Diagnosis: Patchy, cellular bronchiolitis and alveolitis with focal proliferative bronchiolitis and many non-necrotizing granulomas consistent with hypersensitivity pneumonia (extrinsic allergic alveolitis)

Comment: Initially, a diagnosis of pneumocystis pneumonia was considered, but that probability was low because she was on anti-retroviral medications and had a CD4 count >200/µl. The negative BAL excluded the diagnosis. Changes related to past intravenous drug use, LIP, a reaction to her HIV medication, or a non-AIDS-related disease, such as HP or sarcoidosis, remained in the differential diagnosis. After the biopsy, sarcoidosis was considered unlikely because of the diffuse distribution of interstitial lymphoid infiltrates and granulomas. At that time, the clinical history of exposure to animals, the HRCT (inspiratory and expiratory), and the biopsy all pointed toward HP. Screening tests for hypersensitivity pneumonia, including a test for antibody to pigeon proteins, were negative. Nevertheless, she improved without steroid treatment after the animals were removed and has continued treatment with combination antiretroviral agents.

In the biopsy there were no alveolar macrophages filled with black pigment to suggest crack cocaine smoking. Polarized light revealed no birefringent crystals of talc, microcrystalline cellulose, or starch in blood vessels or elsewhere as a residue of intravenous drug use.

Follow-up: Correlation of CD4 Counts, Birds, and Symptoms

Date

12/97

2/98

4/1/98

4/9/98

5/4/98

8/21/98

CD4 cells/µl

116

273

370

255

461

487

Birds

Lovebirds for 2 y; new button quail and diamond dove

---

Parted with all birds

---

---

Lovebirds returned

Symptoms

None

Dyspnea

Dyspnea; CT opacities

Dyspnea

Feeling better; CT clear

Feeling better; CT clear

Was the cause of the hypersensitivity the button quail or the diamond dove? Or was it the return of the lymphocytes that permitted an inflammatory response?


Hypersensitivity Pneumonia (Extrinsic Allergic Alveolitis)

Clinical features: Hypersensitivity to organic dusts may present as acute, subacute, or chronic pneumonia, depending on the host and the type and dose of antigen. Patients with the acute form have fever, myalgias, cough, and dyspnea accompanied by basilar crackles usually beginning 4 to 12 hours after exposure to antigen and disappearing spontaneously. Laboratory tests may show a neutrophilic leukocytosis [1]. Eosinophilia is rare (10% of cases), but may be as high as 20% [2]. Serum immunoglobulin, but not IgE, is increased. PFTs show restriction and decreased DLCO. BAL fluid often has an increase in CD8+ lymphocytes that can be shown to be sensitized to the involved antigen. Specific antibody is also present in lavage fluid [1]. Serum precipitins against one or more antigens are often demonstrable, but asymptomatic persons similarly exposed may also have precipitins [3, 4].

Patients with the subacute or chronic forms have the insidious onset of dyspnea, cough, and sometimes weight loss [3, 5]. Airflow obstruction, as well as restriction, may occur with chronic disease.

Causes: Common causes of hypersensitivity pneumonia are fungi, bacteria, animal danders, and chemicals [1, 6]. An extensive list of causes is given in reference 7. Identification of the causative agent requires careful evaluation of both the home and the workplace.

Clinical Differential Diagnosis of HP: [7]

Recurrent pneumonia

Immune deficiency disease

Toxic organic dust syndrome/pulmonary mycotoxicosis

Cystic fibrosis

Silo filler's disease

Psittacosis

Allergic bronchopulmonary aspergillosis

Sarcoidosis

Idiopathic pulmonary fibrosis (chronic disease)

Summary: Characteristic Features of Acute Hypersensitivity Pneumonia (HP) [8]

Radiographic and CT findings: Acute, subacute, and chronic stages have been described radiographically. In all cases, HRCT is more sensitive than plain radiographs or conventional CT [9]. By HRCT, 4 patients in the acute or subacute stage (<1 y of symptoms) showed rounded opacities, up to 3 mm in diameter, with associated air space opacities (ground-glass). In 6 patients with 1-6 years of symptoms, irregular linear opacities corresponding to fibrosis were seen, again with small nodules and air-space opacification. More recent study of HRCTs yielded a new characteristic: areas of decreased attenuation and mosaic perfusion. Of 22 patients, 19 had decreased attenuation and mosaic perfusion, 18 had ground-glass opacities, 12 had small nodules, and 8 had a reticular pattern. The severity of air trapping measured by RV correlated with the total area of decreased attenuation [10].

HRCT to distinguish HP and IPF: A study designed to determine whether HRCT can distinguish between IPF (UIP/DIP) and HP (many chronic) found that when a definite diagnosis could be made, the diagnosis was correct in 90% (35/39) of cases. A definite diagnosis of HP was based on at least 2 of the following features: widespread ground-glass attenuation, an upper or mid lung predominance, and presence of poorly-defined micronodules. A definite diagnosis of IPF was based on at least 2 of the following: lower zone predominance, peripheral predominance, predominance of linear opacities, and honeycombing. When a definite diagnosis could not be made, the accuracy of diagnosis fell to 60%. Cases of DIP and chronic HP were often misclassified [11].

Radiographic differential diagnosis of ground-glass opacities includes respiratory bronchiolitis (RB), COP, drug toxicities, and alveolar proteinosis. Micronodules may be seen in patients with HP, RB, and intravenous drug abuse [11].

Histologic features of HP: HP is characterized by patchy lymphoid infiltrates around the bronchiolovascular bundle and in alveolar walls, as well as non-necrotizing granulomas. Based on these findings, the pathologist can suggest the diagnosis on a biopsy when the diagnosis is not suspected clinically [12].

Histologic differential diagnosis depends on the prominence of the various histologic features. Bronchiolitis and alveolitis may be seen in viral, mycoplasmal, and chlamydial infections; lymphocytic interstitial pneumonia; or collagen vascular diseases. Granulomas suggest infectious agents, sarcoidosis, beryllium disease, drug reactions, intravenous drug abuse, and aspiration of foreign material. A COP-like picture may be caused by infectious agents, collagen vascular diseases, drugs, or aspiration. Fibrosis and honeycombing occur in a wide variety of chronic lung diseases [12].

Table. Summary of Histologic Features of HP [12, 15]

Diagnosis: Elicitation of the temporal sequence of exposure to an etiologic agent and onset of acute symptoms may suffice for diagnosis of acute disease. Lung biopsy is performed when no history is obtained (diagnosis first suggested by a lung biopsy) or when the history requires confirmation. In a retrospective study of patients with biopsies that showed typical histologic changes with granulomas, up to 60% had no identifiable antigenic cause, yet the clinical outcome was the same for all [12]. In a study of the value of TBB in the diagnosis of HP, two pathologists using the criteria of a diffuse lymphocytic infiltrate ± the presence of non-necrotizing granulomas found that a diagnosis of probable or possible HP could be made in 55 to 80% of 55 cases of HP that were mixed with 50 cases of other types of interstitial lung disease [16]. The authors suggest that TBB be used for cases in which HP is in an intermediate position in the differential diagnosis.

Bronchoalveolar lavage findings in HP: A lymphocytosis occurs in lavage fluid from patients with HP. In acute disease, PMNs are also increased. T cell subsets have also been analyzed. In a study of non-smokers with farmer's lung, of whom 11 kept on working and 7 stopped work but lived on the farm, CD4/CD8 ratios in BAL fluid evaluated 2 wks-4 mo after an acute episode were low (Table 1). Workers who continued their exposure maintained their low CD4/CD8 T-cell ratios, whereas those who stopped their exposure had ratios that became normal [17].

Table 1: CD4/CD8 Ratios in BALF from Patients with HP (mostly Farmer's Lung) [17]

Group

CD4/CD8 ratio--2 wk-4 mo after onset

Follow-up CD4/CD8 ratio

Continuing workers (N=11)

0.52

0.5 at 30 mo

Workers who quit (N=7)

0.55

1.8 at 12 mo

Controls (N=12)

1.9

In another study (Table 2) no differences were found in CD4/CD8 ratios after avoidance of antigen and treatment with steroids for a median of 4 mo [18]. The marked variation in CD4/CD8 ratios both before and after treatment suggests that this measure has little use in diagnosis.

Table 2. CD4/CD8 Ratios in BALF of HP (mostly Farmer's Lung) (18)

Median lymphocyte % (10th-90th percentile)

Median CD4/CD8 ratio (10th-90th percentile)

Before treatment (N=12)

71 (37-80)

4 (0.7-11.8)

After treatment (N=9)

58 (25-69)

6 (1.2-25.9)

Bronchoalveolar lavage findings in HIV infection: Lymphocyte subsets in patients with AIDS (our patient) may be similar to those in patients with HP. In an early study of cellularity of BALF and T cell subsets in patients with HIV infection, a lymphocytosis of >15% was found in 78% of 154 persons with pulmonary infections and 72% of 122 of those for whom infection could not be diagnosed. In 16 of the cases without pulmonary infection, the mean percentage of CD4 cells was 11.0% and CD8 cells, 80.6%. The mean CD4/CD8 ratio was 0.15 (range 0.03 to 1.08) [19]. In a study published 10 y later, BALF cellularity and T cell subsets were compared in HIV negative controls (A), patients without detectable respiratory disease (B) (median blood CD4 cells 480/µl), and those with respiratory infection (C) (median blood CD4 cells 30/µl) [20]. The absolute numbers of different cells in BALF were not significantly increased when compared to controls. Only 10% of group B patients and 27% of group C patients had >15% lymphocytes. In those with >10% lymphocytosis, the percentages of lymphocytes and CD4 and CD8 cells are shown in the table. The lymphocytosis in these patients, in general, is not so great as in those with HP.

Table: Comparison of Percentages of Lymphocytes in BALF for a Subgroup of HIV+ Patients with Lymphocytosis [20]

Subgroup (N) >10% Lymphocytes

Mean % Lymphocytes

Mean % CD4+ T cells

Mean % CD8+ T cells

Mean CD4/CD8 ratio

A (6)

--

62

38

1.6

B (6)

20

32

68

0.47

C (7)

16

7

94

0.074

A= HIV- normal control, B = HIV+ & no respiratory disease, C = HIV+ & respiratory disease

Pathogenesis of HP: HP is believed to result from a combination of immune-complex and cell-mediated injury. Immune-complex injury is suggested by the time of onset of symptoms after exposure (4 to 6 hr), the presence of IgG antibodies in serum and lavage fluid, the demonstration of IgG and antigen in the lung, positive skin reactions to antigen, and positive bronchial challenge tests with the antigen. T cell-mediated reactions are believed to account for the lymphocytic infiltrates, granulomas, and fibrosis. Both CD4 and CD8 T cells are increased in number in lavage fluid. Although we know that CD4 T cells can initiate cell-mediated reactions, the role of the CD8 cells, which are the dominant type of T cell in BALF, is not known [1]. Unexplained also is the lack of disease in persons exposed to antigen who develop antibodies and BALF lymphocytosis but no clinical disease.

Outcome: Follow-up of patients with acute episodes of farmer's lung or pigeon breeder's lung has shown that impairment of pulmonary function is usually mild, even when exposure continues [21-23]. For example, of 89 persons, predominantly female, with farmer's lung (related to cattle tending) followed for a mean of 14 y (range 11-16 y) after the initial diagnosis, DLCO was only 12% lower than in a group of matched control farmers. Persons with recurrent episodes had lower values than those with a single episode. VC, FEV1, and FEV1/FVC did not differ from control subjects, but MMEF was somewhat impaired in those with disease (p=0.08) . There was no difference in outcome of a small subset treated with steroids during the acute episode and those who were not [24].

Follow-up of 21 non-smokers with a history of acute pigeon-breeder's lung 10 years previously showed that pulmonary function and chest radiographs were normal and symptoms absent in 12 despite the fact that most continued to keep pigeons. In the remainder, TLC and/or diffusing capacity were abnormal in 3, chest radiographs were abnormal in 3, and clinical symptoms were present in 5, with chronic bronchitis in 3, but disability was absent [23]. Another study of function over time showed greater than normal declines in FVC, FEV1, and DLCO over 18 years in 7 persons with a history of acute pigeon-breeder's disease compared with 8 pigeon breeders with no history of acute disease. Despite the accelerated decline in PFTs, function was still within normal limits at the end of the study. The authors concluded that disease continues subclinically in those with a history of acute disease and that they should be advised to give up exposure [25].

In contrast to the generally mild course of acute disease, patients with chronic pigeon breeder's disease showed a 29% mortality over a 5 year follow-up period [26]. This mortality rate was lower than that for IPF (84%). Survival from the beginning of symptoms was a median of 134 mo for the pigeon breeders and 69 mo for those with IPF [14].

References

1. Kaltreider B. Hypersensitivity pneumonitis. West J Med 1993; 159:570-578.

2. Emanuel D, Wenzel F, Bowerman C, Lawton B. Farmer's lung. Clinical, pathologic and immunologic study of twenty-four patients. Am J Med 1964; 37:392-401.

3. Hodgson M, Morey P, Simon J, Waters T, Fink J. An outbreak of recurrent acute and chronic hypersensitivity pneumonitis in office workers. Am J Epidemiol 1987; 125:631-638.

4. Scribner G, Barboriak J, Fink J. Prevalence of precipitins in groups at risk of developing hypersensitivity pneumonitis. Clinical Allergy 1980; 10:91-95.

5. Shellito J. Hypersensitivity pneumonitis. Sem Respir Med 1991; 12:196-203.

6. Sharma O, Fujimura N. Hypersensitivity pneumonitis: a noninfectious granulomatosis. Sem Respir Infect 1995; 10:96-106.

7. Richerson H, Bernstein I, Fink J, Hunninghake G, Novey H, Reed C, Salvaggio J, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the subcommittee on hypersensitivity pneumonitis. J Allergy Clin Immunol 1989; 84:839-844.

8. Ando M, Arima K, Yoneda R, Tamura M. Japanese summer-type hypersensitivity pneumonitis. Geographic distribution, home environment, and clinical characteristics of 621 cases. Am Rev Respir Dis 1991; 144:765-769.

9. Silver S, Müller N, Miller R, Lefcoe M. Hypersensitivity pneumonitis: evaluation with CT. Radiology 1989; 173:441-445.

10. Hansell D, Wells A, Padley S, Müller N. Hypersensitivity pneumonitis: correlation of individual CT patterns with functional abnormalities. Radiology 1996; 199:123-128.

11. Lynch D, Newell J, Logan P, King Jr T, Müller N. Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? AJR 1995; 165:807-811.

12. Coleman A, Colby T. Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 1988; 12:514-518.

13. Kawanami O, Basset F, Barrios R, Lacronique J, Ferrans V, Crystal R. Hypersensitivity pneumonitis in man. Light- and electron-microscopic studies of 18 lung biopsies. Am J Pathol 1983; 110:275-289.

14. Pérez-Padilla R, Gaxiola M, Salas J, Mejía M, Ramos C, Selman M. Bronchiolitis in chronic pigeon breeder's disease. Morphologic evidence of a spectrum of small airway lesions in hypersensitivity pneumonitis induced by avian antigens. Chest 1996; 110:371-377.

15. Reyes C, Wenzel F, Lawton B, Emanuel D. The pulmonary pathology of farmer's lung disease. Chest 1982; 81:142-146.

16. Lacasse Y, Fraser R, Fournier M, Cormier Y. Diagnostic accuracy of transbronchial biopsy in acute farmer's lung disease. Chest 1997; 112:1459-1465.

17. Trentin L, Marcer G, Chilosi M, Sci M, Zambello R, Agostini C, Masciarelli M, et al. Longitudinal study of alveolitis in hypersensitivity pneumonitis patients: an immunologic evaluation. J Allergy Clin Immunol 1988; 82:577-585.

18. Wahlström J, Berlin M, Lundgren R, Olerup O, Wigzell H, Eklund A, Grunewald J. Lung and blood T-cell receptor repertoire in extrinsic allergic alveolitis. Eur Respir J 1997; 10:772-779.

19. Guillon J-M, Autran B, Denis M, Fouret P, Plata F, Mayaud C, Akoun G. Human immunodeficiency virus-related lymphocytic alveolitis. Chest 1988; 94:1264-1270.

20. Bofill M, Lipman M, McLaughlin J, Johnson M, Poulter L. Changes in lung lymphocyte populations reflect those seen in peripheral blood in HIV-1 positive individuals. Eur Respir J 1998; 11:548-553.

21. Kokkarinen J, Tukiainen H, Terho E. Recovery of pulmonary function in farmer's lung. A five-year follow-up study. Am Rev Respir Dis 1993; 147:793-796.

22. Lalancette M, Carrier G, Laviolette M, Ferland S, Rodrique J, Bégin R, Cantin A, et al. Farmer's lung. Long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis 1993; 148:216-221.

23. Bourke S, Banham S, Carter R, Lynch P, Boyd G. Longitudinal course of extrinsic allergic alveolitis in pigeon breeders. Thorax 1989; 44:415-418.

24. Erkinjuntti-Pekkanen R, Kokkarinen J, Tukiainen H, Pekkanen J, Husman K, Terho E. Long-term outcome of pulmonary function in farmer's lung: a 14 year follow-up with matched controls. Eur Respir J 1997; 10:2046-2050.

25. Schmidt C, Jensen R, Christensen L, Crapo R, Davis J. Longitudinal pulmonary function changes in pigeon breeders. Chest 1988; 93:359-363.

26. Pérez-Padilla R, Salas J, Chapela R, Sánchez M, Carrillo G, Pérez R, Sansores R, et al. Mortality in Mexican patients with chronic pigeon breeder's lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis 1993; 148:49-53.

Clinical summary

Comments: mw6825@itsa.ucsf.edu

Last revised 7/26/98

Copyright 1998 by Martha L. Warnock. All rights reserved.

Table of Contents