Objectives

1. Understand the significance of hypersensitivity pneumonitis induced by avian antigens, or pigeon breeder’s disease (PBD).
2. Identify the clinical behavior of PBD.
3. Understand the appropriate use of clinical, radiologic, tomographic, and functional studies.
4. Understand the role of BAL, inhalation challenge, and biopsy.
5. Know the differential diagnosis with respect to other acute, subacute, or chronic interstitial lung diseases, and current therapy.

Key words

extrinsic allergic alveolitis; hypersensitivity pneumonitis; interstitial lung disease

Abbreviations

HP = hypersensitivity pneumonitis; HRCT = high-resolution computed tomography; MHC = major histocompatibility complex; PBD = pigeon breeder’s disease; TNF = tumor necrosis factor

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a syndrome resulting from exposure to finely dispersed organic particles that provoke a diffuse and predominantly mononuclear cell inflammation of the small airways and pulmonary parenchyma.¹ One of the most common etiologic agents causing HP is the so-called avian antigen, primarily from pigeons. The prevalence is unknown, primarily because the disease is often unrecognized or misdiagnosed. The prevalence of pigeon breeder’s disease (PBD) among people exposed to relatively low concentrations of avian antigens is essentially unknown.

Risk Factors

Genetic Susceptibility

Because not all exposed individuals develop the disease, the existence of a number of genetic and environmental risk factors has been proposed.¹ Genetically, the disease appears to be associated with the major histocompatibility complex (MHC). In this context, we recently evaluated the polymorphisms of MHC class II alleles and of tumor necrosis factor alpha (TNF-a) promoter by PCR analysis in patients with pigeon breeder’s lung.² The results showed the presence of several alleles and haplotypes that increase the susceptibility to develop disease. Interestingly, patients exhibiting the TNF- 2(–308) allele were younger and displayed more lymphocytes in their BAL fluid. These results strongly support the idea that genetic factors located within the MHC region contribute to the development of HP. In similar work performed in farmer’s lung as well as in PBD, Schaaf et al³ analyzed the –308 TNF-a promoter polymorphism and the TNF-b intron 1 gene polymorphism. TNF bioactivity and the frequency for the TNFA2 allele, a genotype associated with increased TNF-a expression, was higher in farmer’s lung patients than in control individuals or patients with pigeon breeder’s lung.

Smoking

It is known that HP occurs more frequently in nonsmokers compared with smokers at the same risk exposure and that nonsmokers exposed to HP antigens have a significantly higher specific IgG response.^4-7 The findings are similar in our population, in which more than 90% of our cases occur in nonsmoking individuals. However, smoking may unfavorably affect the clinical behavior of the disease changing the clinical course to a more insidious and chronic form.⁸ Although smoking appears to protect against the development of HP, when the disease occurs in smokers the prognosis is significantly worse than in nonsmokers.

Sex, Hormones, and Pregnancy

In our experience, PBD has a 10:1 predominance in women. Studies relating the possible role of hormones as a risk factor for developing the disease are scanty. There appears to be a relationship between the development of PBD and the postpartum state. Symptoms can begin from 5 to 7 months after delivery, even when the antigen exposure starts during or before pregnancy.⁹

The Avian Antigen

The most prevalent form of PBD develops among pigeon fanciers, but similar symptoms can be present after exposure to parakeets, chickens, ducks, turkeys, and small caged birds such as finches and canaries.¹ It is also important to emphasize that PBD could also be caused by unusual sources of exposure, such as feather wreaths or feather/down duvets and pillows.^10-12

Avian antigens represent a complex mixture of high- and low-molecular-weight proteins, and patients usually become sensitized to a wide range of these antigens.¹³ Secretory IgA and mucin are considered the major antigenic components in pigeon secretory materials.^14-16 Bloom, a dust commonly found coating bird feathers that is composed of fine, 1-µm particles of keratin covered with IgA, appears to be a potent antigen.¹⁷ Likewise, pigeon intestinal mucin is present in a variety of materials found in the environment of the pigeon loft, including droppings and bloom.¹⁸ Flying birds, especially pigeons in peak racing condition, produce bloom in large amounts, which may explain why birds such as pigeons and parakeets seem to be more potent sensitizers than chickens and turkeys.

The prevalence of PBD may be between 10 and 20% in those regularly exposed to lofts with high antigen levels, but figures as low as 1.4 per 1,000 and 1 per 5,000 have been reported.^19,20 The prevalence of clinical disease among people with only a few birds at home is largely unknown.

Clinical and Radiographic Features

Intermittent and intense exposure causes an acute form of the disease, characterized by a flulike syndrome occurring 6 to 8 h after exposure. Pulmonary symptoms include severe dyspnea, chest tightness, and a dry or minimally productive cough.

However, most of the patients with PBD present with a subacute or chronic form resulting from continual low-level exposure to avian antigens (typically a few pigeons running freely in the domestic environment). The onset of the disease is insidious, with few symptoms, if any, during the early stages of the pathologic process. Therefore, patients seek medical care several weeks (subacute) or months (chronic) after the beginning of the illness. The main symptoms are progressive dyspnea, fatigue, cough with mucoid sputum, anorexia, malaise, and weight loss. In the subacute form, patients may occasionally have a fever at the onset of the illness.

Unrecognized and untreated acute episodes or subacute HP may progress to chronic HP. It is important to emphasize that in a number of patients with chronic disease, irreversible lung changes develop as a result of interstitial fibrosis, with evolution to right-sided heart failure. Tachypnea and bilateral crackles are usual clinical findings. Wheezing, provoked by small airway obstruction, is not a characteristic physical sign, but it occurs in some patients and may lead to an erroneous diagnostic approach. Subacute/chronic HP should be always considered in the differential diagnosis of an interstitial lung disease.

In the acute and subacute forms of the disease, the chest radiograph usually reveals a ground-glass appearance and/or a fine nodular shadowing (Fig 1). The chronic stages are characterized predominantly by a reticulonodular pattern, which may evolve to honeycombing in advanced cases (Fig 1).

Figure 1. Chest radiographs showing the main alterations observed in PBD. Left, ground-glass attenuation. Center, micronodular opacities. Right, diffuse reticular opacities.

In subacute PBD, high-resolution computed tomography (HRCT) of the chest reveals diffuse or patchy ground-glass attenuation and poorly defined, small micronodules with centrilobular localization. Patients with chronic disease show both fine and coarse reticular opacities, which may evolve to honeycombing. Nodules and ground-glass attenuation are often present in the chronic form, suggesting acute changes superimposed on chronic disease^{21, 22} (Fig 2).

Figure 2. CT scan showing a discrete ground-glass attenuation and, mostly, poorly defined micronodules distributed diffusely throughout both lungs.

Pulmonary Function Tests

Pulmonary function test findings are characterized by a predominantly restrictive ventilatory defect with loss of lung volume, with decreased FVC and total lung capacity.¹ Lung compliance is usually shifted downward and to the right of the normal curve, showing a decrease over the entire range of the reduced inspiratory capacity. The exponential analysis of the pressure-volume curve could be useful in monitoring progression of the disease by serving to differentiate inflammation from fibrosis.²³ Thus, a low constant k suggests increased stiffness of the functioning alveoli by fibrosis rather than a simple decrease of alveolar volume.

Because the disease also affects the peripheral airways (bronchiolitis), a decrease in the maximum to mid-flow rates and in the ratio of dynamic to static lung compliance may be present.²⁴ Patients display impaired gas exchange characterized by hypoxemia that usually worsens with exercise, normal or slightly decreased PaCO₂, and elevated alveolar-arterial oxygen pressure difference. Occasionally, based on the extent and severity of the disease, patients may present with normoxemia at rest but show hypoxemia on exercise.

The correlation between pulmonary functional abnormality and the severity or prognosis of subacute/chronic PBD is poor. Patients with a severe decrease in lung volume and carbon monoxide diffusing capacity of the lung may recover fully, whereas others with relatively mild functional abnormalities at the onset of disease may develop progressive pulmonary fibrosis.

Laboratory Tests

There is no clinically useful diagnostic laboratory test. Likewise, there are no serologic markers to monitor disease activity or progression. In the acute and subacute forms, a slight or moderate neutrophilic leukocytosis with lymphopenia may occur. In chronic disease, leukocyte counts are usually normal. The erythrocyte sedimentation rate may be moderately elevated in some patients, but is always < 100 mm/h. The C-reactive protein, rheumatoid factor, immune complexes, and a mild increase in immunoglobulin G and M have also been described, but are nonspecific findings.¹

Detection of Specific Antibodies

Serum-precipitating IgG antibodies against avian antigens are usually detectable in HP patients, although these specific antibodies may also be found in a certain percentage of similarly exposed but asymptomatic individuals. Nevertheless, the presence of antibodies is still one of the major diagnostic criteria for the disease.

Attempts to find differences between PBD patients and asymptomatic exposed individuals in terms of recognition of specific antigens have been unsuccessful. Two proteins of 55-kDa and ~ 30-kDa molecular weight from pigeon droppings that appear to react only with sera of patients with PBD have been described.^{25, 26} Likewise, IgG3 subclass reactivity specific to pigeon mucin is strongly associated with sera from patients with active lung disease, whereas it is found in < 15% of healthy pigeon breeders.²⁷

Bronchoalveolar Lavage

A significant increase in the total cell count is usually found, and invariably, a remarkable elevation in the percentage of lymphocytes, often > 40%, is seen; the majority of BAL lymphocytes are T cells¹ (Fig 3).

Figure 3. Increase of lymphocytes in a BAL sample.

It is generally thought that there is a predominance of the CD8⁺ T-lymphocyte subset, associated with an imbalance of the CD4⁺ to CD8⁺ ratio. However, it is unclear whether this is a consistent finding. We have found that patients may display either an increase of CD8⁺ or CD4⁺ subsets and may even show an increase of both subpopulations with a CD4/CD8 ratio in the normal range.

The percentage of BAL macrophages in HP is very low, although the absolute number is higher compared with that in control individuals. A moderate but significant increase of the percentage of neutrophils has been found in some patients with chronic PBD, early after antigen exposure.^{28, 29}

Differential Diagnosis

Acute PBD may be indistinguishable from an acute respiratory infection, such as an episode of influenza, or from an atypical pneumonia caused by viral or mycoplasmal agents.³⁰

Subacute/chronic PBD mimics any other interstitial lung disease. The main problem in diagnosis is the absence of pathognomonic abnormalities for HP. The interval between avian exposure and the onset of symptoms may be long, or the exposure history may be so subtle that the cause-and-effect relationship may not be readily apparent. The temporal relationship between exposure to avian antigens and the onset of the clinical symptoms can be vague, especially when the exposure is related to hobbies rather than to occupation.

The differential diagnosis of the subacute form of PBD should include some granulomatous lung infections, such as tuberculosis and noninfectious granulomatous lung disorders, particularly sarcoidosis.

In general, subacute and chronic PBD may be confounded with any interstitial lung disease. Importantly, the chronic progressive form of HP may simulate idiopathic pulmonary fibrosis. The presence of a high proportion of ground-glass attenuation on HRCT, increased BAL lymphocytes, and the antecedent exposure make idiopathic pulmonary fibrosis unlikely.

Inhalation Challenge

When there is diagnostic uncertainty, a provocation test using pigeon serum has been occasionally used for diagnostic purposes, although its role for diagnosis in routine clinical practice has not yet been fully established.³¹ Typically, a positive test is characterized by fever, malaise, headache, and decreased FVC occurring several hours after challenge. In general, it is a reproduction of acute HP symptoms, compounded by laboratory and functional test abnormalities. A false-positive reaction may occur in approximately 10% of patients with other interstitial lung diseases but not in healthy subjects, suggesting that provocation tests can properly identify patients with HP.³¹ Complications of a challenge test are unusual, but the test must be performed under appropriate and controlled conditions.

Lung Biopsy and Morphology

When the diagnosis is not apparent, as in other interstitial lung diseases, a lung biopsy is indicated. Histopathologic features include bronchiolocentric interstitial pneumonitis of mononuclear predominance and nonnecrotizing, poorly formed granulomas. In the chronic form, a variable degree of interstitial fibrosis is noted³² (Fig 4).

Although the presence of granulomas is a classic histologic feature of HP, the granulomas differ from those found in sarcoidosis. The granulomas in PBD are usually small, poorly differentiated, and loosely arranged, and contain a high concentration of lymphocytes. Their borders are usually blurred by surrounding lymphocytes and monocytes (Fig 4).

Figure 4. Interstitial pneumonitis of mononuclear predominance and nonnecrotizing, poorly formed granulomas.

Bronchiolitis is usually found in PBD, and it is characterized by peribronchiolar inflammation and fibrosis and smooth muscle hypertrophy.³³

Fibrosis can be a conspicuous histologic finding in the pulmonary parenchyma of advanced cases of chronic PBD. When present, the association of mild or moderate infiltration with lymphocytes, some giant cells, and the occasional observation of poorly formed granulomas may indicate that the pulmonary fibrosis may be secondary to HP.

Tools for Diagnosis

Major Criteria

1. Evidence of exposure (antecedents and specific circulating antibodies).
2. BAL lymphocytosis (usually > 40%).
3. Histologic changes compatible with HP.
4. Positive inhalation provocation test.

Minor (But Important) Criteria

1. Clinical, radiologic, and functional pattern compatible with interstitial lung disease.
2. Improvement with contact avoidance, or exacerbation of symptoms during reexposure.
3. Diffuse, ill-defined, small, nodular opacities and ground-glass attenuation on HRCT.

Treatment

Early diagnosis and avoidance of antigen exposure are important steps to avoid chronicity. It is critical to emphasize that high levels of bird antigen may persists for prolonged periods of time in the patient’s home, despite removal of the offending birds and a complete environmental cleanup,³⁴ accounting for the persistence of the disease in some patients with HP.

Oral corticosteroids are recommended in subacute/chronic disease; however, their long-term efficacy has yet to be determined. Inhaled corticosteroids may achieve at least similar, if not better, benefits compared with oral prednisone, and without systemic adverse effects.³⁵ Thus, patients may be treated with short-term prednisone (~ 3 months) followed by inhaled corticosteroids. In patients with documented hyperreactive airways, inhaled bronchodilators are also indicated.

Prognosis and Survival

Acute PBD has a favorable prognosis. A long-term follow-up of 24 patients demonstrated that the majority of patients surveyed reported clinical improvement, despite continual exposure to antigens. The study, which provided a follow-up window of 10 years, did not report any acute PBD-related deaths.³⁶

By contrast, chronic PBD may evolve to progressive and irreversible pulmonary damage, and a fairly large percentage of patients risk death as a consequence of diffuse lung fibrosis.³⁷ The best predictors of mortality are the severity of fibrosis revealed on open lung biopsy, the presence of radiographic honeycombing, and digital clubbing.^{21, 37, 38}

Summary

HP is a syndrome resulting from exposure to finely dispersed organic particles that provoke diffuse inflammation of the small airways and pulmonary parenchyma. The pathogenic mechanisms are not completely elucidated. It appears that a complex interaction between antigen exposure and a variety of risk factors can trigger an altered immune response in this disorder. Patients may present with three different clinical forms: acute, subacute, or chronic. The diagnosis rests on a number of clinical, radiographic, functional, and BAL findings. In subacute or chronic cases, when there is diagnostic uncertainty, surgical biopsy is indicated. Avoiding further exposure and taking corticosteroids (for subacute or chronic disease) constitute the cornerstone of treatment.

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