Disorders of the Respiratory System PDF

Disorders of the Respiratory System PART 7 and a focused physical examination. Many patients will subsequently Section 1 Diagnosis of Respiratory under...

Disorders of the Respiratory System PART 7 and a focused physical examination. Many patients will subsequently Section 1 Diagnosis of Respiratory undergo pulmonary function testing, chest imaging, blood and sputum Disorders analysis, a variety of serologic or microbiologic studies, and diagnostic procedures, such as bronchoscopy. This stepwise approach is discussed in detail below. 284 Approach to the Patient with Disease of the HISTORY Dyspnea and Cough The cardinal symptoms of respiratory dis- ease are dyspnea and cough (Chaps. 37 and 38). Dyspnea has many Respiratory System causes, some of which are not predominantly due to lung pathology. The words a patient uses to describe shortness of breath can suggest Bruce D. Levy certain etiologies for dyspnea. Patients with obstructive lung disease often complain of “chest tightness” or “inability to get a deep breath,” whereas patients with congestive heart failure more commonly report The majority of diseases of the respiratory system present with cough “air hunger” or a sense of suffocation. and/or dyspnea and fall into one of three major categories: (1) obstruc- The tempo of onset and the duration of a patient’s dyspnea are tive; (2) restrictive; and (3) vascular diseases. Obstructive pathophys- likewise helpful in determining the etiology. Acute shortness of breath iology is most common and primarily results from airway diseases, is usually associated with sudden physiologic changes, such as acute such as asthma, chronic obstructive pulmonary disease (COPD), airway narrowing (e.g., laryngeal edema, bronchospasm, or mucus bronchiectasis, and bronchiolitis. Diseases resulting in restrictive plugging), acute hypoxemia (e.g., pulmonary edema, pneumonia, or pathophysiology include parenchymal lung diseases, abnormalities pulmonary embolism), or sudden changes in the work of breathing of the chest wall and pleura, and neuromuscular disease. Pulmonary (e.g., pneumothorax). Patients with COPD and idiopathic pulmonary embolism, pulmonary hypertension, and pulmonary venoocclusive fibrosis (IPF) experience a gradual progression of dyspnea on exertion, disease are examples of disorders of the pulmonary vasculature. punctuated by acute exacerbations of shortness of breath. In contrast, Although many specific diseases fall into these major categories, both most asthmatics do not have daily symptoms, but experience intermit- infective and neoplastic processes can affect the respiratory system and tent episodes of dyspnea, cough, and chest tightness that are usually result in myriad pathologic findings, including those listed in the three associated with specific triggers, such as an upper respiratory tract categories above (Table 284-1). infection or exposure to allergens. Disorders can also be grouped according to gas exchange abnor- Specific questioning should focus on factors that incite dyspnea as malities, including hypoxemia, hypercarbia, or combined impairment; well as on any intervention that helps resolve the patient’s shortness of however, many respiratory disorders do not manifest as gas exchange breath. Asthma is commonly exacerbated by specific triggers, although abnormalities. this can also be true of COPD. Many patients with lung disease report As with the evaluation of most patients, the approach to a patient dyspnea on exertion. Determining the degree of activity that results in with a respiratory system disorder begins with a thorough history shortness of breath gives the clinician a gauge of the patient’s degree of disability. Many patients adapt their level of activity to accommodate TABLE 284-1 Categories of Respiratory Disease progressive limitation. For this reason, it is important, particularly in CATEGORY EXAMPLES older patients, to delineate the activities in which they engage and how Obstructive pathophysiology— Asthma these activities have changed over time. Dyspnea on exertion is often airway disease an early symptom of underlying lung or heart disease and warrants a Chronic obstructive pulmonary disease (COPD) thorough evaluation. For cough, the clinician should inquire about the duration of the Bronchiectasis cough, whether or not it is associated with sputum production, and any Bronchiolitis specific triggers that induce it. Acute cough productive of phlegm is Restrictive pathophysiology— Idiopathic pulmonary fibrosis (IPF) often a symptom of infection of the respiratory system, including pro- parenchymal disease Asbestosis cesses affecting the upper airway (e.g., sinusitis, tracheitis), the lower Desquamative interstitial pneumonitis (DIP) airways (e.g., bronchitis, bronchiectasis), and the lung parenchyma Sarcoidosis (e.g., pneumonia). Both the quantity and quality of the sputum, Restrictive pathophysiology— Amyotrophic lateral sclerosis (ALS) including whether it is blood-streaked or frankly bloody, should be neuromuscular weakness Guillain-Barré syndrome determined. Hemoptysis warrants urgent evaluation as delineated in Myasthenia gravis Chap. 39. Restrictive pathophysiology— Kyphoscoliosis Chronic cough (defined as that persisting for >8 weeks) is commonly chest wall/pleural disease associated with obstructive lung diseases, particularly asthma, COPD, Ankylosing spondylitis and chronic bronchiectasis, as well as “nonrespiratory” diseases, such Chronic pleural effusions as gastroesophageal reflux and postnasal drip. Diffuse parenchymal Pulmonary vascular disease Pulmonary embolism lung diseases, including IPF, frequently present as a persistent, non- Pulmonary arterial hypertension (PAH) productive cough. All causes of cough are not respiratory in origin, and Pulmonary venoocclusive disease assessment should encompass a broad differential, including cardiac Vasculitis and gastrointestinal diseases as well as psychogenic causes. Malignancy Bronchogenic carcinoma (non-small-cell and small-cell lung cancer) Additional Symptoms Patients with respiratory disease may Metastatic disease report wheezing, which is suggestive of airways disease, particularly Infectious diseases Pneumonia asthma. Hemoptysis can be a symptom of a variety of lung diseases, Bronchitis including infections of the respiratory tract, bronchogenic carcinoma, Tracheitis and pulmonary embolism. In addition, chest pain or discomfort can be respiratory in origin. As the lung parenchyma is not innervated with HPIM21e_Part7_p2131-p2216.indd 2131 20/01/22 6:20 PM  2132 pain fibers, pain in the chest from respiratory disorders usually results Rhonchi are a manifestation of obstruction of medium-sized air- from either diseases of the parietal pleura (e.g., pneumothorax) or ways, most often with secretions. In the acute setting, this manifes- pulmonary vascular diseases (e.g., pulmonary hypertension). As many tation may be a sign of viral or bacterial bronchitis. Chronic rhonchi diseases of the lung can result in strain on the right side of the heart, suggest bronchiectasis or COPD. In contrast to expiratory wheezes and patients may also present with symptoms of cor pulmonale, including rhonchi, stridor is a high-pitched, focal inspiratory wheeze, usually abdominal bloating or distention and pedal edema (Chap. 257). heard over the neck as a manifestation of upper airway obstruction. Crackles, or rales, are commonly a sign of alveolar disease. Pro- Additional History A thorough social history is an essential cesses that fill the alveoli with fluid may result in crackles, including component of the evaluation of patients with respiratory disease. All pulmonary edema and pneumonia. Crackles in pulmonary edema patients should be asked about current or previous cigarette smoking, are generally more prominent at the bases. Interestingly, diseases that as this exposure is associated with many diseases of the respiratory result in fibrosis of the interstitium (e.g., IPF) also result in crackles that system, including COPD, bronchogenic lung cancer, and select par- sound like Velcro being ripped apart. Although some clinicians make PART 7 enchymal lung diseases (e.g., desquamative interstitial pneumonitis a distinction between “wet” and “dry” crackles, this distinction has not and pulmonary Langerhans cell histiocytosis). For most of these dis- been shown to be a reliable way to differentiate among etiologies of orders, increased cigarette smoke exposure (i.e., cigarette pack-years) respiratory disease. increases the risk of disease. E-cigarette or vaping use can lead to One way to help distinguish between crackles associated with alve- Disorders of the Respiratory System acute or subacute lung injury (i.e., E-cigarette or vaping use-associated olar fluid and those associated with interstitial fibrosis is to assess for lung injury [EVALI]). Secondhand smoke also increases risk for some egophony. Egophony is the auscultation of the sound “AH” instead of respiratory disorders, so patients should also be asked about parents, “EEE” when a patient phonates “EEE.” This change in note is due to spouses, or housemates who smoke. Possible inhalational exposures abnormal sound transmission through consolidated parenchyma and at work (e.g., asbestos, silica) or home (e.g., wood smoke, excrement is present in pneumonia but not in IPF. Similarly, areas of alveolar from pet birds) should be explored (Chap. 289). Travel predisposes to filling have increased whispered pectoriloquy as well as transmission certain infections of the respiratory tract, most notably tuberculosis. of larger-airway sounds (i.e., bronchial breath sounds in a lung zone Potential exposure to fungi is increased in specific geographic regions where vesicular breath sounds are expected). or climates (e.g., Histoplasma capsulatum), so exposures to these The lack or diminution of breath sounds can also help determine the regions should be determined. etiology of respiratory disease. Patients with emphysema often have a Associated symptoms of fever and chills should raise the suspicion quiet chest with diffusely decreased breath sounds. A pneumothorax of infective etiologies, both pulmonary and systemic. A comprehensive or pleural effusion may present with an area of absent breath sounds. review of systems may suggest rheumatologic or autoimmune disease presenting with respiratory tract manifestations. Questions should Other Systems Pedal edema, if symmetric, may suggest cor pul- focus on joint pain or swelling, rashes, dry eyes, dry mouth, or consti- monale; if asymmetric, it may be due to deep venous thrombosis and tutional symptoms. In addition, carcinomas from a variety of primary associated pulmonary embolism. Jugular venous distention may also sources commonly metastasize to the lung and cause respiratory symp- be a sign of volume overload associated with right heart failure. Pulsus toms. Finally, therapy for other conditions, including both irradiation paradoxus is an ominous sign in a patient with obstructive lung dis- and medications, can result in diseases of the chest. ease, as it is associated with significant negative intrathoracic (pleural) pressures required for ventilation and impending respiratory failure. Physical Examination The clinician’s suspicion of respiratory As stated earlier, rheumatologic disease may manifest primarily as disease often begins with the patient’s vital signs. The respiratory rate lung disease. Owing to this association, particular attention should be is informative, whether elevated (tachypnea) or depressed (hypopnea). paid to joint and skin examination. Clubbing can be found in many In addition, pulse oximetry should be measured, as many patients with lung diseases, including cystic fibrosis, IPF, and lung cancer. Cyanosis respiratory disease have hypoxemia, either at rest or with exertion. is seen in hypoxemic respiratory disorders that result in >5 g of deox- The first step of the physical examination is inspection. Patients with ygenated hemoglobin/dL. respiratory disease may be in distress and using accessory muscles of respiration to breathe. Severe kyphoscoliosis can result in restrictive DIAGNOSTIC EVALUATION pathophysiology. Inability to complete a sentence in conversation is The sequence of studies is dictated by the clinician’s differential generally a sign of severe impairment and should result in an expedited diagnosis, as determined by the history and physical examination. evaluation of the patient. Acute respiratory symptoms are often evaluated with multiple tests Percussion of the chest is used to establish diaphragm excursion performed at the same time in order to diagnose any life-threatening and lung size. In the setting of decreased breath sounds, percussion is diseases rapidly (e.g., pulmonary embolism or multilobar pneumonia). used to distinguish between pleural effusions (dull to percussion) and In contrast, chronic dyspnea and cough can be evaluated in a more pneumothorax (hyper-resonant note). protracted, stepwise fashion. The role of palpation is limited in the respiratory examination. Pal- pation can demonstrate subcutaneous air in the setting of barotrauma. Pulmonary Function Testing (See also Chap. 286) The It can also be used as an adjunctive assessment to determine whether initial pulmonary function test obtained is spirometry. This study is an area of decreased breath sounds is due to consolidation (increased an effort-dependent test used to assess for obstructive pathophysiol- tactile fremitus) or a pleural effusion (decreased tactile fremitus). To ogy as seen in asthma, COPD, and bronchiectasis (Table 284-1). A detect unilateral disorders of ventilation, the symmetry and degree diminished-forced expiratory volume in 1 second (FEV1)/forced of chest wall expansion can be assessed during a deep inspiration by vital capacity (FVC) (often defined as 20% has also function testing or demonstration of airway hyperresponsiveness. been proposed as an indicator of reversible airways disease, but it is less Unfortunately, the diagnosis may be difficult to confirm after initia- reliable due to difficulties with quality control and variability of home tion of therapy since airway obstruction and hyperresponsiveness may assessments. Lung volumes and diffusing capacity should be normal in be mitigated with therapy. A trial of tapering medications may be nec- uncomplicated asthma. essary. Studies have shown that more than one-third of patients with a physician diagnosis of asthma do not meet the criteria for the diagnosis. Assessment of Airway Responsiveness In cases where pulmo- Adjunctive evaluation, as outlined below, should be undertaken to nary function tests are nonconfirmatory and the diagnosis remains in identify precipitating factors and underlying mechanisms that may doubt, testing to demonstrate increased reactivity to provocative stim- be amenable to specific therapies (e.g., allergen avoidance). Cases uli in the laboratory can be undertaken. Methacholine, a cholinergic that require more than a daily moderate-dose ICS combined with agonist, inhaled in increasing concentrations is most commonly used. a long-acting β2-agonist (LABA) (together known as ICS/LABA) A provocative dose producing a 20% drop in FEV1 (PD20) is calculated, should undergo more formal evaluation to assess comorbidities that with a value ≤400 μg indicative of airway reactivity. Mannitol is used may make asthma difficult to control and a reassessment of any as well, and occasionally, hypertonic saline may be used. Challenge possible confounding diagnoses that may mimic asthma symptoms with exercise and/or cold, dry air can be performed, with a positive (see Table 287-3). response recorded if there is a ≥10% drop in FEV1 from baseline. In the case of suspected environmental/occupational exposures, specific PRIMARY ASSESSMENT TOOLS FOR allergen challenges may be undertaken in highly specialized labs. ESTABLISHING A DIAGNOSIS ADJUNCTIVE ASSESSMENT TOOLS History Patients with asthma most commonly complain of epi- sodes of wheezing, shortness of breath, chest tightness, mucus pro- Eosinophil Counts A large proportion of asthma patients not duction, or cough upon exposure to triggers listed in Table 287-2. treated with oral or high-dose ICSs will have eosinophil counts Symptoms may be worse on arising in the morning. Some may ≥300 cells/μL. Eosinophil counts correlate with severity of disease have nocturnal symptoms alone. However, such patients should be in population studies. Their presence in patients with severe asthma evaluated for postnasal drip or GERD if that is their sole presenting indicates a likelihood that the patient would respond to medications HPIM21e_Part7_p2131-p2216.indd 2154 20/01/22 6:20 PM  targeted at type 2 inflammation. Extremely elevated levels should TABLE 287-4 Goals of Asthma Therapy 2155 prompt consideration of eosinophilic granulomatosis with polyangiitis 1. Reduction in symptom frequency to ≤2 times/week or primary eosinophilic disorders. 2. Reduction of nighttime awakenings to ≤2 times/month IgE, Skin Tests, and Radioallergosorbent Tests Total serum 3. Reduction of reliever use to ≤2 times a week (except before exercise) IgE levels are useful in considering whether patients with severe 4. No more than 1 exacerbation/year asthma would be eligible for anti-IgE therapy. Levels >1000 IU/mL 5. Optimization of lung function should prompt consideration of ABPA. Skin tests, or their in vitro 6. Maintenance of normal daily activities counterparts that detect IgE directed at specific antigens (radioal- 7. Satisfaction with asthma care with minimal or no side effects of treatment lergosorbent test [RAST]), can be useful in confirming atopy and suggesting allergic rhinitis, which can complicate asthma manage- CHAPTER 287 Asthma ment. Allergy investigations may be useful, when correlated with a the case of those with occupational exposures, removal from the history of reactions, in identifying environmental exposures that may offending environment may sometimes result in complete resolu- be aggravating asthma. tion of symptoms or significant improvement. Secondhand smoke exposure and frequent exposure to combustion products of cann- Exhaled Nitric Oxide Fraction of exhaled nitric oxide (FeNO) abis are remediable environmental exposures as well. The removal in exhaled breath is an approximate indicator of eosinophilic inflam- of pets that are clearly associated with symptoms can reduce symp- mation in the airways. It is easily suppressed by ICSs and, thus, can be toms. Pest control at home and in the school in those with evidence used to assess adherence in patients in whom it was initially elevated. of IgE-mediated sensitivity (skin test or IgE RAST) may also be Elevated levels (>35–40 ppb) in untreated patients are indicative of beneficial. The effect of dust or mold control in reducing asthma eosinophilic inflammation. Levels >20–25 ppb in patients with severe symptoms has been more variable. There is moderate evidence that asthma on moderate- to high-dose ICS indicate either poor adherence dust control (impermeable mattress and pillowcase covers) in those or persistent type 2 inflammation despite therapy. patients with symptoms and sensitization may be effective in reduc- ing symptoms only when conducted as part of a comprehensive ADDITIONAL EVALUATION IN SEVERE/POORLY allergen mitigation strategy. RESPONSIVE ASTHMA In patients with poorly responsive asthma, additional evaluations for Allergen Immunotherapy Allergen immunotherapy reduces IgE- comorbidities (see Table 287-3) may be necessary, including sinus mediated reactions to the allergens administered. It clearly reduces radiographic studies (even in those who have no symptoms of sinus the symptoms of allergic rhinitis and thus may be helpful in reduc- disease) and esophageal studies in those who have symptoms of reflux. ing this comorbidity. The evidence for its effectiveness in isolated In patients with nonreversible disease, many obtain a serum α1 antit- asthma in those who are sensitized and have clinical symptoms is rypsin level. Additionally, the following evaluations may be of utility in variable. Due to the risk of anaphylaxis, guidelines generally rec- poorly responsive asthma. ommend immunotherapy only in patients whose asthma is under control and who have mild to moderate asthma. The evidence base Chest Radiography Chest CT can be useful to assess for the pres- for the effectiveness of sublingual allergen immunotherapy in the ence of bronchiectasis and other structural abnormalities that could treatment of asthma is not substantial. produce airway obstruction. New image analysis tools are being used Vaccination Respiratory infections are a major cause of asthma in the research setting to assess airway properties such as airway wall exacerbations. Patients with asthma are strongly advised to receive thickness, airway diameter, and evidence of air trapping. both types of currently available pneumococcal vaccines and yearly Sputum Induced sputum may be used in more specialized centers influenza vaccines. COVID-19 vaccination is advised, as well. to help characterize type 2 and non–type 2 inflammation by detection of eosinophils and neutrophils, respectively. In severe asthma, there is MEDICATIONS some evidence that some patients may have localized persistent eosin- Bronchodilators Bronchodilators relax airway smooth muscle. ophilic airway inflammation despite lack of peripheral eosinophils on There are three major classes of bronchodilators, β2-agonists, blood analysis. anticholinergics, and theophylline. a2-Agonists Available in inhaled or oral form, these agents acti- vate β2-receptors present on airway smooth muscle. Such receptors TREATMENT are also present on mast cells, but they contribute little to the effi- cacy of these agents in asthma. β2-receptors are G protein–coupled Asthma receptors that activate adenyl cyclase to produce cyclic AMP, which results in relaxation of smooth muscle. GOALS OF ASTHMA THERAPY AND ASSESSMENT OF CONTROL Use β2-Agonists are primarily used in inhaled forms to provide Goals of asthma therapy in terms of achieving control of symptoms relief of bronchospasm or to reduce the degree of bronchospasm and reducing risk (as reflected in frequency of asthma exacerba- anticipated in response to exercise or other provocative stimuli. tions) are listed in Table 287-4. The therapeutic agents used in Regular use has been associated with tachyphylaxis of the bron- treatment are discussed below, and an integrated approach to care choprotective effect and possible increased airway reactivity. This is discussed subsequently. may be more common in patients with a polymorphism at the 16th A comprehensive treatment approach involves avoiding and amino acid position of the β2-receptor. Frequent short-acting β-2 reducing asthma triggers and, if necessary, the adjunctive use of agonist use has been associated with increased asthma mortality medications. Asthma medications are primarily divided into those resulting in decreased enthusiasm for use in isolation without that relax smooth muscle and produce a fairly rapid relief of acute inhaled corticosteroids. symptoms and those that target inflammation or mediator produc- Short-Acting a2-Agonists Albuterol (also known as salbuta- tion. The former medications are commonly referred to as reliever mol) is the most commonly used agent. Bronchodilation begins medications, and the latter are known as controller medications. within 3–5 min of inhalation, and effects generally last 4–6 h. It is most commonly administered by metered-dose inhaler. REDUCING TRIGGERS Solutions for nebulization are also used, especially for relief of Mitigation As shown in Tables 287-1 and 287-2, triggers and bronchospasm in children. Oral forms are available but are not exposures can cause asthma and make it difficult to control. In commonly used. HPIM21e_Part7_p2131-p2216.indd 2155 20/01/22 6:20 PM  2156 Long-Acting a2-Agonists Salmeterol and formoterol are the two nuclear factor-κB. It also attaches to other transcription factors, available LABAs. They have an ~12-h duration of action. Formo- resulting in deactivation of other proinflammatory pathways. terol has a quick onset comparable to the short-acting β2-agonists. Use Corticosteroids reduce airway hyperresponsiveness, improve Salmeterol has a slower onset of action. These agents can be used airway function, prevent asthma exacerbations, and improve asthma for prophylaxis of exercise-induced bronchospasm. In contrast to symptoms. Corticosteroid use by inhalation (ICSs) minimizes sys- their use in chronic obstructive pulmonary disease (COPD), these temic toxicity and represents a cornerstone of asthma treatment. agents are not recommended for use as monotherapy in the treat- ment of asthma. Their use in asthma is generally restricted to use in ICS and ICS/LABA ICSs are the cornerstone of asthma therapy. combination with an ICS. They take advantage of the pleiotropic effects of corticosteroids to produce salutary impact at levels of systemic effect consider- Ultra-Long-Acting a2-Agonists These agents (indacaterol, olo- ably lower than oral corticosteroids. Their use is associated with daterol, and vilanterol) have a 24-h effect. They are only used in decreased asthma mortality. They are generally used regularly twice PART 7 combination with ICSs in the treatment of asthma. a day as first-line therapy for all forms of persistent asthma. Doses Safety β2-Agonists are fairly specific for the β2-receptors, but are increased, and they are combined with LABAs to control asthma in some patients and especially at higher doses, they can pro- of increasing severity. European guidelines now recommend their duce tremor, tachycardia, palpitations, and hypertension. They intermittent use even in intermittent asthma. Combining them with Disorders of the Respiratory System promote potassium reentry into cells, and at high doses, they can LABAs permits effective control at lower ICS dose. Longer-acting produce hypokalemia. Type B (nonhypoxic) lactic acidosis can preparations permitting once-a-day use are available. Their effects also occur and is thought to be secondary to increased glycoge- can be noticeable in several days, but continued improvement may nolysis and glycolysis and increased lipolysis, leading to a rise occur over months of therapy, with the majority of improvement in fatty acid levels, which can inhibit conversion of pyruvate to evident within the first month of regular use. Adherence to reg- acetyl-coenzyme A. ular therapy is generally poor, with as few as 25% of total annual Increased asthma mortality was associated with high- prescriptions being refilled. Very high doses are sometimes used to potency β2-agonists in Australia and New Zealand. Increased use reduce oral corticosteroid requirements. Not all patients respond to of β2-agonists for relief of bronchospasm is a clear marker of poor ICS. Increasing evidence suggests that the most responsive patients asthma control and has been associated with increased mortality. are those with significant type 2–mediated asthma. Questions had been raised as to whether adding LABAs to ICS Oral Corticosteroids Chronic oral corticosteroids (OCSs) at the might be associated with severe adverse asthma outcomes, but lowest doses possible (due to side effects) are used in patients who several studies have not detected such outcomes in comparison to cannot achieve acceptable asthma control without them. Alter- maintaining the ICS dose. nate-day dosing may be preferred, and pneumocystis pneumonia Anticholinergics Cholinergic nerve–induced smooth-muscle prophylaxis should be administered for those maintained on a daily constriction plays a role in asthmatic bronchospasm. Anticholiner- prednisone dose of ≥20 mg. OCSs are also used to treat asthma gic medications can produce smooth-muscle relaxation by antago- exacerbations, frequently at a dose of 40–60 mg/d of prednisone or nizing this mechanism of airway narrowing. Agents that have been equivalent for 1–2 weeks. Since they are well absorbed, they may developed for asthma have been pharmacologically designed to be also be used for managing hospitalized patients. less systemically absorbed so as to minimize their systemic anticho- Intravenous Corticosteroids Intravenous preparations are fre- linergic effects. The long-acting agents in this class are known as quently used in hospitalized patients. Patients are rapidly transi- long-acting muscarinic antagonists (LAMAs). tioned to OCS once their condition has stabilized. Use The short-acting agents in this class can be used alone for Intramuscular Corticosteroids In high-risk, poorly adherent acute bronchodilation. They appear to be somewhat less effective patients, intramuscular triamcinolone acetonide has been used to than β2-agonists and have a slower onset of action as well. achieve asthma control and reduce exacerbations. Safety Dry mouth may occur. At higher doses and in the elderly, Safety Chronic administration of systemic corticosteroids is acute glaucoma and urinary retention have been reported. There associated with a plethora of side effects including diabetes, oste- was a numerical (but not significant) difference in mortality in oporosis, cataracts and glaucoma, bruising, weight gain, truncal African Americans treated with ICS/LAMA versus ICS/LABA for obesity, hypertension, ulcers, depression, and accelerated cardiac asthma. risk, among others. Appropriate monitoring and infectious (pneu- Theophylline Theophylline, an oral compound that increases mocystis pneumonia prophylaxis for those treated chronically with cyclic AMP levels by inhibiting phosphodiesterase, is now rarely ≥20 mg prednisone/d) and bone health prophylaxis are necessary. used for asthma due to its narrow therapeutic window, drug-drug Intermittent “bursts” of systemic corticosteroids to treat asthma interactions, and reduced bronchodilation as compared to other exacerbations are associated with reduced side effects, but observa- agents. tional studies have suggested that the cumulative dose over time is associated with deleterious side effects. Controller (Anti-Inflammatory/Antimediator) Therapies So-called ICSs have dramatically reduced side effects as compared to “controller” therapies reduce asthma exacerbations and improve OCSs. At higher doses, bruising occurs and osteoporosis can accel- long-term control, decreasing the need for intermittent use of erate. There is a small increase in glaucoma and cataracts. Local bronchodilator therapies. None of these therapies have yet been effects include thrush, which can be reduced by use of a spacer and shown to prevent progression of airway remodeling or the more gargling. Hoarseness may be the result of a direct myopathic effect rapid decline in lung function that can occur in a subset of asthma on the vocal cords. Rare patients exhibit side effects even at mod- patients. erate doses of ICS. Children may experience growth suppression. Corticosteroids Corticosteroids are particularly effective in Leukotriene Modifiers Agents that inhibit production of leu- reducing type 2 inflammation and airway hyperresponsiveness. kotrienes (zileuton, an inhibitor of 5-lipoxygenase) or the action of Corticosteroids bind to a cytoplasmic glucocorticoid receptor to leukotrienes at the CysLT1 receptor (montelukast and zafirlukast) form a complex that translocates to the nucleus. The complex binds are moderately effective in asthma. to positive and negative response elements that result in inhibition They can improve airway function and reduce exacerbations but of T-cell activation; eosinophil function, migration, and prolifera- not to the same degree as bronchodilators or ICS, respectively. They tion; and proinflammatory cytokine elaboration and activation of are also effective in reducing symptoms of allergic rhinitis and, thus, HPIM21e_Part7_p2131-p2216.indd 2156 20/01/22 6:20 PM  can be used in patients with concomitant allergic rhinitis. Montelu- improve moderately as well. In patients who are not on chronic 2157 kast, in particular, is frequently used in children with mild asthma OCSs, these drugs are less effective in those with eosinophil counts due to concerns of ICS-related growth suppression. Montelukast 60% of predicted will fre- ified, the cornerstone of preferred therapy is the intensification of quently respond to β2-agonists alone. If they fail to respond in 1–2 h, ICS therapy in conjunction with the use of a LABA to achieve greater intravenous corticosteroids should be administered. Supplemental control at lower ICS doses. oxygen is usually administered to correct hypoxemia. An LTRA A major change in the stepwise approach, advocated for more and magnesium are sometimes given as well. Nebulized anticholin- than two decades, has occurred. Evidence has accumulated that ergics can be administered to produce additional bronchodilation. as-needed ICS can be used instead of regular ICS in milder asthma Failure to achieve PEFR >60% or persistent severe tachypnea over and that the trigger for such use could be patient perception of the 4–6 h should prompt consideration of admission to the hospital. need to use a reliever inhaler. Since formoterol is a LABA with a In-hospital treatment may include continuous bronchodilator neb- rapid onset, combination ICS/formoterol has been used as a single ulization. Noninvasive positive-pressure ventilation to assist with agent in multiple studies: as needed without background therapy in respiratory exhaustion is sometimes used to prevent a need for milder asthma, and as needed in addition to twice daily ICS/for- intubation, and helium-oxygen mixtures may be used to decrease moterol in more severe asthma. Since asthma mortality can occur the work of breathing. Antibiotics should be administered only if even in mild asthma (albeit at lower rates than more severe asthma), there are signs of infection. GINA, as part of a comprehensive strategy of asthma management, Mechanical ventilation may be difficult in patients with status recommends ICS/formoterol be used as the reliever in all steps asthmaticus due to high positive pressures in the setting of high of asthma severity, including intermittent asthma (Step 1). NAEPP resistance to airflow due to airway obstruction. Most patients with guidelines utilizing evidence-based studies recommend that ICS/ asthma attacks present with hypocapnia due to a high respiratory formoterol be used as the reliever medication in patients requiring rate. Normal or near-normal Pco2 in a patient with asthma in step 3 and 4 therapy (see Table 287-5) and that as-needed concom- respiratory distress should raise concerns of impending respiratory itant ICS and short-acting β-agonist (SABA) can be used as a ther- failure and need for mechanical ventilation. Mechanical ventilation apy in step 2. For the sake of simplicity, an adapted GINA approach should aim for low respiratory rates and/or ventilation volumes to is outlined in Table 287-5 with footnotes identifying the major decrease peak airway pressures. This can frequently be achieved by differences from the NAEPP. Leukotriene receptor antagonists “permissive hypercapnia”—allowing the Pco2 to rise and, if neces- (LTRAs) are alternative medications in step 2, which may be used sary, temporarily correcting critical acidosis with administration in those concerned about the minimal ICS side effects. However, of fluids to increase the pH. Neuromuscular paralysis may some- recent warnings about suicidal ideation associated with montelu- times be beneficial. Bronchoscopy to clear mucus plugs has been kast may make this approach less appealing. Leukotriene modifiers described but may be dangerous in the setting of difficulties with and long-acting anticholinergics are possible add-on (adjunctive) mechanical ventilation. therapies in those requiring step 4 and/or 5 therapies. Biologics are incredibly effective in their specific endotypes (type 2 with exacer- bations and specific biomarkers, as previously described), but their SPECIAL CONSIDERATIONS high cost currently relegates them to step 5 therapy or beyond. HIGH-RISK ASTHMA PATIENTS Three to four thousand people die from asthma in the United States each year. Table 287-6 lists characteristics of patients at high risk for asthma death. These characteristics should be considered in evaluating TREATMENT and treating patients who present with asthma. Asthma Attacks EXERCISE-INDUCED SYMPTOMS Asthma deteriorations of mild to moderate severity can be initially In many cases, the degree of exercise intolerance may reflect poor treated with a β2-agonist administered up to every 1 h. Increasing asthma control. Treatment involves step therapy of asthma as outlined the dose of ICSs by four- to fivefold may be helpful as well. If in Table 287-5. In other cases, however, asthma may be well controlled patients fail to achieve adequate control and continue to require in all other respects, but patients may report that they cannot under- β2-agonists hourly for several hours, they should be referred for take the level of exercise they desire. Some increase in exercise capacity HPIM21e_Part7_p2131-p2216.indd 2158 20/01/22 6:20 PM  TABLE 287-6 Patients at Greater Risk for Asthma Mortality SEVERE ASTHMA 2159 1. History of intensive care unit admission for asthma Severe and difficult-to-treat asthma, which composes ~5–10% of 2. History of intubation for asthma asthma, is defined as asthma that, having undergone appropriate evalu- ation for comorbidities and mimics, education, and trigger mitigation, 3. Illicit drug use remains uncontrolled on step 5 therapy or requires step 5 therapy for 4. Depression its control. Severe asthma can account for almost 50% of the cost of 5. New diagnosis asthma care in the United States. A significant proportion of these 6. ≥2 emergency unit visits in past 6 months patients have trouble with adherence and/or inhaler technique, and 7. Severe psychosocial problems these factors need to be investigated vigorously. Almost half of these 8. Lower socioeconomic status patients have evidence of persistent eosinophilic inflammation as CHAPTER 287 Asthma 9. On daily prednisone prior to admission evidenced by peripheral blood eosinophils and/or induced sputum. Those with recurrent exacerbations have a substantially increased likelihood of responding to the type 2 targeted biologics. Treatment can be achieved by starting at lower levels of exercise (warming up) and for those with mixed inflammation, isolated neutrophilic inflamma- by using a mask in colder weather to condition the air. Pretreatment tion, or pauci-granulocytic inflammation remains to be determined. with an SABA can increase the threshold of ventilation required to Some data suggest that many of these patients may have aberrations induce bronchoconstriction. LABAs may extend the period of protec- in the pathways responsible for resolution of inflammation. A rare tion, but their use alone in asthma is to be discouraged. For occasional patient may have biochemical abnormalities that interfere with steroid exercise, ICS/LABA can be used, but regular use may expose the response pathways. Macrolides are of use in a subset. Studies targeting patient to unnecessary doses of ICS. If regular exercise is undertaken, mast cells, IL-6, IL-33, and other pathways illustrated in Fig. 287-3 are then LTRAs may provide protection and can be used regularly. A SABA underway. Therapies aimed at improving pro-resolving pathways may (or ICS/formoterol) should always be available for quick relief. also be promising. Exercise-induced airway narrowing in elite athletes may be related to direct epithelial injury. In addition to the above, conditioning ELDERLY PATIENTS WITH ASTHMA of incoming air may be of major assistance. Ipratropium has been Asthma may present at or persist into older age. The mortality of reported to be of utility as well. asthma in those >65 years old is five times greater than that of younger cohorts even when adjusting for comorbidities. Many of these patients PREGNANCY had asthma as children, some with quiescent periods as they entered Asthma may improve, deteriorate, or remain unchanged during preg- adulthood. Of those with new-onset asthma, almost half were smok- nancy. Poor asthma control, especially exacerbations, is associated with ers or are currently smoking. One-quarter of adult-onset asthma is poor fetal outcomes. The general principles of asthma management believed to be due to occupational exposure. Patients presenting with and its goals are unchanged. Avoidance of triggers, especially smoking eosinophilic inflammation appear to have more severe asthma. Besides environments, is critical in view of the risk of loss of control and, in investigations of comorbidities, these patients may require adjustment the case of smoking, its clear effects on risk of development of asthma to step therapy based on intolerance of β2-agonist therapy due to in the child. There is extensive experience suggesting the safety of arrhythmia or tremulousness. The coexistence of COPD needs to be inhaled albuterol, beclomethasone, budesonide, and fluticasone, with carefully considered (see below). reassuring information on formoterol and salmeterol in pregnancy. Animal studies have not suggested toxicity for montelukast, zafirlukast, ASTHMA-COPD OVERLAP omalizumab, and ipratropium. Antibodies cross the placenta, and there Most clinicians agree that asthma-COPD overlap is not a syndrome, are few human data on the safety of IL-5–active drugs or anti–IL-4Rα. but rather recognize that it may be useful to identify patients who Chronic use of OCS has been associated with neonatal adrenal insuffi- present with symptoms related to airway dysfunction that may be ciency, preeclampsia, low birth weight, and a slight increase in the fre- due to simultaneous coexistence of both asthma and COPD. From an quency of cleft palate. However, it is clear that poorly controlled asthma asthma perspective, recognition that COPD and smoking can alter the during pregnancy carries greater risk to the fetus and mother than response to asthma therapies may be important. Smoking can blunt the these effects. There should be no hesitancy in administering routine response to ICS. Further, it has been difficult to demonstrate the effec- pharmacotherapy for acute exacerbations. Initiation of allergen immu- tiveness of biologic agents targeted at type 2 inflammation in patients notherapy or omalizumab during pregnancy is not recommended. In with COPD despite the presence of ≥300 circulating eosinophils/μL. cases where prostaglandins are needed to manage pregnancy, PGF2-α Additionally, in patients with both diseases, earlier initiation of anti- should be avoided since it is associated with bronchoconstriction. cholinergics may be considered. ASPIRIN-EXACERBATED RESPIRATORY DISEASE Acknowledgment A subset of patients (5–10%) present in adulthood with difficult-to- Peter J. Barnes contributed to this chapter in the 20th edition, and some control asthma and type 2 inflammation with eosinophilia, sinusitis, material from that chapter has been retained here. nasal polyposis, and severe asthma exacerbations that are precipitated by ingesting inhibitors of cyclooxygenase, with aspirin being the FURTHER READING most prominent of such inhibitors. Such patients, classified as hav- Cloutier MM et al: 2020 focused updates to the asthma management ing aspirin-exacerbated respiratory disease, overproduce leukotrienes guidelines: A report from the National Asthma Education and Pre- in response to inhibition of cyclooxygenase-1, probably secondary vention Program Coordinating Committee Expert Panel Working to inhibition of PGE2. These patients should avoid inhibitors of Group. J Allergy Clin Immunol 146:1217, 2020. cyclooxygenase-1, (aspirin and NSAIDs) but can generally tolerate Global Initiative for Asthma: 2020 GINA Report, global strategy inhibitors of cyclooxygenase-2 and acetaminophen. They should be for asthma management and prevention. https://ginasthma.org/ treated with leukotriene modifiers. Aspirin desensitization can be gina-reports/. undertaken to decrease upper respiratory symptoms and to allow Israel E, Reddel HK: Severe and difficult-to-treat asthma in adults. chronic administration of aspirin or NSAIDs for those that require N Engl J Med 377:965, 2017. it. Dupilumab and the IL-5–active biologics appear to be particularly Kaur R, Chupp G: Phenotypes and endotypes of adult asthma: Moving helpful and appear to be superseding aspirin desensitization in man- toward precision medicine. J Allergy Clin Immunol 144:1, 2019. agement except when chronic administration of aspirin or NSAIDs is Zaidan MF et al: Management of acute asthma in adults in 2020. required for another therapeutic indication. JAMA 323:563, 2020. HPIM21e_Part7_p2131-p2216.indd 2159 20/01/22 6:20 PM  2160 TABLE 288-1 Examples of Hypersensitivity Pneumonitis 288 Hypersensitivity Pneumonitis and DISEASE Farming/Food Processing ANTIGEN SOURCE Pulmonary Infiltrates with Farmer’s lung Thermophilic actinomycetes (e.g., Saccharopolyspora Grain, moldy hay, silage Eosinophilia Bagassosis rectivirgula); fungus Thermophilic actinomycetes Sugarcane Praveen Akuthota, Michael E. Wechsler Cheese washer’s lung Penicillium casei; Aspergillus Cheese clavatus Coffee worker’s lung Coffee bean dust Coffee beans PART 7 Malt worker’s lung Aspergillus species Barley HYPERSENSITIVITY PNEUMONITIS Miller’s lung Sitophilus granarius (wheat Wheat flour INTRODUCTION AND DEFINITION weevil) Hypersensitivity pneumonitis (HP), also referred to as extrinsic aller- Mushroom worker’s Thermophilic actinomycetes; Mushrooms gic alveolitis, is a pulmonary disease that occurs due to inhalational lung mushroom spores Disorders of the Respiratory System exposure to a variety of antigens leading to an inflammatory response Potato riddler’s lung Thermophilic actinomycetes; Moldy hay around of the alveoli and small airways. Systemic manifestations such as fever Aspergillus species potatoes and fatigue can accompany respiratory symptoms. Although sensiti- Tobacco grower’s lung Aspergillus species Tobacco zation to an inhaled antigen as manifested by specific circulating IgG Wine maker’s lung Botrytis cinerea Grapes antibodies is necessary for the development of HP, sensitization alone Birds and Other Animals is not sufficient as a defining characteristic, because many sensitized individuals do not develop HP. The incidence and prevalence of HP are Bird fancier’s lung (also Proteins derived by parakeets, Bird feathers, named by specific bird pigeons, budgerigars droppings, serum variable, depending on geography, occupation, avocation, and environ- exposures) proteins ment of the cohort being studied. As yet unexplained is the decreased Duck fever Duck feathers, serum proteins Ducks risk of developing HP in smokers. Fish meal worker’s lung Fish meal dust Fish meal OFFENDING ANTIGENS Furrier’s lung Dust from animal furs Animal furs HP can be caused by any of a large list of potential offending inhaled Laboratory worker’s Rat urine, serum, fur Laboratory rats antigens (Table 288-1). The various antigens and environmental con- lung ditions described to be associated with HP give rise to an expansive Pituitary snuff taker’s Animal proteins Pituitary snuff from list of monikers given to specific forms of HP. Antigens derived from lung bovine and porcine sources fungal, bacterial, mycobacterial, bird-derived, and chemical sources have all been implicated in causing HP. Poultry worker’s lung Chicken serum proteins Chickens Categories of individuals at particular risk in the United States Turkey handling disease Turkey serum proteins Turkeys include farmers, bird owners, industrial workers, and hot tub users. Other Occupational and Environmental Exposures Farmer’s lung occurs as a result of exposure to one of several possible Chemical worker’s lung Isocyanates Polyurethane foam, sources of bacterial or fungal antigens such as grain, moldy hay, or varnish, lacquer silage. Potential offending antigens include thermophilic actinomy- Detergent worker’s lung Bacillus subtilis enzymes Detergent cetes or Aspergillus species. Bird fancier’s lung (also referred to by Hot tub lung Cladosporium species; Contaminated water, names corresponding to specific birds) must be considered in patients Mycobacterium avium mold on ceiling who give a history of keeping birds in their home and is precipitated complex by exposure to antigens derived from feathers, droppings, and serum Humidifier fever (and air Several microorganisms Humidifiers and proteins. Occupational exposure to birds may also cause HP, as is conditioner lung) including: Aureobasidium air conditioners seen in poultry worker’s lung. Chemical worker’s lung is provoked by pullulans; Candida albicans; (contaminated water) exposure to occupational chemical antigens such as diphenylmethane thermophilic actinomycetes; diisocyanate and toluene diisocyanate. Mycobacteria may cause HP Mycobacterium species; rather than frank infection, a phenomenon observed in hot tub lung Klebsiella oxytoca; Naegleria gruberi and in HP due to metalworking fluid. Machine operator’s lung Pseudomonas species; Metal working fluid Mycobacteria species PATHOPHYSIOLOGY Sauna taker’s lung Aureobasidium species; other Sauna water While much remains to be learned regarding the pathophysiology of antigens HP, it has been established that HP is an immune-mediated condition Suberosis Penicillium glabrum; Cork dust that occurs in response to inhaled antigens that are small enough Chrysonilia sitophila to deposit in distal airways and alveoli. From an immunologic per- Summer-type Trichosporon cutaneum House dust mites, spective, HP is characterized by dysregulated TH1 and TH17 immune pneumonitis bird droppings responses. Although the presence of precipitating IgG antibodies Woodworker’s lung Alternaria species; Bacillus Oak, cedar, pine, against specific antigens in HP suggests a prominent role for adaptive subtilis mahogany dusts immunity in the pathophysiology of HP, innate immune mechanisms likely also make an important contribution. This is highlighted by the observation that Toll-like receptors and downstream signaling pro- CLINICAL PRESENTATION teins such as MyD88 are activated in HP, leading to neutrophil recruit- Given the heterogeneity among patients, variability in offending ment. Although no clear genetic basis for HP has been established, antigens, and differences in the intensity and duration of exposure to in specific cohorts, polymorphisms in genes involved in antigen antigen, the presentation of HP is accordingly variable. Although these processing and presentation, including TAP1 and major histocom- categories are not fully satisfactory in capturing this variability, HP has patibility complex type II, have been observed. In chronic HP, bone been traditionally categorized as having acute, subacute, and chronic marrow–derived fibrocytes may contribute to lung inflammation and forms. Acute HP usually manifests itself 4–8 h following exposure fibrosis. to the inciting antigen, often intense in nature. Systemic symptoms, HPIM21e_Part7_p2131-p2216.indd 2160 20/01/22 6:20 PM  including fevers, chills, and malaise, are prominent and are accompa- 2161 nied by dyspnea. Symptoms resolve within hours to days if no further exposure to the offending antigen occurs. In subacute HP resulting from ongoing antigen exposure, the onset of respiratory and systemic symptoms is typically more gradual over the course of weeks. A sim- ilar presentation may occur as a culmination of intermittent episodes of acute HP. Although respiratory impairment may be quite severe, antigen avoidance generally results in resolution of the symptoms, but with a slower time course, on the order of weeks to months, than that seen with acute HP. Chronic HP can present with an even more grad- CHAPTER 288 Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia ual onset of symptoms than subacute HP, with progressive dyspnea, cough, fatigue, weight loss, and clubbing of the digits. The insidious onset of symptoms and frequent lack of an anteceding episode of acute HP make diagnosing chronic HP a challenge. Unlike with the other forms of HP, there can be an irreversible component to the respiratory impairment that is not responsive to removal of the responsible antigen from the patient’s environment. The disease progression of chronic HP to lung fibrosis with honeycombing on chest imaging and hypoxemic respiratory failure can mirror that seen in idiopathic pulmonary fibro- sis (IPF), with a similar prognosis. Diagnostic uncertainty between these two entities is not uncommon. Fibrotic lung disease is a potential FIGURE 288-1 Chest computed tomography scan of a patient with subacute feature of chronic HP due to exposure to bird antigens, whereas an hypersensitivity pneumonitis in which scattered regions of ground-glass infiltrates emphysematous phenotype may be seen in farmer’s lung. in a mosaic pattern consistent with air trapping are seen bilaterally. This patient had The categories of acute, subacute, and chronic HP are not completely bird fancier’s lung. (Courtesy of TJ Gross; with permission.) sufficient in classifying HP. The HP Study Group found on cluster anal- ysis that a cohort of HP patients is best described in bipartite fashion, with one group featuring recurrent systemic signs and symptoms and (Fig. 288-1). Reticular changes and traction bronchiectasis can be the other featuring more severe respiratory findings. Some experts observed in chronic HP. Subpleural honeycombing similar to that seen have argued for a reclassification of HP into acute/inflammatory and in IPF may be present in advanced cases, although unlike in IPF, the chronic/fibrotic categories. lung bases are frequently spared. Concordant with the variability in the presentation of HP is the Pulmonary Function Testing Either restrictive or obstructive observed variability in outcome. HP that has not progressed to chronic PFTs can be present in HP, so the pattern of PFT change is not useful lung disease has a more favorable outcome with likely resolution if in establishing the diagnosis of HP. However, obtaining PFTs is of use antigen avoidance can be achieved. However, chronic HP resulting in in characterizing the physiologic impairment of an individual patient lung fibrosis has a poorer prognosis, with patients with chronic pigeon and in gauging the response to antigen avoidance and/or corticosteroid breeder’s lung having demonstrated a similar mortality as seen in IPF. therapy. Diffusion capacity for carbon monoxide may be significantly impaired, particularly in cases of chronic HP with fibrotic pulmonary DIAGNOSIS parenchymal changes. Although there is no set of universally accepted criteria for arriving at a diagnosis of HP, diagnosis depends foremost on establishing a history Serum Precipitins Assaying for IgG antibodies against specific of exposure to an offending antigen that correlates with respiratory and antigens, either through precipitin testing or direct serum measure- systemic symptoms. A careful occupational and home exposure history ment, can be a useful adjunct in the diagnosis of HP. However, the pres- should be taken and may be supplemented if necessary by a clinician ence of an immunologic response alone is not sufficient for establishing visit to the work or home environment. Specific inquiries will be influ- the diagnosis, because many asymptomatic individuals with high levels enced by geography and the occupation of the patient. When HP is of exposure to antigen may display specific IgG, as has been observed suspected by history, the additional workup is aimed at establishing an in farmers and in pigeon breeders. It should also be noted that pan- immunologic and physiologic response to inhalational antigen expo- els that test for several specific antigens often provide false-negative sure with chest imaging, pulmonary function testing (PFT), serologic results, because they represent an extremely limited proportion of the studies, bronchoscopy, and, on occasion, lung biopsy. Re-exposure to universe of potential offending environmental antigens. the offending environment may be performed to aid in confirming the Bronchoscopy Bronchoscopy with bronchoalveolar lavage (BAL) diagnosis of HP. may be used in the evaluation of HP. Although not a specific finding, BAL lymphocytosis is characteristic of HP. However, in active smokers, Chest Imaging Chest x-ray findings in HP are nonspecific and can a lower threshold should be used to establish BAL lymphocytosis, even lack any discernible abnormalities. In cases of acute and subacute because smoking will result in lower lymphocyte percentages. Most HP, findings may be transient and can include ill-defined micronod- cases of HP have a CD4+/CD8+ lymphocyte ratio of 25% eosinophils. Although the predominant symptoms of Cryptogenic organizing pneumonia acute eosinophilic pneumonia are cough, dyspnea, malaise, myalgias, Hypersensitivity pneumonitis night sweats, and pleuritic chest pain, physical examination findings Idiopathic pulmonary fibrosis include high fevers, basilar rales, and rhonchi on forced expiration. Pulmonary Langerhans cell granulomatosis Acute eosinophilic pneumonia most often affects males between age Malignant Neoplasms Associated with Eosinophilia 20 and 40 with no history of asthma. Although no clear etiology has been identified, several case reports have linked acute eosinophilic Leukemia pneumonia to recent initiation of tobacco smoking or even electronic Lymphoma cigarette inhalation (vaping), or exposure to other environmental stim- Lung cancer uli including dust from indoor renovations. Adenocarcinoma of various organs In addition to a suggestive history, the key to establishing a diagnosis Squamous cell carcinoma of various organs of acute eosinophilic pneumonia is the presence of >25% eosinophilia Systemic Disease Associated with Eosinophilia on BAL fluid. While lung biopsies show eosinophilic infiltration with acute and organizing diffuse alveolar damage, it is generally not nec- Postradiation pneumonitis essary to proceed to biopsy to establish a diagnosis. Although patients Rheumatoid arthritis present with an elevated white blood cell count, in contrast to other Sarcoidosis pulmonary eosinophilic syndromes, acute eosinophilic pneumonia is Sjögren’s syndrome often not associated with peripheral eosinophilia upon presentation. However, between 7 and 30 days of disease onset, peripheral eosino- philia often occurs with mean eosinophil counts of 1700. Erythrocyte sedimentation rate (ESR), C-reactive protein, and IgE levels are high can help distinguish between different diseases. Often, however, BAL, but nonspecific, whereas HRCT is always abnormal with bilateral ran- transbronchial, or open lung biopsies are required. In many cases, dom patchy ground-glass or reticular opacities and small pleural effu- biopsies or noninvasive diagnostic studies of other organs (e.g., echoc- sions in as many as two-thirds of patients. Pleural fluid is characterized ardiogram, electromyogram, or bone marrow biopsy) can be helpful. by a high pH with marked eosinophilia. PATHOPHYSIOLOGY Clinical Course and Response to Therapy Although some Pathologically, the pulmonary eosinophilic syndromes are character- patients improve spontaneously, most patients require admission to ized by tissue infiltration by eosinophils (Fig. 288-2). In eosinophilic an intensive care unit and respiratory support with either invasive granulomatosis with polyangiitis (EGPA), extravascular granulomas (intubation) or noninvasive mechanical ventilation. However, what and necrotizing vasculitis may occur in the lungs, as well as in the distinguishes acute eosinophilic pneumonia from both other cases of heart, skin, muscle, liver, spleen, and kidneys, and may be associated acute lung injury as well as some of the other pulmonary eosinophilic with fibrinoid necrosis and thrombosis. syndromes is the absence of organ dysfunction or multisystem organ The exact etiology of the various pulmonary eosinophilic syn- failure other than respiratory failure. One of the characteristic features dromes is unknown; however, it is felt that these syndromes result from of acute eosinophilic pneumonia is the high degree of corticosteroid dysregulated eosinophilopoiesis or an autoimmune process because of responsiveness and the excellent prognosis. Another distinguishing the prominence of allergic features and the presence of immune com- feature of acute eosinophilic pneumonia is that complete clinical and plexes, heightened T-cell immunity, and altered humoral immunity as radiographic recovery without recurrence or residual sequelae occurs evidenced by elevated IgE, IgG4, and rheumatoid factor. Because of in almost all patients within several weeks of initiation of therapy. its integral involvement in eosinophilopoiesis, interleukin 5 (IL-5) has been hypothesized to play an etiologic role. Monoclonal antibodies CHRONIC EOSINOPHILIC PNEUMONIA against IL-5 are now in clinical use for the treatment of eosinophilic In contrast to acute eosinophilic pneumonia, chronic eosinophilic asthma and eosinophilic granulomatosis with polyangiitis and are pneumonia is a more indolent syndrome that is characterized by pul- under investigation for other conditions characterized by pulmonary monary infiltrates and eosinophilia in both the tissue and blood. Most infiltrates with eosinophilia. Antineutrophil cytoplasmic antibodies patients are female nonsmokers with a mean age of 45, and patients do (ANCAs) are present in about one-third to two-thirds of patients with not usually develop the acute respiratory failure and significant hypox- EGPA; binding of ANCAs to vascular walls likely contributes to vascu- emia appreciated in acute eosinophilic pneumonia. Similar to EGPA, a lar inflammation and injury as well as chemotaxis of inflammatory cells. majority have asthma, with many having a history of allergies. Patients present with a subacute illness over weeks to months, with ACUTE EOSINOPHILIC PNEUMONIA cough, low-grade fevers, progressive dyspnea, weight loss, wheezing, Acute eosinophilic pneumonia is a syndrome characterized by fevers, malaise, and night sweats, and a chest x-ray with migratory bilateral acute respiratory failure that often requires mechanical ventilation, peripheral or pleural-based opacities. Although this “photographic HPIM21e_Part7_p2131-p2216.indd 2163 20/01/22 6:20 PM  2164 negative pulmonary edema” appearance on chest x-ray and chest CT is NEUROLOGIC Over three-fourths of EGPA patients have neurologic pathognomonic of chronic eosinophilic pneumonia, 50% of patients bleeding, and colitis. Ischemic bowel, pancreatitis, and cholecystitis relapse, and many require prolonged courses of corticosteroids for have also been reported in association with EGPA and usually portend months to years. a worse prognosis. RENAL Renal involvement is more common than once thought, and EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA) ~25% of patients have some degree of renal involvement. This may Previously known as allergic angiitis granulomatosis or Churg-Strauss include proteinuria, glomerulonephritis, renal insufficiency, and rarely, syndrome, this complex syndrome is characterized by eosinophilic renal infarct. vasculitis that may involve multiple organ systems including the lungs, Lab Abnormalities Systemic eosinophilia is the hallmark labora- heart, skin, GI tract, and nervous system. Although EGPA is charac- tory finding in patients with EGPA and reflects the likely pathogenic terized by peripheral and pulmonary eosinophilia with infiltrates on role that the eosinophil plays in this disease. Eosinophilia >10% is one chest x-ray, the primary features that distinguish EGPA from other of the defining features of this illness and may be as high as 75% of the pulmonary eosinophilic syndromes are the presence of eosinophilic peripheral white blood cell count. It is present at the time of diagnosis vasculitis in the setting of asthma and involvement of multiple end in >80% of patients, but may respond quickly (often within 24 h) to organs (a feature it shares with hypereosinophilic syndrome). Although initiation of systemic corticosteroid therapy. Even in the absence of perceived to be quite rare, in the last few years, there has appeared to be systemic eosinophilia, tissue eosinophilia may be present. an increased incidence of this disease, particularly in association with Although not specific to EGPA, ANCAs are present in approxi- various asthma therapies, including leukotriene modifiers and anti- mately one-third to two-thirds of patients, mostly in a perinuclear IGE therapy with omalizumab, possibly due to concurrent systemic staining pattern, with specific antibodies against myeloperoxidase corticosteroid withdrawal (forme fruste EGPA). detected. Nonspecific lab abnormalities that may be present in patients The primary features of EGPA include asthma, peripheral eosino- with EGPA include a marked elevation in ESR, a normochromic nor- philia, neuropathy, pulmonary infiltrates, paranasal sinus abnormality, mocytic anemia, an elevated IgE, hypergammaglobulinemia, and pos- and presence of eosinophilic vasculitis. The mean age at diagnosis is itive rheumatoid factor and antinuclear antibodies (ANA). Although 48 years, with a range of 14–74 years; the average length of time BAL often reveals significant eosinophilia, this may be seen in other between diagnosis of asthma and vasculitis is 9 years. EGPA typically eosinophilic lung diseases. Similarly, PFT often reveals an obstructive occurs in several phases. The prodromal phase is characterized by defect similar to asthma.