Harrison’s Manual of Medicine



Hypersensitivity Pneumonitis

DEFINITION   Increased responsiveness of lower airways to multiple stimuli; episodic, and with reversible obstruction; may range in severity from mild without limitation of pt’s activity to severe and life-threatening. Severe obstruction persisting for days or weeks is known as status asthmaticus.
EPIDEMIOLOGY AND ETIOLOGY   Some 4–5% of adults and up to 10% of children are estimated to experience episodes of asthma. Basic abnormality is airway hyperresponsiveness to both specific and nonspecific stimuli. All pts demonstrate enhanced bronchoconstriction in response to inhalation of methacholine or histamine (nonspecific bronchoconstrictor agents). Some pts may be classified as having allergic asthma; these experience worsening of symptoms on exposure to pollens or other allergens. They characteristically give personal and/or family history of other allergic diseases, such as rhinitis, urticaria, and eczema. Skin tests to allergens are positive; serum IgE may be
. Bronchoprovocation studies may demonstrate positive responses to inhalation of specific allergens.
A significant number of asthmatic pts have negative allergic histories and do not react to skin or bronchoprovocation testing with specific allergens. Many of these develop bronchospasm after a URI. These pts are said to have idiosyncratic asthma.
Some pts experience worsening of symptoms on exercise or exposure to cold air or occupational stimuli. Many note increased wheezing following viral URI or in response to emotional stress.
PATHOGENESIS   Common denominator underlying the asthmatic diathesis is nonspecific hyperirritability of the tracheobronchial tree. The etiology of airway hyperresponsiveness in asthma is unknown, but airway inflammation is believed to play a fundamental role. Airway reactivity may fluctuate, and fluctuations correlate with clinical symptoms. Airway reactivity may be increased by a number of factors: allergenic, pharmacologic, environmental, occupational, infectious, exercise-related, and emotional. Among the more common are airborne allergens, aspirin, b-adrenergic blocking agents (e.g., propranolol, timolol), sulfites in food, air pollution (ozone, nitrogen dioxide), and respiratory infections.

Approach to the Patient

History   Symptoms: wheezing, dyspnea, cough, fever, sputum production, other allergic disorders. Possible precipitating factors (allergens, infection, etc.); asthma attacks often occur at night. Response to medications. Course of previous attacks (e.g., need for hospitalization, steroid treatment).
Physical Exam   General: tachypnea, tachycardia, use of accessory respiratory muscles, cyanosis, pulsus paradoxus (accessory muscle use and pulsus paradoxus correlate with severity of obstruction). Lungs: adequacy of aeration, symmetry of breath sounds, wheezing, prolongation of expiratory phase, hyperinflation. Heart: evidence for CHF. ENT/skin: evidence of allergic nasal, sinus, or skin disease.
Laboratory   While PFT findings are not diagnostic, they are very helpful in judging severity of airway obstruction and in following response to therapy in both chronic and acute situations. Forced vital capacity (FVC), FEV1, maximum mid- and peak expiratory flow rate (MMEFR, PEFR), FEV1/FVC are decreased; residual volume and TLC increased during episodes of obstruction; DLCO usually normal or slightly increased. Reduction of FEV1 to <25% predicted or <0.75 L after administration of a bronchodilator indicates severe disease. CBC may show eosinophilia. IgE may show mild elevations; marked elevations may suggest evidence of allergic bronchopulmonary aspergillosis (ABPA). Sputum examination: eosinophilia, Curschmann’s spirals (casts of small airways), Charcot-Leyden crystals; presence of large numbers of neutrophils suggests bronchial infection. ABGs: uniformly show hypoxemia during attacks; usually hypocarbia and respiratory alkalosis present; normal or elevated PCO2 worrisome as it may suggest severe respiratory muscle fatigue and airways obstruction. CXR not always necessary: may show hyperinflation, patchy infiltrates due to atelectasis behind plugged airways; important when complicating infection is a consideration.
DIFFERENTIAL DIAGNOSIS   “All that wheezes is not asthma”: CHF; chronic bronchitis/emphysema; upper airway obstruction due to foreign body, tumor, laryngeal edema; carcinoid tumors (usually associated with stridor, not wheezing); recurrent pulmonary emboli; eosinophilic pneumonia; vocal cord dysfunction; systemic vasculitis with pulmonary involvement.

Removal of inciting agent, if possible, is most successful treatment. Desensitization or immunotherapy, although popular, has limited scientific support and minimal clinical effectiveness.
Pharmacologic agents for treating asthma can be divided into two general categories: (1) drugs that inhibit smooth-muscle contraction, “quick relief medications” (b-adrenergic agonists, methylxanthines, and anticholinergics); and (2) agents that prevent or reverse inflammation, “long-term control medications” (glucocorticoids, leukotriene inhibitors and receptor antagonists, and mast cell–stabilizing agents).
1.   b-Adrenergic agonists: Inhaled route provides most rapid effect and best therapeutic index; resorcinols (metaproterenol, terbutaline, fenoterol), saligenins (albuterol), and catecholamines (isoproterenol, isoetharine) may be given by nebulizer or metered-dose inhaler. Epinephrine, 0.3 mL of 1:1000 solution SC (for use in acute situations in absence of cardiac history). Salmeterol, a very long-acting congener of albuterol (9–12 mL), is not recommended for acute attacks but may be helpful for nocturnal or exercise-induced asthma. IV administration of b-adrenergic agents for severe asthma is not considered justified due to the risk of toxicity.
2.   Methylxanthines: Theophylline and various salts; adjust dose to maintain blood level between 5 and 15 µg/mL; may be given PO or IV (as aminophylline). Theophylline clearance varies widely and is reduced with age, hepatic dysfunction, cardiac decompensation, cor pulmonale, febrile illness. Many drugs also alter theophylline clearance (decrease half-life: cigarettes, phenobarbital, phenytoin; increase half-life: erythromycin, allopurinol, cimetidine, propranolol). Long-acting oral compounds permit qd or bid dosing. Single dose at nighttime reduces nocturnal symptoms. For acute therapy, intravenous therapy is used. In children and young-adult smokers, a loading dose of 6 mg/kg is given, followed by an infusion of 1.0(mg/kg)/h for 12 h, after which the infusion is reduced to 0.8(mg/kg)/h. In other pts not on theophylline, the loading dose remains the same, but the infusion rate is reduced to 0.1–0.5 (mg/kg)/h. In pts already taking theophylline, the loading dose is withheld or reduced. Theophylline compounds have lost favor in asthma therapy due to narrow toxic-therapeutic margin.
3.   Anticholinergics: Aerosolized atropine and related compounds, such as ipratropium, a nonabsorbable quaternary ammonium. May enhance the bronchodilation achieved by sympathomimetics but is slow acting (60–90 min to peak bronchodilation). Ipratropium may be given by metered-dose inhaler, 2 puffs up to every 6 h. Expectorants and mucolytic agents add little to the management of acute or chronic asthma.
4.   Glucocorticoids: Systemic or oral administration most beneficial for severe or refractory asthma. For hospitalized patients, methylprednisolone 40–60 mg q6h IV is usual. Prednisone 60 mg q6h orally is equivalent. Lower doses may be equally effective with fewer side effects. Steroids in acute asthma require ³6h to have an effect.
For exacerbations of asthma in the outpatient setting, prednisone 40–60 mg PO daily, followed by tapering schedule of 50% reduction every 3–5 d. Inhaled glucocorticoid preparations are important adjuncts to chronic therapy; not useful in acute attacks. Effects of inhaled steroids are dose-dependent. Inhaled steroids are a mainstay of outpatient management and should be started in any pt not easily controlled with occasional use of inhaled adrenergic agents. Agents available include beclamethasone, budesonide, flunisolide, fluticasone proprionate, and triamcinolone acetonide. Dosing should be adjusted to disease activity, with frequent attempts to taper to low maintenance (1–2 puffs, 1–2 times/day). In addition to local symptoms (dysphonia, thrush), systemic effects may occur (e.g., adrenal suppression, cataracts, bone loss).
5.   Cromolyn sodium and Nedocromil sodium: Not bronchodilators; useful in chronic therapy for prevention, not useful during acute attacks; administered as metered-dose inhaler or nebulized powder, 2 puffs daily. A trial of 4–6 weeks is often necessary to determine effectiveness in chronic asthma. Because the drugs may block acute bronchoconstriction when administered 15–20 min before exposure to antigens, chemicals, or exercise, they may be of use in selected pts who have predictable attacks of extrinsic asthma.
6.   Leukotriene modifiers: The 5-lipoxygenase inhibitor, zileuton, and the LTD4 receptor antagonists, zafirlukast and monteleukast, are recent additions to anti-inflammatory therapy of asthma. The LTD4 receptor antagonists are long-acting, permitting qd or bid dosing. Effective in about one-half of pts. Modest bronchodilators with action against exercise-induced asthma. May reduce nocturnal symptoms.
Emergencies   Aerosolized b2 agonists are the primary therapy of acute episodes of asthma. Give every 20 min for 3 doses, then every 2 h until attack subsides. Aminophylline may speed resolution after first hour in 5–10% of pts. Paradoxical pulse, accessory muscle use, and marked hyperinflation indicate severe disease and mandate ABG measurement and monitoring of PEFR or FEV1. PEFR ³20% predicted on presentation with failure to double after 60 min of treatment suggests addition of steroid therapy. Failure of PEFR to improve to ³70% of baseline with emergency treatment suggests need for hospitalization, with final decision made on individual factors (symptoms, past history, etc.). PEFR £40% after emergency treatment mandates admission.
Chronic Treatment First-line therapy for intermittent asthma consists of b2 agonists. Persistence of symptoms should prompt addition of an anti- inflammatory agent (glucocorticoids or a mast cell–stabilizing agent). Medication adjustments should be based on objective measurement of lung function (PEFR, FEV1), and pts should monitor PEFR regularly.

Hypersensitivity Pneumonitis
DEFINITION   Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is an immunologically mediated inflammation of lung parenchyma involving alveolar walls and terminal airways secondary to repeated inhalation of a variety of organic dusts by a susceptible host.
ETIOLOGY   A number of inhaled substances have been implicated (Table 253-1, p. 1464 in HPIM-15). These substances are usually organic antigens, particularly thermophilic actinomycetes, but may include inorganic compounds such as isocyanates.
CLINICAL MANIFESTATIONS   Symptoms may be acute, subacute, or chronic depending on the frequency and intensity of exposure to the causative agent; in acute form, cough, fever, chills, dyspnea appear 6–8 h after exposure to antigen; in subacute and chronic forms, temporal relationship to antigenic exposure may be lost, and insidiously increasing dyspnea may be predominant symptom.
DIAGNOSIS   History   Occupational history and history of possible exposures and relationship to symptoms are very important.
Physical Exam   Nonspecific; may reveal rales in lung fields, cyanosis in advanced cases.
Laboratory   Serum precipitins to offending antigen may be present but are not specific. After acute exposure to antigen, neutrophilia and lymphopenia are common, as are increased nonspecific tests of inflammation (C-reactive protein, rheumatoid factor, serum immunoglobulins).
CXR: nonspecific changes in interstitial structures; pleural changes or hilar adenopathy rare. High-resolution chest CT may show characteristic constellation of findings: (1) global lung involvement with
lung density, (2) prominence of medium-sized bronchial walls, (3) patchy airspace consolidation, and (4) absence of lymphadenopathy. PFTs and ABGs: restrictive pattern possibly associated with airway obstruction; diffusing capacity decreased; hypoxemia at rest or with exercise. Bronchoalveolar lavage may show increased lymphocytes of suppressor-cytotoxic phenotype. Lung biopsy may be necessary in some pts who do not have sufficient other criteria; transbronchial biopsy may suffice, but open lung biopsy is frequently necessary.
DIFFERENTIAL DIAGNOSIS   Other interstitial lung diseases, including sarcoidosis, idiopathic pulmonary fibrosis, lung disease associated with collagen-vascular diseases, drug-induced lung disease; eosinophilic pneumonia; allergic bronchopulmonary aspergillosis; silo-fillers’ disease; “pulmonary mycotoxicosis” or “atypical” farmer’s lung; infection.

Avoidance of offending antigen is essential. Chronic form may be partially irreversible at the time of diagnosis. Prednisone 1(mg/dg)/d for 7–14 d, followed by tapering schedule over 2–4 weeks to lowest possible dose. Subacute form may have severe physiologic impairment and may progress for several days in hospital. Prednisone therapy is used at the same initial dose, tapered after 7–14 d over 5–6 weeks at a rate dictated by Sx. Pts with acute form usually recover without glucocorticoids.


For a more detailed discussion, see Mcfadden ER Jr: Asthma, Chap. 252, p. 1456; and Kline JN, Hunninghake GW: Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia, Chap. 253, p. 1463, in HPIM- 15.



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