fibrosis, bronchiectasis, as well as other causes of chronic hypoxemia such as sleep-disordered breathing, alveolar hypoventilation syndromes, and high altitude exposure.
Group 4 (pulmonary hypertension secondary to chronic thromboembolism): This group consists of patients with pulmonary hypertension due to thromboembolic occlusion of the proximal and distal pulmonary arteries. (The current classification no longer includes patients with non-thrombotic occlusion such as tumors or foreign objects.)
Group 5 (pulmonary arterial hypertension secondary to hematologic, systemic, metabolic, or miscellaneous causes): These patients have pulmonary hypertension secondary to hematologic disorders (eg, myeloproliferative disorders, splenectomy), systemic disorders (eg, sarcoidosis, vasculitis, pulmonary Langerhans cell histiocytosis, neurofibromatosis type 1), metabolic disorders (eg, glycogen storage disease, Gaucher disease, thyroid disease), and miscellaneous causes (tumor embolization, external compression of the pulmonary vasculature, end-stage renal disease on dialysis).
The clinical severity of pulmonary hypertension is classified according to the New York Heart Association (NYHA) classification system, which was originally developed for heart failure but subsequently modified by the World Health Organization; it is based primarily on symptoms and functional status.
Class I: Pulmonary hypertension without limitation of physical activity. No dyspnea, fatigue, chest pain or near syncope with exertion.
Class II: Pulmonary hypertension resulting in slight limitation of physical activity. No symptoms at rest but ordinary physical activity causes dyspnea, fatigue, chest pain, or near syncope.
Class III: Pulmonary hypertension resulting in marked limitation of physical activity. No symptoms at rest but less than ordinary activity causes dyspnea, fatigue, chest pain, or near syncope.
Class IV: Pulmonary hypertension with inability to perform any physical activity without symptoms. Evidence of right heart failure. Dyspnea and fatigue at rest and worsening of symptoms with any activity.
There are no specific symptoms or signs but patients with pulmonary hypertension typically experience dyspnea with exertion and even, with advanced disease, at rest. Anginal pain, nonproductive cough, malaise, and fatigue may be present. Syncope occurs with exertion when there is insufficient cardiac output or if there is an arrhythmia. Hemoptysis is a rare but life-threatening event in pulmonary hypertension usually caused by the rupture of a pulmonary artery.
Findings on physical examination can include jugular venous distention, accentuated pulmonary valve component of the second heart sound, right-sided third heart sound, tricuspid regurgitation murmur, hepatomegaly, and lower extremity edema. Cyanosis can occur in patients with an open patent foramen ovale and right-to-left shunt due to increased right atrial pressure.
Routine blood work is often normal; any abnormalities noted are usually related to the underlying disease in secondary pulmonary hypertension. On arterial blood gas analysis, patients with idiopathic pulmonary arterial hypertension often have normal Pao2 at rest but show evidence of hyperventilation with a decrease in Paco2. All patients should be screened for HIV and collagen vascular disease.
The ECG is typically normal except in advanced disease where right ventricular hypertrophy (right axis deviation, incomplete right bundle branch block) and right atrial enlargement (peaked P wave in the inferior and right-sided leads) can be noted.
Radiographs and CT scans of the chest are useful in diagnosis. Enlargement of the right and left main pulmonary arteries is common; right ventricular and right atrial enlargement is seen in advanced disease. Chest imaging and pulmonary function testing are also useful in determining the cause of pulmonary hypertension for patients in Group 3 (pulmonary hypertension due to lung disease). On pulmonary function testing, the combination of decreased single-breath diffusing capacity, normal FVC on spirometry, normal TLC on lung volume measurement, and increased wasted ventilation on cardiopulmonary exercise testing is suggestive of pathologically increased pulmonary arterial pressures.
Patients in whom pulmonary hypertension is suspected should undergo echocardiography with Doppler flow. The echocardiogram is useful in the assessment of underlying cardiac disease while Doppler flow can estimate the right ventricular systolic pressure. Right ventricular systolic pressure can be estimated based on tricuspid jet velocity and right atrial pressure. The severity of pulmonary hypertension can also be assessed based on the right ventricular size and function. Right-sided cardiac catheterization remains the gold standard for the diagnosis and quantification of pulmonary hypertension and should be performed prior to initiation of advanced therapies. Estimated pressures on echocardiogram correlate with right heart catheterization measurement but can vary by at least 10 mm Hg in > 50% of cases so should not be used to direct therapy. Cardiac catheterization is particularly helpful in differentiating pulmonary arterial hypertension from pulmonary venous hypertension by assessment of the drop in pressure across the pulmonary circulation, also known as the transpulmonary gradient. Vasodilator challenge is often performed during right heart catheterization and for a significant acute vasodilator response consists of a drop in mean pulmonary pressure of > 10 mm Hg (or 20%) to < 40 mm Hg.
In patients with unexplained pulmonary hypertension who have a history of PE or risk factors for thromboembolic disease, chronic thromboembolic disease (Group 4 pulmonary hypertension) should be excluded prior to diagnosing idiopathic pulmonary hypertension. (/) lung scanning is a very sensitive test that can differentiate chronic thromboembolic pulmonary hypertension from idiopathic pulmonary arterial hypertension. Currently, pulmonary angiography is considered the most definitive diagnostic procedure for defining the distribution and extent of disease in chronic thromboembolic pulmonary hypertension.
Primary therapy refers to treatment directed at the underlying cause of pulmonary hypertension. Currently, there are no primary therapies available targeting the underlying lesion for patients in Group 1 (pulmonary arterial hypertension) but advanced therapies are available directly targeting the pulmonary hypertension itself. The advanced therapy chosen is typically based on patient symptoms and functional status according to the NYHA/WHO classification. Based on observational studies showing improved functional status and possible decreased mortality, first-line therapy consists of oral calcium channel blockers. However, these drugs should only be given to patients with positive acute vasodilator response when tested in the cardiac catheterization laboratory because they may be harmful to nonresponders. Preferred treatments for Group 1 patients in functional class II include oral endothelin receptor antagonists (ambrisentan, bosentan), and phosphodiesterase inhibitors (sildenafil, tadalafil). RCTs using either endothelin receptor antagonists or phosphodiesterase inhibitors have shown improvement in symptoms, 6-minute walk distance, WHO functional status, and hemodynamic measurements. For Group 1 patients in functional classes III and IV or Group 1 patients who are not responsive to previous therapies, prostanoid agents are available. Continuous long-term intravenous epoprostenol infusion improved mortality in a prospective RCT. Limitations to intravenous prostacyclins (epoprostenol, treprostinil) include short medication half-life requiring a reliable continuous infusion, difficulty in titration, and high cost of therapy. Inhaled prostanoids (iloprost, treprostinil) and subcutaneous prostanoids (treprostinil) are available for patients unable to tolerate continuous intravenous infusion. Oral formulation of prostacyclin analogs are in clinical trials.
Treatment of patients with Group 2 pulmonary hypertension (secondary to left heart failure) is discussed in Chapter 10.
Patients with Group 3 pulmonary hypertension (due to lung disease) and hypoxemia at rest or with physical activity should receive supplemental oxygen. In patients with COPD and hypoxemia, administration of supplemental oxygen for ≥ 15 hours per day has been shown to slow the progression of pulmonary hypertension. The main goal is to decrease pulmonary venous pressure by treating heart failure and volume overload.
For patients with Group 1 pulmonary hypertension and Group 4 pulmonary hypertension (due to thromboembolic disease), long-term anticoagulation is recommended and generally accepted, based solely on observational studies suggesting improvement in survival. For Group 4 patients in functional class IV and no response to other advanced therapies, thromboendarterectomy is recommended. Only patients with surgically accessible lesions and acceptable perioperative risk should undergo this procedure.
Lung transplantation is a treatment option for selected patients with pulmonary hypertension when medical therapy is no longer effective. Double-lung transplant is the preferred method although single lung transplant is routinely done as well. In some cases, transplantation of the heart and both lungs is needed.
The prognosis of idiopathic (some Group 1) pulmonary hypertension is poor and is not affected by therapies primarily used to treat symptoms. Conversely, the prognosis for patients with secondary pulmonary hypertension (some Group 1 and Groups 2–5) depends on the underlying disease and its response to treatment. In all cases, right ventricular function is one of the most important prognostic factors. The presence of cor pulmonale carries a poor survival outcome regardless of the underlying cause.
When to Refer
Patients with pulmonary arterial hypertension and symptoms of dyspnea, fatigue, chest pain, or near syncope should be referred to a pulmonologist or cardiologist at a specialized center for expert management.
When to Admit
Hassoun PM et al. Update in pulmonary vascular diseases 2011. Am J Respir Crit Care Med. 2012 Jun;185(11):1177–82. [PMID: 22661524]
Lourenço AP et al. Current pathophysiological concepts and management of pulmonary hypertension. Int J Cardiol. 2012 Mar22;155(3):350–61. [PMID: 21641060]
Granulomatosis with polyangiitis 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 20).
Allergic angiitis and granulomatosis (Churg-Strauss syndrome) is an idiopathic multisystem vasculitis of small and medium-sized arteries that occurs in patients with asthma. The skin and lungs are most often involved, but other organs, including the paranasal sinuses, the heart, gastrointestinal tract, liver, and peripheral nerves, may also be affected. Peripheral eosinophilia > 1500 cells/mcL (> 1.5 × 109/L) or > 10% of peripheral WBCs is the rule. Abnormalities on chest radiographs range from transient opacities to multiple nodules. This illness may be part of a spectrum that includes polyarteritis nodosa. The diagnosis requires demonstration of histologic features including fibrinoid necrotizing epithelioid and eosinophilic granulomas.
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 granulomatosis with polyangiitis, 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 orally per day initially, with dosage adjustments to avoid neutropenia) is given 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 granulomatosis with polyangiitis. The addition of trimethoprim-sulfamethoxazole (one double-strength tablet by mouth twice daily) to standard therapy may help prevent relapses.
Gibelin A et al. Epidemiology and etiology of wegener granulomatosis, microscopic polyangiitis, churg-strauss syndrome and goodpasture syndrome: vasculitides with frequent lung involvement. Semin Respir Crit Care Med. 2011 Jun;32(3): 264–73. [PMID: 21674413]
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 single-breath diffusing capacity for carbon monoxide (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, granulomatosis with polyangiitis, 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 detected by immunofluorescence in glomeruli or alveoli 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 orally per day) and plasmapheresis have yielded excellent results.
Idiopathic pulmonary hemosiderosis 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.
de Prost N et al. Diffuse alveolar hemorrhage in immunocompetent patients: etiologies and prognosis revisited. Respir Med. 2012 Jul;106(7):1021–32. [PMID: 22541718]
Newsome BR et al. Diffuse alveolar hemorrhage. South Med J. 2011 Apr;104(4):269–74. [PMID: 21606695]
ENVIRONMENTAL & OCCUPATIONAL LUNG DISORDERS
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 may exceed those attributed to the burns themselves. The death rate of patients with both severe burns and smoke inhalation exceeds 50%.
All patients in whom significant smoke inhalation is suspected must be assessed for three consequences of smoke inhalation: impaired tissue oxygenation, thermal injury to the upper airway, and injury to the lower airways and lung parenchyma. Impaired tissue oxygenation may result from inhalation of a hypoxemia gas mixture, carbon monoxide or cyanide, or from alterations in (/) matching, and is an immediate threat to life. Immediate treatment with 100% oxygen is essential. The management of patients with carbon monoxide and cyanide poisoning is discussed in Chapter 38. The clinician must recognize that patients with carbon monoxide poisoning display a normal partial pressure of oxygen in arterial blood (Pao2) but have a low measured (ie, not oximetric) hemoglobin saturation (Sao2). Treatment with 100% oxygen 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 super-heated gases. Complications including mucosal edema, upper airway obstruction, and impaired ability to clear oral secretions usually become evident by 18–24 hours and produce inspiratory stridor. Respiratory failure occurs in severe cases. Early management (see Chapter 37) 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 critical 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. 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.
Injury to the lower airways and lung parenchyma 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 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.
Albright JM et al. The acute pulmonary inflammatory response to the graded severity of smoke inhalation injury. Crit Care Med. 2012 Apr;40(4):1113–21. [PMID: 22067627]
PULMONARY ASPIRATION SYNDROMES
Aspiration of material into the tracheobronchial tree results from various disorders that impair normal deglutition, especially disturbances of consciousness and esophageal dysfunction.
Acute aspiration of gastric contents may be catastrophic. The pulmonary response depends on the characteristics and amount of 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 may be audible at the bases of the lungs. Hypoxemia may be noted immediately after aspiration occurs. Radiographic abnormalities, consisting of patchy alveolar opacities 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 infection.
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 prophylactic antibiotics or corticosteroids after gastric aspiration. Secondary pulmonary infection, which occurs in about one-fourth of patients, typically appears 2–3 days after aspiration. Management of infection depends on the observed flora of the tracheobronchial tree. Hypotension secondary to alveolar capillary membrane injury and intravascular volume depletion is common and is managed with the judicious administration of intravenous fluids.
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 or caffeine, and use of theophylline are known to relax the lower esophageal sphincter. Pulmonary disorders linked to gastroesophageal reflux and chronic aspiration include asthma, chronic cough, bronchiectasis, and pulmonary fibrosis. Even in the absence of aspiration, acid in the esophagus may trigger bronchospasm or bronchial hyperreactivity through reflex mechanisms.
The diagnosis and management of gastroesophageal reflux and chronic aspiration is challenging. A discussion of strategies for the evaluation, prevention, and management of extraesophageal reflux manifestations can be found in Chapter 15.
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 atelectasis, postobstructive hyperinflation, both acute and recurrent pneumonia, bronchiectasis, and lung abscess. 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.
Most patients suffer no serious sequelae from aspiration of inert material. However, it may cause asphyxia if the amount aspirated is massive and if cough is impaired, in which case immediate tracheobronchial suctioning is necessary.
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 of ingested products 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 usually occurs in elderly patients with impaired swallowing. Patchy opacities in dependent lung zones and lipid-laden macrophages in expectorated sputum are characteristic findings.
Kwong JC et al. New aspirations: the debate on aspiration pneumonia treatment guidelines. Med J Aust. 2011 Oct3; 195(7): 380–1. [PMID: 21978335]
Raghavendran K et al. Aspiration-induced lung injury. Crit Care Med. 2011 Apr;39(4):818–26. [PMID: 21263315]
OCCUPATIONAL PULMONARY DISEASES
Many acute and chronic pulmonary diseases are directly related to inhalation of noxious substances encountered in the workplace. Disorders that are linked to occupational exposures may be classified as follows: (1) pneumoconioses, (2) hypersensitivity pneumonitis, (3) obstructive airway disorders, (4) pulmonary edema, (5) lung cancer, (6) pleural diseases, and (7) miscellaneous disorders.
Pneumoconioses are chronic fibrotic lung diseases caused by the inhalation of inorganic dusts. Pneumoconioses due to inhalation of inert dusts may be asymptomatic disorders with diffuse nodular opacities on chest radiograph or may be severe, symptomatic, life-shortening disorders. Clinically important pneumoconioses include coal worker’s pneumoconiosis, silicosis, and asbestosis (Table 9–21). Treatment for each is supportive.
Table 9–21. Selected pneumoconioses.
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, that 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.
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. 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.
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 first 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. 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.
Centers for Disease Control and Prevention (CDC). Pneumoconiosis and advanced occupational lung disease among surface coal miners—16 states, 2010–2011. MMWR Morb Mortal Wkly Rep. 2012 Jun15;61(23):431–4. [PMID: 22695382]
Lazarus A et al. Asbestos-related pleuropulmonary diseases: benign and malignant. Postgrad Med. 2012 May;124(3): 116–30. [PMID: 22691906]
Leung CC et al. Silicosis. Lancet. 2012 May26;379(9830): 2008–18. [PMID: 22534002]
Hypersensitivity pneumonitis (also called extrinsic allergic alveolitis) is a nonatopic, nonasthmatic inflammatory pulmonary disease. It is manifested mainly as an occupational disease (Table 9–22), in which exposure to inhaled organic antigens leads to an acute illness. Prompt diagnosis is essential since symptoms are usually reversible if the offending antigen is removed from the patient’s environment early in the course of illness. Continued exposure may lead to progressive disease. The histopathology of acute hypersensitivity pneumonitis is characterized by interstitial infiltrates of lymphocytes and plasma cells, with noncaseating granulomas in the interstitium and air spaces.
Table 9–22. Selected causes of hypersensitivity pneumonitis.
The symptoms are characterized by sudden onset of malaise, chills, fever, cough, dyspnea, and nausea 4–8 hours after exposure to the offending antigen. 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. 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. Pulmonary function studies reveal restrictive dysfunction and reduced diffusing capacity.
A subacute hypersensitivity pneumonitis syndrome (15% of cases) is characterized by the insidious onset of chronic cough and slowly progressive dyspnea, anorexia, and weight loss. Chronic exposure leads to progressive respiratory insufficiency and the appearance of pulmonary fibrosis on chest imaging. Surgical lung biopsy may be necessary for the diagnosis of subacute and chronic hypersensitivity pneumonitis. Even with surgical lung biopsy, however, chronic hypersensitivity pneumonitis may be difficult to diagnose because histopathologic patterns overlap with several idiopathic interstitial pneumonias.
Treatment of acute hypersensitivity pneumonitis consists of identification of the offending agent and avoidance of further exposure. In severe acute or protracted cases, oral corticosteroids (prednisone, 0.5 mg/kg daily as a single morning dose for 2 weeks, tapered to nil over 4–6 weeks) may be given. Change in occupation is often unavoidable.
Lacasse Y et al. Recent advances in hypersensitivity pneumonitis. Chest. 2012 Jul;142(1):208–17. [PMID: 22796841]
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 is chronic bronchitis found in coal miners and others exposed to cotton, flax, or hemp dust. Chronic disability from industrial bronchitis is infrequent.
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 from inhalation of irritant gases is discussed in the section on smoke inhalation. 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. Inhalation of the compound diacetyl, a constituent of butter-flavoring, has been linked to the development of bronchiolitis obliterans among microwave popcorn production workers.
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.
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.
Occupational agents are also responsible for other pulmonary disorders. These include exposure to beryllium, which now occurs in machining and handling of beryllium products and alloys. Beryllium miners are not at risk for berylliosis and beryllium is no longer used in fluorescent lamp production, which was a source of exposure before 1950. Berylliosis, an acute or chronic pulmonary disorder, occurs from absorption of beryllium through the lungs or skin and wide dissemination 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.
Cartier A et al. Clinical assessment of occupational asthma and its differential diagnosis. Immunol Allergy Clin North Am. 2011 Nov;31(4):717–28. [PMID: 21978853]
Henneberger PK et al; ATS Ad Hoc Committee on Work-Exacerbated Asthma. An official American Thoracic Society statement: work-exacerbated asthma. Am J Respir Crit Care Med. 2011 Aug1;184(3):368–78. [PMID: 21804122]
Malo JL et al. Definitions and classification of work-related asthma. Immunol Allergy Clin North Am. 2011 Nov;31(4): 645–62. [PMID: 21978849]
Myers R. Asbestos-related pleural disease. Curr Opin Pulm Med. 2012 Jul;18(4):377–81. [PMID: 22617814]
Smith AM. The epidemiology of work-related asthma. Immunol Allergy Clin North Am. 2011 Nov;31(4):663–75. [PMID: 21978850]
MEDICATION-INDUCED LUNG DISEASE
Typical patterns of pulmonary response to medications implicated in medication-induced respiratory disease are summarized in Table 9–23. Pulmonary injury due to medications 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 9–23. Pulmonary manifestations of selected medication toxicities.
Precise diagnosis of medication-induced pulmonary disease is often difficult because results of routine laboratory studies are not helpful and radiographic findings are not specific. A high index of suspicion and a thorough history of medication usage are critical to establishing the diagnosis of medication-induced lung disease. The clinical response to cessation of the suspected offending agent is also helpful. Acute episodes of medication-induced pulmonary disease usually disappear 24–48 hours after the medication has been discontinued, but chronic syndromes may take longer to resolve. Challenge tests to confirm the diagnosis are risky and rarely performed.
Treatment of medication-induced lung disease consists of discontinuing the offending agent immediately and managing the pulmonary symptoms appropriately.
Inhalation of crack cocaine may cause a spectrum of acute pulmonary syndromes, including pulmonary infiltration with eosinophilia, pneumothorax and pneumomediastinum, bronchiolitis obliterans, and acute respiratory failure associated with diffuse alveolar damage and alveolar hemorrhage. Corticosteroids have been used with variable success to treat alveolar hemorrhage.
Piciucchi S et al. Prospective evaluation of drug-induced lung toxicity with high-resolution CT and transbronchial biopsy. Radiol Med. 2011 Mar;116(2):246–63. [PMID: 21311994]
Schwaiblmair M et al. Cytochrome P450 polymorphisms and drug-induced interstitial lung disease. Expert Opin Drug Metab Toxicol. 2011 Dec;7(12):1547–60. [PMID: 22070131]
RADIATION LUNG INJURY
The lung is an exquisitely radiosensitive organ that can be damaged by external beam radiation therapy. The degree of pulmonary injury is determined by the volume of lung irradiated, the dose and rate of exposure, and potentiating factors (eg, concurrent chemotherapy, previous radiation therapy in the same area, and simultaneous withdrawal of corticosteroid therapy). Symptomatic radiation lung injury occurs in about 10% of patients treated for carcinoma of the breast, 5–15% of patients treated for carcinoma of the lung, and 5–35% of patients treated for lymphoma. Two phases of the pulmonary response to radiation are apparent: an acute phase (radiation pneumonitis) and a chronic phase (radiation fibrosis).
Acute radiation pneumonitis usually occurs 2–3 months (range 1–6 months) after completion of radiotherapy and is characterized by insidious onset of dyspnea, intractable dry cough, chest fullness or pain, weakness, and fever. Late radiation pneumonitis may develop 6–12 months after completion of radiation. The pathogenesis of acute radiation pneumonitis is unknown, but there is speculation that hypersensitivity mechanisms are involved. The dominant histopathologic findings are a lymphocytic interstitial pneumonitis progressing to an exudative alveolitis. Inspiratory crackles may be heard in the involved area. In severe disease, respiratory distress and cyanosis occur that are characteristic of ARDS. An increased white blood cell count and elevated sedimentation rate are common. Pulmonary function studies reveal reduced lung volumes, reduced lung compliance, hypoxemia, reduced diffusing capacity, and reduced maximum voluntary ventilation. Chest radiography, which correlates poorly with the presence of symptoms, usually demonstrates alveolar or nodular opacities limited to the irradiated area. Air bronchograms are often observed. Sharp borders of an opacity may help distinguish radiation pneumonitis from other conditions such as infectious pneumonia, lymphangitic spread of carcinoma, and recurrent tumor; however, the opacity may extend beyond the radiation field. No specific therapy is proved to be effective in radiation pneumonitis, but prednisone (1 mg/kg/d orally) is commonly given immediately for about 1 week. The dose is then reduced and maintained at 20–40 mg/d for several weeks, then slowly tapered. Radiation pneumonitis may improve in 2–3 weeks following onset of symptoms as the exudative phase resolves. Acute respiratory failure, if present, is treated supportively. Death from ARDS is unusual in radiation pneumonitis.
Radiation fibrosis may occur with or without antecedent radiation pneumonitis. Cor pulmonale and chronic respiratory failure are rare. Radiographic findings include obliteration of normal lung markings, dense interstitial and pleural fibrosis, reduced lung volumes, tenting of the diaphragm, and sharp delineation of the irradiated area. No specific therapy is proven effective, and corticosteroids have no value. Pulmonary fibrosis may develop after an intervening period (6–12 months) of well-being in patients who experience radiation pneumonitis. Pulmonary radiation fibrosis occurs in most patients who receive a full course of radiation therapy for cancer of the lung or breast. Most patients are asymptomatic, although slowly progressive dyspnea may occur.
Other complications of radiation therapy directed to the thorax include pericardial effusion, constrictive pericarditis, tracheoesophageal fistula, esophageal candidiasis, radiation dermatitis, and rib fractures. Small pleural effusions, radiation pneumonitis outside the irradiated area, spontaneous pneumothorax, and complete obstruction of central airways are unusual occurrences.
Pain due to acute pleural inflammation is caused by irritation of the parietal pleura. Such pain is localized, sharp, and fleeting; it is made worse by coughing, sneezing, deep breathing, or movement. When the central portion of the diaphragmatic parietal pleura is irritated, pain may be referred to the ipsilateral shoulder. There are numerous causes of pleuritis. The setting in which pleuritic pain develops helps narrow the differential diagnosis. In young, otherwise healthy individuals, pleuritis is usually caused by viral respiratory infections or pneumonia. The presence of pleural effusion, pleural thickening, or air in the pleural space requires further diagnostic and therapeutic measures. Simple rib fracture may cause severe pleurisy.
Treatment of pleuritis consists of treating the underlying disease. Analgesics and anti-inflammatory drugs (eg, indomethacin, 25 mg orally two or three times daily) are often helpful for pain relief. Codeine (30–60 mg orally every 8 hours) or other opioids may be used to control cough associated with pleuritic chest pain if retention of airway secretions is not a likely complication. Intercostal nerve blocks are sometimes helpful but the benefit is usually transient.
ESSENTIALS OF DIAGNOSIS
May be asymptomatic; chest pain frequently seen in the setting of pleuritis, trauma, or infection; dyspnea is common with large effusions.
Dullness to percussion and decreased breath sounds over the effusion.
Radiographic evidence of pleural effusion.
Diagnostic findings on thoracentesis.
There is constant movement of fluid from parietal pleural capillaries into the pleural space at a rate of 0.01 mL/kg body weight/h. Absorption of pleural fluid occurs through parietal pleural lymphatics. The resultant homeostasis leaves 5–15 mL of fluid in the normal pleural space. A pleural effusion is an abnormal accumulation of fluid in the pleural space. Pleural effusions may be classified by differential diagnosis (Table 9–24) or by underlying pathophysiology. Five pathophysiologic processes account for most pleural effusions: increased production of fluid in the setting of normal capillaries due to increased hydrostatic or decreased oncotic pressures (transudates); increased production of fluid due to abnormal capillary permeability (exudates); decreased lymphatic clearance of fluid from the pleural space (exudates); infection in the pleural space (empyema); and bleeding into the pleural space (hemothorax). Parapneumonic pleural effusions are exudates that accompany bacterial pneumonias.
Table 9–24. Causes of pleural fluid transudates and exudates.
Diagnostic thoracentesis should be performed whenever there is a new pleural effusion and no clinically apparent cause. Observation is appropriate in some situations (eg, symmetric bilateral pleural effusions in the setting of heart failure), but an atypical presentation or failure of an effusion to resolve as expected warrants thoracentesis. Sampling allows visualization of the fluid in addition to chemical and microbiologic analyses to identify the underlying pathophysiologic process.
Patients with pleural effusions most often report dyspnea, cough, or respirophasic chest pain. Symptoms are more common in patients with existing cardiopulmonary disease. Small pleural effusions are less likely to be symptomatic than larger effusions. Physical findings are usually absent in small effusions. Larger effusions may present with dullness to percussion and diminished or absent breath sounds over the effusion. Compressive atelectasis may cause bronchial breath sounds and egophony just above the effusion. A massive effusion with increased intrapleural pressure may cause contralateral shift of the trachea and bulging of the intercostal spaces. A pleural friction rub indicates infarction or pleuritis.
The gross appearance of pleural fluid helps identify several types of pleural effusion. Grossly purulent fluid signifies empyema. Milky white pleural fluid should be centrifuged. A clear supernatant above a pellet of white cells indicates empyema, whereas a persistently turbid supernatant suggests a chylous effusion; analysis of this supernatant reveals chylomicrons and a high triglyceride level (> 100 mg/dL [1 mmol/L]), often from disruption of the thoracic duct. Hemorrhagic pleural effusion is a mixture of blood and pleural fluid. Ten thousand red cells per milliliter create blood-tinged pleural fluid; 100,000 red cells/mL create grossly bloody pleural fluid. Hemothorax is the presence of gross blood in the pleural space, usually following chest trauma or instrumentation. It is defined as a ratio of pleural fluid hematocrit to peripheral blood hematocrit > 0.5.
Pleural fluid samples should be sent for measurement of protein, glucose, and LD in addition to total and differential white blood cell counts. Chemistry determinations are used to classify effusions as transudates or exudates. This classification is important because the differential diagnosis and subsequent evaluation for each entity is vastly different (Table 9–24). A pleural exudate is an effusion that has one or more of the following laboratory features: (1) ratio of pleural fluid protein to serum protein > 0.5; (2) ratio of pleural fluid LD to serum LD > 0.6; (3) pleural fluid LD greater than two-thirds the upper limit of normal serum LD. Pleural transudates occur in the setting of normal capillary integrity and demonstrate none of the laboratory features of exudates. A transudate suggests the absence of local pleural disease; characteristic laboratory findings include a glucose equal to serum glucose, pH between 7.40 and 7.55, and fewer than 1.0 × 103 white blood cells/mcL (1.0 × 109/L) with a predominance of mononuclear cells.
Heart failure accounts for 90% of transudates. Bacterial pneumonia and cancer are the most common causes of exudative effusion. Other causes of exudates with characteristic laboratory findings are summarized in Table 9–25.
Table 9–25. Characteristics of important exudative pleural effusions.
Pleural fluid pH is useful in the assessment of parapneumonic effusions. A pH below 7.30 suggests the need for drainage of the pleural space. An elevated amylase level in pleural fluid suggests pancreatitis, pancreatic pseudocyst, adenocarcinoma of the lung or pancreas, or esophageal rupture.
Suspected tuberculous pleural effusion should be evaluated by thoracentesis with culture along with pleural biopsy, since pleural fluid culture positivity for M tuberculosis is low (< 23–58% of cases). Closed pleural biopsy reveals granulomatous inflammation in approximately 60% of patients, and culture of three pleural biopsy specimens combined with histologic examination of a pleural biopsy for granulomas yields a diagnosis in up to 90% of patients. Tests for pleural fluid adenosine deaminase (approximately 90% sensitivity and specificity for pleural tuberculosis at levels >70 units/L) and interferon-gamma (89% sensitivity, 97% specificity in a meta-analysis) can be extremely helpful diagnostic aids, particularly in making decisions to pursue invasive testing in complex patients.
Between 40% and 80% of exudative pleural effusions are malignant, while over 90% of malignant pleural effusions are exudative. Almost any form of cancer may cause effusions, but the most common causes are lung cancer (one-third of cases) and breast cancer. In 5–10% of malignant pleural effusions, no primary tumor is identified. The term “paramalignant” pleural effusion refers to an effusion in a patient with cancer when repeated attempts to identify tumor cells in the pleura or pleural fluid are nondiagnostic but when there is a presumptive relation to the underlying malignancy. For example, superior vena cava syndrome with elevated systemic venous pressures causing a transudative effusion would be “paramalignant.”
Pleural fluid specimens should be sent for cytologic examination in all cases of exudative effusions in patients suspected of harboring an underlying malignancy. The diagnostic yield depends on the nature and extent of the underlying malignancy. Sensitivity is between 50% and 65%. A negative cytologic examination in a patient with a high prior probability of malignancy should be followed by one repeat thoracentesis. If that examination is negative, thoracoscopy is preferred to closed pleural biopsy. The sensitivity of thoracoscopy is 92–96%.
The lung is less dense than water and floats on pleural fluid that accumulates in dependent regions. Subpulmonary fluid may appear as lateral displacement of the apex of the diaphragm with an abrupt slope to the costophrenic sulcus or a greater than 2 cm separation between the gastric air bubble and the lung. On a standard upright chest radiograph, approximately 75–100 mL of pleural fluid must accumulate in the posterior costophrenic sulcus to be visible on the lateral view, and 175–200 mL must be present in the lateral costophrenic sulcus to be visible on the frontal view. Chest CT scans may identify as little as 10 mL of fluid. At least 1 cm of fluid on the decubitus view is necessary to permit blind thoracentesis. Ultrasonography is useful to guide thoracentesis in the setting of smaller effusions.
Pleural fluid may become trapped (loculated) by pleural adhesions, thereby forming unusual collections along the lateral chest wall or within lung fissures. Round or oval fluid collections in fissures that resemble intraparenchymal masses are called pseudotumors. Massive pleural effusion causing opacification of an entire hemithorax is most commonly caused by cancer but may be seen in tuberculosis and other diseases.
Transudative pleural effusions characteristically occur in the absence of pleural disease. Therefore, treatment is directed at the underlying condition. Therapeutic thoracentesis for severe dyspnea typically offers only transient benefit. Pleurodesis and tube thoracostomy are rarely indicated.
Chemotherapy or radiation therapy or both offer temporary control in some malignant effusions but are generally ineffective in lung cancer in the pleural space except for small cell lung cancer. Asymptomatic malignant effusions usually do not require specific treatment. Symptomatic patients should have a therapeutic thoracentesis. If symptoms are relieved but the effusion returns, the options are serial thoracenteses, attempted pleurodesis, or placement of an indwelling drainage catheter that the patient can access at home. Choice among these options depends on the rate of reaccumulation in addition to the functional status, tolerance for discomfort, and life expectancy of the patient. Consultation with a thoracic specialist is advised. (See Chapter 39.)
Parapneumonic pleural effusions are divided into three categories: simple or uncomplicated, complicated, and empyema. Uncomplicated parapneumonic effusions are free-flowing sterile exudates of modest size that resolve quickly with antibiotic treatment of pneumonia. They do not need drainage. Empyema is gross infection of the pleural space indicated by positive Gram stain or culture. Empyema should always be drained by tube thoracostomy to facilitate clearance of infection and to reduce the probability of fibrous encasement of the lung, causing permanent pulmonary impairment.
Complicated parapneumonic effusions present the most difficult management decisions. They tend to be larger than simple parapneumonic effusions and to show more evidence of inflammatory stimuli such as low glucose level, low pH, or evidence of loculation. Inflammation probably reflects ongoing bacterial invasion of the pleural space despite rare positive bacterial cultures. The morbidity associated with complicated effusions is due to their tendency to form a fibropurulent pleural “peel,” trapping otherwise functional lung and leading to permanent impairment. Tube thoracostomy is indicated when pleural fluid glucose is < 60 mg/dL (< 3.3 mmol/L) or the pH is < 7.2. These thresholds have not been prospectively validated and should not be interpreted strictly. The clinician should consider drainage of a complicated effusion if the pleural fluid pH is between 7.2 and 7.3 or the LD is > 1000 units/L (> 20 mckat/L). Pleural fluid cell count and protein have little diagnostic value in this setting.
Tube thoracostomy drainage of empyema or complicated parapneumonic effusions is frequently complicated by loculation that prevents adequate drainage. Intrapleural instillation of fibrinolytic agents has not been shown in controlled trials to improve drainage. The combination of intrapleural tissue plasminogen activator and deoxyribonuclease (DNase), an enzyme that catalyses extracellular DNA and degrades biofilm formation within the pleural cavity, has been found to improve clinical outcome (increased drainage, decrease length of stay and surgical referral) compared with placebo or either agent alone.
A small-volume hemothorax that is stable or improving on chest radiographs may be managed by close observation. In all other cases, hemothorax is treated by immediate insertion of a large-bore thoracostomy tube to: (1) drain existing blood and clot, (2) quantify the amount of bleeding, (3) reduce the risk of fibrothorax, and (4) permit apposition of the pleural surfaces in an attempt to reduce hemorrhage. Thoracotomy may be indicated to control hemorrhage, remove clot, and treat complications such as bronchopleural fistula formation.
Light RW. Pleural effusions. Med Clin North Am. 2011 Nov;95(6):1055–70. [PMID: 22032427]
Rahman NM et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011 Aug11;365(6):518–26. [PMID: 21830966]
Rodriguez-Panadero F et al. Management of malignant pleural effusions. Curr Opin Pulm Med. 2011 Jul;17(4):269–73. [PMID: 21519264]
Ryu JH et al. Update on uncommon pleural effusions. Respirology. 2011 Feb;16(2):238–43. [PMID: 21073678]
ESSENTIALS OF DIAGNOSIS
Acute onset of unilateral chest pain and dyspnea.
Minimal physical findings in mild cases; unilateral chest expansion, decreased tactile fremitus, hyperresonance, diminished breath sounds, mediastinal shift, cyanosis and hypotension in tension pneumothorax.
Presence of pleural air on chest radiograph.
Pneumothorax, or accumulation of air in the pleural space, is classified as spontaneous (primary or secondary) or traumatic. Primary spontaneous pneumothorax occurs in the absence of an underlying lung disease, whereas secondary spontaneous pneumothorax is a complication of preexisting pulmonary disease. Traumatic pneumothorax results from penetrating or blunt trauma. Iatrogenic pneumothorax may follow procedures such as thoracentesis, pleural biopsy, subclavian or internal jugular vein catheter placement, percutaneous lung biopsy, bronchoscopy with transbronchial biopsy, and positive-pressure mechanical ventilation. Tension pneumothorax usually occurs in the setting of penetrating trauma, lung infection, cardiopulmonary resuscitation, or positive-pressure mechanical ventilation. In tension pneumothorax, the pressure of air in the pleural space exceeds ambient pressure throughout the respiratory cycle. A check-valve mechanism allows air to enter the pleural space on inspiration and prevents egress of air on expiration.
Primary pneumothorax affects mainly tall, thin boys and men between the ages of 10 and 30 years. It is thought to occur from rupture of subpleural apical blebs in response to high negative intrapleural pressures. Family history and cigarette smoking may also be important factors.
Secondary pneumothorax occurs as a complication of COPD, asthma, cystic fibrosis, tuberculosis, Pneumocystis pneumonia, menstruation (catamenial pneumothorax), and a wide variety of interstitial lung diseases including sarcoidosis, lymphangioleiomyomatosis, Langerhans cell histiocytosis, and tuberous sclerosis. Aerosolized pentamidine and a prior history of Pneumocystis pneumonia are considered risk factors for the development of pneumothorax. One-half of patients with pneumothorax in the setting of recurrent (but not primary) Pneumocystis pneumonia will develop pneumothorax on the contralateral side. The mortality rate of pneumothorax in Pneumocystis pneumonia is high.
Chest pain ranging from minimal to severe on the affected side and dyspnea occur in nearly all patients. Symptoms usually begin during rest and usually resolve within 24 hours even if the pneumothorax persists. Alternatively, pneumothorax may present with life-threatening respiratory failure if underlying COPD or asthma is present.
If pneumothorax is small (< 15% of a hemithorax), physical findings, other than mild tachycardia, are normal. If pneumothorax is large, diminished breath sounds, decreased tactile fremitus, and decreased movement of the chest are often noted. Tension pneumothorax should be suspected in the presence of marked tachycardia, hypotension, and mediastinal or tracheal shift.
Arterial blood gas analysis is often unnecessary but reveals hypoxemia and acute respiratory alkalosis in most patients. Left-sided primary pneumothorax may produce QRS axis and precordial T wave changes on the ECG that may be misinterpreted as acute myocardial infarction.
Demonstration of a visceral pleural line on chest radiograph is diagnostic and may only be seen on an expiratory film. A few patients have secondary pleural effusion that demonstrates a characteristic air-fluid level on chest radiography. In supine patients, pneumothorax on a conventional chest radiograph may appear as an abnormally radiolucent costophrenic sulcus (the “deep sulcus” sign). In patients with tension pneumothorax, chest radiographs show a large amount of air in the affected hemithorax and contralateral shift of the mediastinum.
If the patient is a young, tall, thin, cigarette-smoking man, the diagnosis of primary spontaneous pneumothorax is usually obvious and can be confirmed by chest radiograph. In secondary pneumothorax, it is sometimes difficult to distinguish loculated pneumothorax from an emphysematous bleb. Occasionally, pneumothorax may mimic myocardial infarction, pulmonary embolism, or pneumonia.
Tension pneumothorax may be life-threatening. Pneumomediastinum and subcutaneous emphysema may occur as complications of spontaneous pneumothorax. If pneumomediastinum is detected, rupture of the esophagus or a bronchus should be considered.
Treatment depends on the severity of pneumothorax and the nature of the underlying disease. In a reliable patient with a small (< 15% of a hemithorax), stable spontaneous primary pneumothorax, observation alone may be appropriate. Many small pneumothoraces resolve spontaneously as air is absorbed from the pleural space; supplemental oxygen therapy may increase the rate of reabsorption. Simple aspiration drainage of pleural air with a small-bore catheter (eg, 16 gauge angiocatheter or larger drainage catheter) can be performed for spontaneous primary pneumothoraces that are large or progressive. Placement of a small-bore chest tube (7F to 14F) attached to a one-way Heimlich valve provides protection against development of tension pneumothorax and may permit observation from home. The patient should be treated symptomatically for cough and chest pain, and followed with serial chest radiographs every 24 hours.
Patients with secondary pneumothorax, large pneumothorax, tension pneumothorax, or severe symptoms or those who have a pneumothorax on mechanical ventilation should undergo chest tube placement (tube thoracostomy). The chest tube is placed under water-seal drainage, and suction is applied until the lung expands. The chest tube can be removed after the air leak subsides.
All patients who smoke should be advised to discontinue smoking and warned that the risk of recurrence is 50% if cigarette smoking is continued. Future exposure to high altitudes, flying in unpressurized aircraft, and scuba diving should be avoided.
Indications for thoracoscopy or open thoracotomy include recurrences of spontaneous pneumothorax, any occurrence of bilateral pneumothorax, and failure of tube thoracostomy for the first episode (failure of lung to reexpand or persistent air leak). Surgery permits resection of blebs responsible for the pneumothorax and pleurodesis by mechanical abrasion and insufflation of talc.
Management of pneumothorax in patients with Pneumocystis pneumonia is challenging because of a tendency toward recurrence, and there is no consensus on the best approach. Use of a small chest tube attached to a Heimlich valve has been proposed to allow the patient to leave the hospital. Some clinicians favor its insertion early in the course.
An average of 30% of patients with spontaneous pneumothorax experience recurrence of the disorder after either observation or tube thoracostomy for the first episode. Recurrence after surgical therapy is less frequent. Following successful therapy, there are no long-term complications.
Grundy S et al. Primary spontaneous pneumothorax: a diffuse disease of the pleura. Respiration. 2012;83(3):185–9. [PMID: 22343477]
DISORDERS OF CONTROL OF VENTILATION
The principal influences on ventilatory control are arterial Pco2, pH, Po2, and brainstem tissue pH. These variables are monitored by peripheral and central chemoreceptors. Under normal conditions, the ventilatory control system maintains arterial pH and Pco2 within narrow limits; arterial Po2 is more loosely controlled.
Abnormal control of ventilation can be seen with a variety of conditions ranging from rare disorders such as Ondine curse, neuromuscular disorders, myxedema, starvation, and carotid body resection to more common disorders such as asthma, COPD, obesity, heart failure, and sleep-related breathing disorders. A few of these disorders will be discussed in this section.
Silvestrelli G et al. Ventilatory disorders. Front Neurol Neurosci. 2012;30:90–3. [PMID: 22377872]
OBESITY-HYPOVENTILATION SYNDROME (Pickwickian Syndrome)
In obesity-hypoventilation syndrome, alveolar hypoventilation appears to result from a combination of blunted ventilatory drive and increased mechanical load imposed upon the chest by obesity. Voluntary hyperventilation returns the Pco2 and the Po2 toward normal values, a correction not seen in lung diseases causing chronic respiratory failure such as COPD. Most patients with obesity-hypoventilation syndrome also suffer from obstructive sleep apnea (see below), which must be treated aggressively if identified as a comorbid disorder. Therapy of obesity-hypoventilation syndrome consists mainly of weight loss, which improves hypercapnia and hypoxemia as well as the ventilatory responses to hypoxia and hypercapnia. NPPV is helpful in some patients. Respiratory stimulants may be helpful and include theophylline, acetazolamide, and medroxyprogesterone acetate, 10–20 mg every 8 hours orally. Improvement in hypoxemia, hypercapnia, erythrocytosis, and cor pulmonale are goals of therapy.
Piper AJ et al. Obesity hypoventilation syndrome: mechanisms and management. Am J Respir Crit Care Med. 2011 Feb1;183(3):292–8. [PMID: 21037018]
Hyperventilation is an increase in alveolar ventilation that leads to hypocapnia. It may be caused by a variety of conditions, such as pregnancy, hypoxemia, obstructive and infiltrative lung diseases, sepsis, hepatic dysfunction, fever, and pain. The term “central neurogenic hyperventilation” denotes a monotonous, sustained pattern of rapid and deep breathing seen in comatose patients with brainstem injury of multiple causes. Functional hyperventilation may be acute or chronic. Acute hyperventilation presents with hyperpnea, paresthesias, carpopedal spasm, tetany, and anxiety. Chronic hyperventilation may present with various nonspecific symptoms, including fatigue, dyspnea, anxiety, palpitations, and dizziness. The diagnosis of chronic hyperventilation syndrome is established if symptoms are reproduced during voluntary hyperventilation. Once organic causes of hyperventilation have been excluded, treatment of acute hyperventilation consists of breathing through pursed lips or through the nose with one nostril pinched, or rebreathing expired gas from a paper bag held over the face in order to decrease respiratory alkalemia and its associated symptoms. Anxiolytic drugs may also be useful.
SLEEP-RELATED BREATHING DISORDERS
Abnormal ventilation during sleep is manifested by apnea (breath cessation for at least 10 seconds) or hypopnea (decrement in airflow with drop in hemoglobin saturation of at least 4%). Episodes of apnea are central if ventilatory effort is absent for the duration of the apneic episode, obstructive if ventilatory effort persists throughout the apneic episode but no airflow occurs because of transient obstruction of the upper airway, and mixed if absent ventilatory effort precedes upper airway obstruction during the apneic episode. Pure central sleep apnea is uncommon; it may be an isolated finding or may occur in patients with primary alveolar hypoventilation or with lesions of the brainstem. Obstructive and mixed sleep apneas are more common and may be associated with life-threatening cardiac arrhythmias, severe hypoxemia during sleep, daytime somnolence, pulmonary hypertension, cor pulmonale, systemic hypertension, and secondary erythrocytosis.
OBSTRUCTIVE SLEEP APNEA
ESSENTIALS OF DIAGNOSIS
Daytime somnolence or fatigue.
A history of loud snoring with witnessed apneic events.
Overnight polysomnography demonstrating apneic episodes with hypoxemia.
Upper airway obstruction during sleep occurs when loss of normal pharyngeal muscle tone allows the pharynx to collapse passively during inspiration. Patients with anatomically narrowed upper airways (eg, micrognathia, macroglossia, obesity, tonsillar hypertrophy) are predisposed to the development of obstructive sleep apnea. Ingestion of alcohol or sedatives before sleeping or nasal obstruction of any type, including the common cold, may precipitate or worsen the condition. Hypothyroidism and cigarette smoking are additional risk factors for obstructive sleep apnea. Before making the diagnosis of obstructive sleep apnea, a drug history should be obtained and a seizure disorder, narcolepsy, and depression should be excluded.
Most patients with obstructive or mixed sleep apnea are obese, middle-aged men. Systemic hypertension is common. Patients may complain of excessive daytime somnolence, morning sluggishness and headaches, daytime fatigue, cognitive impairment, recent weight gain, and impotence. Bed partners usually report loud cyclical snoring, breath cessation, witnessed apneas, restlessness, and thrashing movements of the extremities during sleep. Personality changes, poor judgment, work-related problems, depression, and intellectual deterioration (memory impairment, inability to concentrate) may also be observed.
Physical examination may be normal or may reveal systemic and pulmonary hypertension with cor pulmonale. The patient may appear sleepy or even fall asleep during the evaluation. The oropharynx is frequently found to be narrowed by excessive soft tissue folds, large tonsils, pendulous uvula, or prominent tongue. Nasal obstruction by a deviated nasal septum, poor nasal airflow, and a nasal twang to the speech may be observed. A “bull neck” appearance is common.
Erythrocytosis is common. Thyroid function tests (serum, TSH, FT4) should be obtained to exclude hypothyroidism.
Observation of the sleeping patient may reveal loud snoring interrupted by episodes of increasingly strong ventilatory effort that fail to produce airflow. A loud snort often accompanies the first breath following an apneic episode. Definitive diagnostic evaluation for suspected sleep apnea includes otorhinolaryngologic examination and overnight polysomnography (the monitoring of multiple physiologic factors during sleep). Screening may be performed using home nocturnal pulse oximetry, which when normal has a high negative predictive value in ruling out significant sleep apnea. A completepolysomnography examination includes electroencephalography, electro-oculography, electromyography, ECG, pulse oximetry, and measurement of respiratory effort and airflow. Polysomnography reveals apneic episodes lasting as long as 60 seconds. Oxygen saturation falls, often to very low levels. Bradydysrhythmias, such as sinus bradycardia, sinus arrest, or atrioventricular block, may occur. Tachydysrhythmias, including paroxysmal supraventricular tachycardia, atrial fibrillation, and ventricular tachycardia, may be seen once airflow is reestablished.
Weight loss and strict avoidance of alcohol and hypnotic medications are the first steps in management. Weight loss may be curative, but most patients are unable to lose the 10–20% of body weight required. Nasal continuous positive airway pressure (nasal CPAP) at night is curative in many patients. Polysomnography is frequently necessary to determine the level of CPAP (usually 5–15 cm H2O) necessary to abolish obstructive apneas. Unfortunately, only about 75% of patients continue to use nasal CPAP after 1 year. Pharmacologic therapy for obstructive sleep apnea is disappointing. Supplemental oxygen may lessen the severity of nocturnal desaturation but may also lengthen apneas; it should not be routinely prescribed. Polysomnography is necessary to assess the effects of oxygen therapy. Mechanical devices inserted into the mouth at bedtime to hold the jaw forward and prevent pharyngeal occlusion have modest effectiveness in relieving apnea; however, patient compliance is not optimal.
Uvulopalatopharyngoplasty (UPPP), a procedure consisting of resection of pharyngeal soft tissue and amputation of approximately 15 mm of the free edge of the soft palate and uvula, is helpful in approximately 50% of selected patients. It is more effective in eliminating snoring than apneic episodes. UPPP may be performed on an outpatient basis with a laser. Nasal septoplasty is performed if gross anatomic nasal septal deformity is present. Tracheostomy relieves upper airway obstruction and its physiologic consequences and represents the definitive treatment for obstructive sleep apnea. However, it has numerous adverse effects, including granuloma formation, difficulty with speech, and stoma and airway infection. Furthermore, the long-term care of the tracheostomy, especially in obese patients, can be difficult. Tracheostomy and other maxillofacial surgery approaches are reserved for patients with life-threatening arrhythmias or severe disability who have not responded to conservative therapy.
Aurora RN et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep. 2012 Jan1;35(1):17–40. [PMID: 22215916]
Park JG et al. Updates on definition, consequences, and management of obstructive sleep apnea. Mayo Clin Proc. 2011 Jun;86(6):549–54. [PMID: 21628617]
Piper AJ et al. Obesity hypoventilation syndrome: mechanisms and management. Am J Respir Crit Care Med. 2011 Feb1;183(3):292–8. [PMID: 21037018]
ACUTE RESPIRATORY FAILURE
Respiratory failure is defined as respiratory dysfunction resulting in abnormalities of oxygenation or ventilation (CO2 elimination) severe enough to threaten the function of vital organs. Arterial blood gas criteria for respiratory failure are not absolute but may be arbitrarily established as a Po2 under 60 mm Hg (7.8 kPa) or a PCO2 over 50 mm Hg (6.5 kPa). Acute respiratory failure may occur in a variety of pulmonary and nonpulmonary disorders (Table 9–26). Only a few selected general principles of management will be reviewed here.
Table 9–26. Selected causes of acute respiratory failure in adults.
Symptoms and signs of acute respiratory failure are those of the underlying disease combined with those of hypoxemia or hypercapnia. The chief symptom of hypoxemia is dyspnea, though profound hypoxemia may exist in the absence of complaints. Signs of hypoxemia include cyanosis, restlessness, confusion, anxiety, delirium, tachypnea, bradycardia or tachycardia, hypertension, cardiac dysrhythmias, and tremor. Dyspnea and headache are the cardinal symptoms of hypercapnia. Signs of hypercapnia include peripheral and conjunctival hyperemia, hypertension, tachycardia, tachypnea, impaired consciousness, papilledema, and asterixis. The symptoms and signs of acute respiratory failure are both insensitive and nonspecific; therefore, the clinician must maintain a high index of suspicion and obtain arterial blood gas analysis if respiratory failure is suspected.
Treatment of the patient with acute respiratory failure consists of: (1) specific therapy directed toward the underlying disease; (2) respiratory supportive care directed toward the maintenance of adequate gas exchange; and (3) general supportive care. Only the last two aspects are discussed below.
Respiratory support has both nonventilatory and ventilatory aspects.
Several modes of positive-pressure ventilation are available. Controlled mechanical ventilation (CMV; also known as assist-control or A-C) and synchronized intermittent mandatory ventilation (SIMV) are ventilatory modes in which the ventilator delivers a minimum number of breaths of a specified tidal volume each minute. In both CMV and SIMV, the patient may trigger the ventilator to deliver additional breaths. In CMV, the ventilator responds to breaths initiated by the patient above the set rate by delivering additional full tidal volume breaths. In SIMV, additional breaths are not supported by the ventilator unless the pressure support mode is added. Numerous alternative modes of mechanical ventilation now exist, the most popular being pressure support ventilation (PSV), pressure control ventilation (PCV), and CPAP.
PEEP is useful in improving oxygenation in patients with diffuse parenchymal lung disease such as ARDS. It should be used cautiously in patients with localized parenchymal disease, hyperinflation, or very high airway pressure requirements during mechanical ventilation.
Acute respiratory alkalosis caused by overventilation is common. Hypotension induced by elevated intrathoracic pressure that results in decreased return of systemic venous blood to the heart may occur in patients treated with PEEP, those with severe airflow obstruction, and those with intravascular volume depletion. Ventilator-associated pneumonia is another serious complication of mechanical ventilation.
Maintenance of adequate nutrition is vital; parenteral nutrition should be used only when conventional enteral feeding methods are not possible. Overfeeding, especially with carbohydrate-rich formulas, should be avoided, because it can increase CO2 production and may potentially worsen or induce hypercapnia in patients with limited ventilatory reserve. However, failure to provide adequate nutrition is more common. Hypokalemia and hypophosphatemia may worsen hypoventilation due to respiratory muscle weakness. Sedative-hypnotics and opioid analgesics are frequently used. They should be titrated carefully to avoid oversedation, leading to prolongation of intubation. Temporary paralysis with a nondepolarizing neuromuscular blocking agent is occasionally used to facilitate mechanical ventilation and to lower oxygen consumption. Prolonged muscle weakness due to an acute myopathy is a potential complication of these agents. Myopathy is more common in patients with kidney injury and in those given concomitant corticosteroids.
Psychological and emotional support of the patient and family, skin care to avoid pressure ulcers, and meticulous avoidance of health care–associated infection and complications of tracheal tubes are vital aspects of comprehensive care for patients with acute respiratory failure.
Attention must also be paid to preventing complications associated with serious illness. Stress gastritis and ulcers may be avoided by administering sucralfate (1 g orally twice a day), histamine H2-receptor antagonists, or PPIs. There is some concern that the latter two agents, which raise the gastric pH, may permit increased growth of gram-negative bacteria in the stomach, predisposing to pharyngeal colonization and ultimately HCAP; many clinicians therefore prefer sucralfate. The risk of DVT and PE may be reduced by subcutaneous administration of heparin (5000 units every 12 hours), the use of LMWH (see Table 14–15), or placement of sequential compression devices on the lower extremities.
Course & Prognosis
The course and prognosis of acute respiratory failure vary and depend on the underlying disease. The prognosis of acute respiratory failure caused by uncomplicated sedative or opioid overdose is excellent. Acute respiratory failure in patients with COPD who do not require intubation and mechanical ventilation has a good immediate prognosis. On the other hand, ARDS associated with sepsis has an extremely poor prognosis, with mortality rates of about 90%. Overall, adults requiring mechanical ventilation for all causes of acute respiratory failure have survival rates of 62% to weaning, 43% to hospital discharge, and 30% to 1 year after hospital discharge.
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ACUTE RESPIRATORY DISTRESS SYNDROME
ESSENTIALS OF DIAGNOSIS
Acute onset of respiratory failure.
Bilateral radiographic pulmonary opacities.
Respiratory failure not fully explained by heart failure or volume overload.
Ratio of partial pressure of oxygen in arterial blood (PaO2) to fractional concentration of inspired oxygen (FIO2) < 300 mm Hg, with PEEP ≥ 5 cm H2O.
ARDS denotes acute hypoxemic respiratory failure following a systemic or pulmonary insult without evidence of heart failure. ARDS is the most severe form of acute lung injury and is characterized by an acute onset within 1 week of a known clinical insult, bilateral radiographic pulmonary infiltrates, respiratory failure not fully explained by heart failure or volume overload, and a PaO2/FIO2 ratio < 300 mm Hg (according to the Berlin Definition). The severity of ARDS is based on the level of oxygenation impairment. Mild ARDS is defined by a Pao2/Fio2 ratio of between 200 and 300 mm Hg, moderate ARDS is defined by a Pao2/Fio2 ratio between 100 and 200 mm Hg, and severe ARDS is defined by a Pao2/Fio2 ratio less than 100 mm Hg. ARDS may follow a wide variety of clinical events (Table 9–27). Common risk factors for ARDS include sepsis, aspiration of gastric contents, shock, infection, lung contusion, nonthoracic trauma, toxic inhalation, near-drowning, and multiple blood transfusions. About one-third of ARDS patients initially have sepsis syndrome. Although the mechanism of lung injury varies with the cause, damage to capillary endothelial cells and alveolar epithelial cells is common to ARDS regardless of cause. Damage to these cells causes increased vascular permeability and decreased production and activity of surfactant; these abnormalities lead to interstitial and alveolar pulmonary edema, alveolar collapse, and hypoxemia.
Table 9–27. Selected disorders associated with ARDS.
ARDS is marked by the rapid onset of profound dyspnea that usually occurs 12–48 hours after the initiating event. Labored breathing, tachypnea, intercostal retractions, and crackles are noted on physical examination. Chest radiography shows diffuse or patchy bilateral infiltrates that rapidly become confluent; these characteristically spare the costophrenic angles. Air bronchograms occur in about 80% of cases. Upper lung zone venous engorgement is distinctly uncommon. Heart size is normal, and pleural effusions are small or nonexistent. Marked hypoxemia occurs that is refractory to treatment with supplemental oxygen. Many patients with ARDS demonstrate multiple organ failure, particularly involving the kidneys, liver, gut, central nervous system, and cardiovascular system.
Since ARDS is a physiologic and radiographic syndrome rather than a specific disease, the concept of differential diagnosis does not strictly apply. Normal-permeability (“cardiogenic” or hydrostatic) pulmonary edema must be excluded, however, because specific therapy is available for that disorder. Measurement of pulmonary capillary wedge pressure by means of a flow-directed pulmonary artery catheter may be required in selected patients with suspected cardiac dysfunction. Routine use of the Swan-Ganz catheter in ARDS is discouraged.
No measures that effectively prevent ARDS have been identified; specifically, prophylactic use of PEEP in patients at risk for ARDS has not been shown to be effective. Intravenous methylprednisolone does not prevent ARDS when given early to patients with sepsis syndrome or septic shock.
Treatment of ARDS must include identification and specific treatment of the underlying precipitating and secondary conditions (eg, sepsis). Meticulous supportive care must then be provided to compensate for the severe dysfunction of the respiratory system associated with ARDS and to prevent complications (see above).
Treatment of the hypoxemia seen in ARDS usually requires tracheal intubation and positive-pressure mechanical ventilation. The lowest levels of PEEP (used to recruit atelectatic alveoli) and supplemental oxygen required to maintain the Pao2 above 55 mm Hg (7.13 kPa) or the Sao2 above 88% should be used. Efforts should be made to decrease Fio2 to less than 60% as soon as possible in order to avoid oxygen toxicity. PEEP can be increased as needed as long as cardiac output and oxygen delivery do not decrease and airway pressures do not increase excessively. Prone positioning may transiently improve oxygenation in selected patients by helping recruit atelectatic alveoli; however, great care must be taken during the maneuver to avoid dislodging catheters and tubes.
A variety of mechanical ventilation strategies are available. A multicenter study of 800 patients demonstrated that a protocol using volume-control ventilation with low tidal volumes (6 mL/kg of ideal body weight) resulted in a 10% absolute mortality reduction over therapy with standard tidal volumes (defined as 12 mL/kg of ideal body weight); this trial reported the lowest mortality (31%) of any intervention to date for ARDS.
Approaches to hemodynamic monitoring and fluid management in patients with acute lung injury have been carefully studied. A prospective RCT comparing hemodynamic management guided either by a pulmonary artery catheter or a central venous catheter using an explicit management protocol demonstrated that a pulmonary artery catheter should not be routinely used for the management of acute lung injury. A subsequent randomized, prospective clinical study of restrictive fluid intake and diuresis as needed to maintain central venous pressure < 4 mm Hg or pulmonary artery occlusion pressure < 8 mm Hg (conservative strategy group) versus a fluid management protocol to target a central venous pressure of 10–14 mm Hg or a pulmonary artery occlusion pressure 14–18 mm Hg (liberal strategy group), showed that patients in the conservative strategy group experienced faster improvement in lung function and spent significantly fewer days on mechanical ventilation and in the ICU without an improvement in death by 60 days or worsening nonpulmonary organ failure at 28 days. Oxygen delivery can be increased in anemic patients by ensuring that hemoglobin concentrations are at least 7 g/dL (70 g/L); patients are not likely to benefit from higher levels. Increasing oxygen delivery to supranormal levels through the use of inotropes and high hemoglobin concentrations is not clinically useful and may be harmful. Strategies to decrease oxygen consumption include the appropriate use of sedatives, analgesics, and antipyretics.
A large number of innovative therapeutic interventions to improve outcomes in ARDS patients have been or are being investigated. Unfortunately, to date, none have consistently shown benefit in clinical trials. Systemic corticosteroids have been studied extensively with variable and inconsistent results. While a few small studies suggest some specific improved outcomes when given within the first 2 weeks after the onset of ARDS, the routine use of corticosteroids is not recommended.
Course & Prognosis
The mortality rate associated with ARDS is 30–40%. If ARDS is accompanied by sepsis, the mortality rate may reach 90%. The major causes of death are the primary illness and secondary complications such as multiple organ system failure or sepsis. Median survival is about 2 weeks. Many patients who succumb to ARDS and its complications die after withdrawal of ventilator support (see Chapter 5). Most survivors of ARDS are left with some pulmonary symptoms (cough, dyspnea, sputum production), which tend to improve over time. Mild abnormalities of oxygenation, diffusing capacity, and lung mechanics persist in some individuals.
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The ARDS Definition Task Force; Ranieri VM et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun20;307(23):2526–33. [PMID: 22797452]