Hypersensitivity Merck Manual Chapter 76

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Hypersensitivity (allergic) diseases of the lungs include

hypersensitivity pneumonitis (extrinsic allergic alveolitis),

allergic bronchopulmonary aspergillosis, and many drug reactions.

Eosinophilic pneumonias and certain noninfectious pulmonary

granulomatoses are suspected to be of allergic origin. Bronchial

asthma is discussed in Ch. 68; occupational asthma, in Ch. 75.

Hypersensitivity reactions (see also Ch. 148) may be classified into

four types based on their pathogenetic mechanisms (see Table 76-1).

Although the classification has been criticized as an

oversimplification, it is useful in understanding immune-mediated

reactions injurious to host tissue.

Hypersensitivity diseases of the lungs may be caused by more than

one type of hypersensitivity reaction. For example, hypersensitivity

pneumonitis may involve types III and IV; allergic bronchopulmonary

aspergillosis, types I and III.

Hypersensitivity Pneumonitis

A diffuse interstitial granulomatous lung disease caused by an

allergic response to inhaled organic dusts or, less commonly, to

simple chemicals.

Hypersensitivity pneumonitis (extrinsic allergic alveolitis)

includes numerous examples that are caused by specific antigens.

Farmer's lung, associated with repeated inhalation of dusts from hay

containing thermophilic actinomycetes, is the prototype.

Etiology and Pathogenesis

The number of specific substances known to be capable of causing

hypersensitivity pneumonitis is increasing. Most commonly, the agent

is a microorganism or a foreign animal or vegetable protein.

However, simple chemicals, when inhaled in considerable amounts, may

also cause the disease. Table 76-2 lists common causative antigens

with examples of the associated diseases.

Hypersensitivity pneumonitis is thought to be immunologically

mediated, although pathogenesis is not completely clear.

Precipitating antibodies to the causative antigen are usually

demonstrated, suggesting a type III reaction, although vasculitis is

not common. Type IV hypersensitivity is suggested by the

granulomatous primary tissue reaction and findings in animal models.

Only a small proportion of exposed persons develop symptoms, and

only after weeks to months of exposure, which is required for

induction of sensitization. Chronic progressive parenchymal disease

may result from continuous or frequent low-level exposure to the

antigen. A history of allergic disease (eg, asthma, hay fever) is

uncommon and is not a predisposing factor.

Diffuse granulomatous interstitial pneumonitis is characteristic but

not definitive or specific. Lymphocyte and plasma cell infiltrates

occur along airways and in thickened alveolar septa; granulomas are

single, nonnecrotizing, and randomly scattered in the parenchyma

without mural vascular involvement. The degree of fibrosis is

usually mild but depends on the stage of the disease. Bronchiolitis

occurs to some degree in about 50% of patients with farmer's lung.

Symptoms and Signs

In the acute form, episodes of fever, chills, cough, and dyspnea

occur in a previously sensitized person, typically 4 to 8 h after

reexposure. Anorexia, nausea, and vomiting may also be present. Fine-

to-medium inspiratory rales may be heard on auscultation. Wheezing

is unusual. With avoidance of the antigen, symptoms usually lessen

within hours, although complete recovery may take weeks and

pulmonary fibrosis may follow repeated episodes. A subacute form may

develop insidiously with cough and dyspnea over days to weeks, with

progression sometimes requiring urgent hospitalization. In the

chronic form, progressive exertional dyspnea, productive cough,

fatigue, and weight loss may develop over months to years; the

disease may progress to respiratory failure.

Chest x-ray findings range from normal to diffuse interstitial

fibrosis. Bilateral patchy or nodular infiltrates, coarsening of

bronchovascular markings, or a fine acinar pattern suggestive of

pulmonary edema may be seen. Hilar lymphadenopathy and pleural

effusion are rare. CT, especially high-resolution CT, may be

superior in assessing the type and extent of abnormalities, but

there are no pathognomonic CT findings.

Pulmonary function tests show a restrictive pattern with decreased

lung volumes, a decreased carbon monoxide diffusing capacity,

abnormal ventilation/perfusion ratios, and hypoxemia. Airway

obstruction is unusual in acute disease but may develop in chronic

disease. Eosinophilia is not usual.

Diagnosis

Diagnosis depends on a history of environmental exposure and

compatible clinical features, chest x-ray findings, and pulmonary

function test results. The presence of specific precipitating

antibodies to the suspected antigen in the serum helps confirm the

diagnosis, although neither their presence nor absence is

definitive. A history of exposure may provide clues (eg, persons

exposed at work may become symptom-free every weekend, or symptoms

may reappear 4 to 8 h after reexposure). History of exposure to

causative antigens may not be elicited easily, particularly for air-

conditioner (humidifier) lung, and an assessment of the environment

by experts may help in difficult cases. In puzzling cases or in

those without a history of environmental exposure, open lung biopsy

may be useful. Bronchoalveolar lavage is often used to help diagnose

interstitial lung diseases, but its value is not established. The

number of lymphocytes, particularly T cells, may be increased in

hypersensitivity pneumonitis (and in sarcoidosis). The CD8+

(suppressor/cytotoxic) T-cell subset may predominate in some stages

of hypersensitivity pneumonitis, whereas the CD4+ (helper/inducer)

subset may predominate in active sarcoidosis. Transbronchial biopsy

is of very limited value and may be misleading because the sample

size is small.

Atypical farmer's lung (pulmonary mycotoxicosis) refers to a

syndrome of fever, chills, and cough occurring within hours of

massive exposure to moldy silage (eg, when uncapping a silo);

precipitins are not present, suggesting a nonimmunologic mechanism.

Pulmonary infiltrates are usually present. This condition,

associated with aspergillus-contaminated old silage, is to be

distinguished from silo filler's disease, caused by toxic oxides of

nitrogen given off by fresh silage. Organic dust toxic syndrome is

characterized by transient fever and muscle aches, with or without

respiratory symptoms, and no evidence of sensitization after

exposure to agricultural dusts (eg, grain fever). Humidifier fever

refers to cases associated with contaminated heating, cooling, and

humidifying systems (see under Sick Building Syndrome in Ch. 75).

Endotoxin is thought to have an etiologic role in organic dust toxic

syndrome and humidifier fever.

Hypersensitivity pneumonitis can be distinguished from psittacosis,

viral pneumonia, and other infective pneumonias by cultures and

serologic tests. Because of similar clinical features, x-ray

findings, and pulmonary function test results, idiopathic pulmonary

fibrosis (Hamman-Rich syndrome, cryptogenic fibrosing alveolitis,

usual interstitial pneumonia of Liebow) may be difficult to

distinguish from hypersensitivity pneumonitis when the typical

history of exposure followed by an acute episode is not elicited.

Variants of bronchiolitis in adults (eg, bronchiolitis obliterans

with organizing pneumonia) may appear as restrictive (interstitial)

disease and may be difficult to differentiate in the absence of

relevant history or typical findings in open lung biopsy.

Evidence of autoimmunity, such as positive antinuclear antibody or

latex fixation test or the presence of a collagen vascular disorder,

suggests an idiopathic or a secondary type of usual interstitial

pneumonia. Chronic eosinophilic pneumonias are often accompanied by

peripheral blood eosinophilia. Sarcoidosis often results in hilar

and paratracheal lymph node enlargement and may affect other organs.

Pulmonary angiitis-granulomatosis syndromes (Wegener's,

lymphomatoid, and allergic granulomatosis [Churg-Strauss syndrome])

are usually accompanied by upper respiratory tract or kidney

disease. Bronchial asthma and allergic bronchopulmonary

aspergillosis produce eosinophilia and airway obstruction rather

than restrictive abnormalities.

Prophylaxis and Treatment

The most effective treatment is cessation of further exposure to the

causative antigen. Acute disease is self-limiting if additional

exposure is avoided. Socioeconomic factors may preclude a complete

change of environment. Dust control or the use of protective masks

to filter the causative dust particles in contaminated areas may be

effective. Sometimes, chemical means can be used to prevent the

growth of antigenic microorganisms (eg, in hay). Extensive cleaning

of wet ventilation systems and corresponding work areas is also

effective in some settings.

Corticosteroids may be useful in severe acute or subacute cases but

have not been shown to alter eventual outcome in chronic disease.

Prednisone 60 mg/day is given po for 1 to 2 wk and then tapered over

the next 2 wk to 20 mg/day, followed by weekly decrements of 2.5 mg

until withdrawal is complete. Recurrence or progression of symptoms

requires modification of this regimen. Antibiotics are not indicated

unless there is a superimposed infection.

Eosinophilic Pneumonias

A group of diseases of known or unknown etiology characterized by

eosinophilic pulmonary infiltrates and, commonly, peripheral blood

eosinophilia.

Eosinophilic pneumonia is sometimes called the pulmonary infiltrates

with eosinophilia (PIE) syndrome.

Etiology and Pathogenesis

Causes include parasites (eg, roundworms, Toxocara larvae,

filariae), drugs (eg, penicillin, aminosalicylic acid, hydralazine,

nitrofurantoin, chlorpropamide, sulfonamides), chemical sensitizers

(eg, nickel carbonyl inhaled as a vapor), and fungi (eg, Aspergillus

fumigatus, which causes allergic bronchopulmonary aspergillosis--see

below). Most eosinophilic pneumonias, however, are of unknown

etiology, although a hypersensitivity mechanism is suspected.

Eosinophilia suggests a type I hypersensitivity reaction; other

features of the syndrome (vasculitis, round cell infiltrates)

suggest type III and possibly type IV reactions.

Eosinophilic pneumonias (see Table 76-3) are often associated with

bronchial asthma. Those associated with asthma and those of unknown

etiology can be classified into three general groups: extrinsic

bronchial asthma with the PIE syndrome, which often is allergic

bronchopulmonary aspergillosis; intrinsic bronchial asthma with the

PIE syndrome (chronic eosinophilic pneumonia), commonly with

characteristic peripheral infiltrates on chest x-ray; and allergic

granulomatosis (Churg-Strauss syndrome), a variant of polyarteritis

nodosa with a predilection for the lungs. Simple eosinophilic

pneumonia (Löffler's syndrome) may occasionally be associated with

mild asthma.

Eosinophilic pneumonias not associated with asthma include acute

eosinophilic pneumonia, the eosinophilia-myalgia syndrome, and the

hypereosinophilic syndrome. Acute eosinophilic pneumonia, a distinct

entity of unknown cause, results in acute fever, severe hypoxemia,

diffuse pulmonary infiltrates, and > 25% eosinophils in

bronchoalveolar lavage fluid; it resolves promptly and completely

with corticosteroid therapy. The eosinophilia-myalgia syndrome is

associated with ingestion of large doses of contaminated L-

tryptophan used as a dietary supplement. Pulmonary infiltrates

occasionally occur along with the expected features of myalgia,

muscle weakness, skin rash, and soft tissue induration resembling

scleroderma. Diagnostic criteria for the hypereosinophilic syndrome

are persistent eosinophilia > 1500 eosinophils/mm3 for more than 6

mo, lack of evidence for other known causes of eosinophilia, and

systemic involvement of the heart, liver, spleen, CNS, or lungs. The

heart is commonly affected. Fever, weight loss, and anemia are

common. Thromboembolic disease, arterial more commonly than venous,

occurs often.

Characteristically, alveoli are filled with eosinophils and large

mononuclear cells, and septa are infiltrated by eosinophils, plasma

cells, and large and small mononuclear cells. Mucus plugging of

bronchioles and vascular infiltrations also occur.

Symptoms and Signs

Symptoms and signs may be mild or life threatening. Löffler's

syndrome may include low-grade fever, minimal (if any) respiratory

symptoms, and prompt recovery. Other forms of the PIE syndrome may

produce fever and symptoms of bronchial asthma, including cough,

wheezing, and dyspnea at rest. Without therapy, chronic eosinophilic

pneumonia is often progressive and life threatening, as is acute

eosinophilic pneumonia. Marked blood eosinophilia (between 20 and

40%, at times considerably higher) is usually striking. Chest x-rays

show rapidly developing and disappearing infiltrates in various

lobes (migratory infiltrates).

Diagnosis

Helminthic infections should be sought, depending on the patient's

geographic location. Parasites and A. fumigatus may be present in

the sputum. A complete drug history should be elicited. Differential

diagnosis includes TB, sarcoidosis, Hodgkin's disease and other

lymphoproliferative disorders, eosinophilic granuloma of the lung,

desquamative interstitial pneumonitis, and collagen vascular

disorders. Hypersensitivity pneumonitis and Wegener's granulomatosis

are not commonly associated with eosinophilia.

Treatment

The disease may be self-limited and benign, requiring no treatment.

If symptoms are sufficiently severe, however, treatment with

corticosteroids (eg, prednisone, as for hypersensitivity pneumonitis-

-see above) is usually dramatically effective; in acute eosinophilic

pneumonia and idiopathic chronic eosinophilic pneumonia, such

treatment may be lifesaving. When bronchial asthma is present, usual

asthma therapy is indicated (see Asthma in Ch. 68). For helminthic

infections, appropriate vermifuges should be used (see Ch. 161).

Allergic Bronchopulmonary Aspergillosis

An allergic reaction to Aspergillus fumigatus occurring in asthmatic

patients as eosinophilic pneumonia.

Rarer organisms, such as Penicillium, Candida, Curvularia, or

Helminthosporium sp, may cause identical syndromes more accurately

termed allergic bronchopulmonary mycoses.

Etiology and Pathogenesis

The presence of A. fumigatus growing in the bronchial lumen provokes

an allergic response in the airways and parenchyma. Types I and III

(and possibly type IV) hypersensitivity reactions are involved in

pathogenesis. This form of aspergillosis is not invasive.

The affected alveoli are packed with eosinophils. Granulomatous

interstitial pneumonitis, with peribronchial and alveolar septal

infiltration by plasma cells, mononuclear cells, and numerous

eosinophils, may be present. The number of bronchiolar mucous glands

and goblet cells may be increased. Proximal bronchiectasis develops

in advanced cases. Fibrosis can lead to severe, irreversible airway

obstruction.

Symptoms and Signs

The patient usually presents with an exacerbation of bronchial

asthma and may have an intermittent low-grade fever and systemic

symptoms. Signs of airway obstruction (prolonged expiration and

wheezing) are noted during chest examination.

Serial chest x-rays show transient shadows that may migrate from

lobe to lobe. Mucus plugs may produce atelectasis. CT is useful in

delineating bronchiectasis, which usually occurs in proximal

airways. Bronchograms should not be performed. Sputum examination

may detect small yellowish or brownish flecks or plugs containing A.

fumigatus mycelia, Curschmann's spirals (mucoid casts), Charcot-

Leyden crystals (elongated eosinophilic bodies formed from

eosinophilic granules), mucus, and eosinophils. All of these except

mycelia also occur in sputum of asthmatics. Sputum cultures may be

positive for Aspergillus but are inconsistent; occasionally,

demonstrating the fungus is difficult. Pulmonary function tests show

an obstructive pattern with decreased flow rates. Blood eosinophilia

is usually > 1000/µL, and levels for total IgE and IgE antibodies

specific for A. fumigatus may be extremely high. Serologic tests

commonly detect precipitating antibodies to A. fumigatus. Skin

testing with Aspergillus antigen may result in a biphasic positive

reaction with an immediate type I wheal and flare reaction, followed

by a late-onset reaction (erythema, edema, and tenderness that is

maximum at 6 to 8 h). The significance of the late reaction is

uncertain, however, and the late reaction is both unnecessary and

insufficient for the diagnosis.

Diagnosis

Diagnostic features include extrinsic (atopic, allergic) asthma

(usually long-standing), pulmonary infiltrates, sputum and blood

eosinophilia, and hypersensitivity to Aspergillus or another

relevant fungus as shown by a wheal and flare skin test,

precipitating antibodies in the serum, and high levels of total and

specific IgE. The presence of these features (see Table 76-4) makes

the diagnosis very likely.

Presenting features mimic those of uncomplicated asthma and may

resemble those of allergic granulomatosis and other chronic

eosinophilic pneumonias. In hypersensitivity pneumonitis, pulmonary

abnormalities are restrictive rather than obstructive, and

eosinophilia is rare.

Invasive aspergillosis (see Aspergillosis in Ch. 158) usually occurs

as a serious opportunistic pneumonia in immunosuppressed patients.

Aspergillomas may occur in old cavitary disease (eg, TB) or, rarely,

in rheumatoid spondylitis due to colonization within cystic

airspaces of the upper lobes.

Treatment

Because A. fumigatus is ubiquitous, avoiding it is difficult.

Treatment with corticosteroids and other antiasthmatic drugs

(theophylline, sympathomimetics) is usually successful in allowing

expectoration of the mucus plugs and the Aspergillus with them.

Prednisone as for hypersensitivity pneumonitis (see above) is

appropriate, although 7.5 to 15 mg/day may be necessary for

maintenance in long-term treatment and for prevention of

progressive, irreversible disease. The success rate for maintenance

therapy with inhaled corticosteroids is not established.

Immunotherapy and fungicidal or fungistatic drugs are not

recommended. Hyposensitization with extracts of A. fumigatus is

contraindicated because it produces bothersome local reactions and

may exacerbate symptoms.

A sign of successful treatment and favorable prognosis is a

sustained fall in serum IgE. Spirometry and chest x-rays should be

performed periodically because the disease may progress without

obvious clinical symptoms.