Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

Author: André Mascarenhas Oliveira - Pathology Resident
Mayo Clinic, Rochester, MN - USA

Definition

Kaltreider defines hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, as "a group of related inflammatory interstitial lung diseases that result from hypersensitivity immune reactions to the repeated inhalation or ingestion of various antigens derived from fungal, bacterial, animal protein, or reactive chemical sources"¹.

Etiology

Multiple causative agents have been identified² but the two most common are: (1) thermophilic actinomycetes, responsible for farmer's lung, and (2) avian proteins, which induce bird fancier's lung^1,3.

Classification

HP has been traditionally classified in acute, subacute and chronic phases. However, only two clinical phases or syndromes are identified: acute and subacute/chronic³.

Pathogenesis

Two types of hypersensitivity reactions have been described in HP: in the acute phase, the type III or immune complex-mediated hypersensitivity reaction occurs; in the subacute/chronic phase, the type IV or T cell-mediated hypersensitivity reaction predominates¹.

Clinical Manifestations

The acute phase is characterized by fever, chills, dyspnea, generalized myalgia, nonproductive cough, and bibasilar rales that occur 4 to 6 hours after antigen exposure. These manifestations resolve without any specific treatment in 1 to 3 days^3,4.

In the subacute/chronic phase, the patients presents with slowly progressive dyspnea, fatigue, low-grade fever, weight loss, chronic nonproductive cough, and bibasilar crackles over months or years; cor pulmonale may occur in the late stage of chronic HP^3,4,5.

Radiology

In the acute phase, chest radiographs are normal in 70% of cases; bilateral reticulonodular interstitial infiltrates in the middle and lower lungs with sparing of the costophrenic angles are the most common abnormal findings. On CT scan, these infiltrates have a more diffuse distribution³.

In the subacute/chronic phase, the chest radiographs reveal reticulonodular to small nodular interstitial infiltrates in the early stage. Traction bronchiectasis, honeycombing, and interstitial fibrosis, predominantly in the middle and upper lobes, are observed in the late stage; cardiomegaly is present in cases associated with cor pulmonale3.

Pulmonary Function Test

The subacute/chronic phase is characterized by a restrictive ventilatory pattern and a decreased diffusing capacity for carbon monoxide; a mild obstructive pattern is sometimes observed^1,4,6. The acute phase does have the same findings but these are transient1.

Broncoalveolar Lavage (BAL)

The Acute phase is characterized by an increased number of neutrophils and T CD4+ lymphocytes^2,5. In contrast, an increased number of T CD8+ lymphocytes is observed in the subacute/chronic phase^1,5.

Serologic Studies

These studies, which include precipitin analysis, antigen-induced lymphocyte proliferation, and skin testing, indicate sensitization with a specific antigen and support the diagnosis of HP. However, these tests are not usually available for routine clinical practice^1,5.

Histopathology

The subacute/chronic phase is characterized by the histologic triad of cellular bronchiolitis, interstitial fibrosis/chronic inflammation, and small nonnecrotizing granulomas⁷. This triad is present in 80% of cases⁸. The histopathologic findings observed in HP are listed in table 1 and showed in figures 1 and 2. Little is known about the histolopathology of the acute phase.

Figure 1. (click here to zoom)
Figure 1. Interstitial inflammation and fibrosis with multiple nonnecrotizing granulomas in hypersensitivity pneumonits (H&E, 47x).

Figure 2. (click here to zoom)
Figure 2. Nonnecrotizing granuloma in hypersensitivity pneumonitis (H&E, 160x).

Diagnosis

The diagnosis is established by clinical and laboratory findings. The table 2 shows the diagnostic criteria for HP.

The diagnosis requires the presence of (1) four or more major criteria, (2) at least 2 minor criteria, and (3) exclusion of other lung diseases with similar clinical features.

Differential Diagnosis

The clinical differential diagnosis include mainly²:
a) idiopathic pulmonary fibrosis
b) interstitial lung diseases associated with connective tissue disorders
c) sarcoidosis
d) drug-induced interstitial lung disease

Histopathologically, the most important considerations are⁸:
a) usual interstitial pneumonia (UIP)
b) sarcoidosis
c) berylliosis
d) infectious pneumonitis

Treatment

The most important measure is the avoidance of exposure to antigen^1-5. The acute phase of HP tends to resolve spontaneously; the subacute/chronic phase may require treatment with prednisone^2,3. Azathioprine and cyclophosphamide have also been used is specific clinical situations⁷.

Prognosis

The prognosis is excellent in the acute phase. The subacute/chronic phase is characterized by a variable clinical course but usually favorable, mainly with no further exposure to antigen^1,2,6.

Some hints

1. Wheezing is not a clinical feature of HP. Remember: HP is basically a restrictive disorder*.
2. Eosinophilia is not usually observed. Remember: types III and IV are the hypersensitivity reactions associated with HP.
3. Histologically, eosinophils are not commonly observed.
4. Histologic examination is not usually required for the diagnosis.

*Sometimes wheezing can be observed when an associated BOOP is present.

References

1. Kaltreider, HB. Hypersensitivity pneumonitis. West J Med 1993; 159: 570-78.
2. Hunninghake, GW, Richerson, HB. Hypersensitivity pneumonitis and eosinophilic pneumonias. In Fauci, AS et al (ed). Harrison's Principles of Internal Medicine 14th ed. New York, NY. McGraw-Hill, 1998, pp 1426-29.
3. Mcadams, HP, McElaney, B, Erasmus, J. Chest case of the day - case 2: hypersensitivity pneumonitis. AJR 1995; 165: 186-191.
4. Shuyler, M. The diagnosis of hypersensitivity pneumonitis (editorial). Chest 1997: 111 (3): 534-36.
5. Shuyler, M. Lessons from hypersensitivity pneumonitis (editorial). West J Med 1993; 159 (5):620-22.
6. Krasnick, J, Meuwissen, HJ, Nakao, MA, Yeldandi, A, Patterson, R. Hypersensitivity pneumonitis: problems in diagnosis. J Allerg Clin Immunol 1996; 97 (4): 1027-30.
7. Coleman, A, Colby, TV. Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 1988; 2(7): 514-518.
8. Reyes, CN, Wenzel, FJ, Lawton, BR, Emanuel, DA. The pulmonary pathology of farmer's lung disease. Chest 1982; 81: 142-6.

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