Abstract

Summary of Recommendations
1. In patients with suspected hypersensitivity pneumonitis (HP), we suggest gathering a thorough clinical history of exposures focused on establishing the type, extent, and temporal relationship of exposure(s) to symptoms (Ungraded Consensus-Based Statement).
Remarks: Accurate and timely HP diagnosis relies on gathering and integrating a detailed and comprehensive exposure history. Although an important factor in reducing diagnostic uncertainty is the identification of a compelling exposure, an unrevealing exposure history does not exclude HP. If the exposure history is unclear, the process of exposure history gathering, integration, and interpretation of possible exposure data should continue until an HP diagnosis or its exclusion is more certain. All patients should complete a comprehensive environmental and occupational questionnaire tailored to the geographic region.
Remarks: During the diagnostic workup of a patient with suspected HP, interpretation of a positive or negative diagnostic test is dependent upon the presence or absence of an identifiable exposure and disease prevalence (pretest probability).

2. In patients with suspected HP, if the inciting antigen (IA) is thought to be related to an occupational exposure, we suggest considering the inclusion of an occupational medicine specialist and an environmental hygienist during the multidisciplinary diagnostic workup, especially when the source of exposure is obscure or unverified (Ungraded Consensus-Based Statement).

3. In patients with suspected HP, we suggest classifying patients based on the likelihood of an occupational or environmental inciting antigen exposure (Weak Recommendation, Very Low-Quality Evidence).
Remarks: Correct identification of the IA and the subsequent elimination of that exposure facilitates the management and helps determine the prognosis of HP. Unless a thorough exposure history is performed, the IA may go unrecognized with resultant ongoing exposure possibly adversely impacting disease progression and survival. In some scenarios, the disease may flare or continue to progress despite apparent remediation of the suspected exposure(s). This suggests that other factors may be associated with disease progression, and/or that other exposure(s) may be contributing.
Remarks: Given the prognostic importance of antigen identification and avoidance, surveillance for exposure and patient education focused on antigen avoidance at every visit is the highest priority. This is particularly important for those unwilling to remove the antigen source despite the negative clinical consequences, patients with disease progression despite pharmacological or environmental management, those with a recurrence of symptoms after an initial appropriate response, in cases of disease clustering (e.g., multiple cases identified in one geographic area), and when symptoms are attributed to an occupational or suspected but unverified exposure. While the prognostic implications of a suspected but unverified exposure remain unclear, additional investigative strategies to identify a potential exposure (e.g., workplace inspection) may support the diagnosis and help guide management decisions.

4. For patients with either newly diagnosed or a working diagnosis of HP, we suggest classifying the disease as fibrotic or nonfibrotic based on the presence or absence of fibrosis on high-resolution computed tomography (HRCT) of the chest (Weak Recommendation, Very Low-Quality Evidence).
Remarks: HRCT findings indicative of lung fibrosis include one or more of the following: reticular abnormality or ground-glass opacity associated with traction bronchiectasis, honeycombing, and loss of lobar volume.
Remarks: Several studies demonstrate that the presence or absence of lung fibrosis provides important prognostic information. Further, as chronic HP does not always follow acute disease and only a subgroup of HP patients with chronic disease will develop lung fibrosis, a time-based classification scheme (eg, acute, subacute, chronic) is inferior to the identification of the presence or absence of fibrosis as a prognostic marker. Furthermore, in addition to prognosis, both fibrosis and antigen characterization have important diagnostic and treatment implications.

5. In patients with suspected HP, if an IA exposure is identified and then completely avoided, we suggest using clinical improvement with antigen avoidance to support the diagnosis of HP, but not relying solely on the lack of clinical improvement with antigen avoidance to rule out the diagnosis of HP (Weak Recommendation, Very Low-Quality Evidence).
Remarks: Clinically appreciable improvement in symptomatic, physiologic, and radiographic features may be seen only in patients with non-fibrotic HP. Measurable clinical improvement may not occur if the remediated antigen is not causative, if there are multiple exposures causing disease, if complete avoidance cannot be achieved, or in subjects with severe or progressive pulmonary fibrosis. Moreover, in a significant proportion of patients with fibrotic HP, an antigen will not be identified. Therefore, clinical improvement with antigen avoidance may support the diagnosis of HP, but the absence of clinical improvement does not rule it out.

6. For patients with suspected HP, we suggest not relying solely on clinical improvement with medical therapy to confirm a diagnosis of HP or on the lack of clinical improvement with medical therapy alone to rule out the diagnosis of HP (Weak Recommendation, Very Low-Quality Evidence).
Remarks: Clinical improvement refers to improvement in physiologic and radiologic features. Failure to respond to medical treatment (eg, systemic corticosteroids) alone does not necessarily exclude the diagnosis of HP as the response rate to medical therapy can be highly variable. For example, clinical improvement with medical treatment appears to occur frequently in nonfibrotic HP, while the lack of clinical improvement, regardless of therapy, is common in fibrotic HP. Clinical improvement with medical therapy supports but does not confirm the diagnosis of HP as other interstitial lung diseases with similar presentations, such as idiopathic NSIP, may also improve with immunosuppressive treatment.

7. For patients with suspected HP, we suggest not relying solely on serum antigen-specific immunoglobulin G (IgG) or immunoglobulin A (IgA) testing to confirm or rule out the diagnosis of HP (Weak Recommendation, Very Low-Quality Evidence).
Remarks: Major limitations to the diagnostic utility of serum antigen-specific IgG/IgA testing in HP are the lack of standardized antigen preparations for most IAs, the lack of standardized immunoassays techniques, variable diagnostic cutoff thresholds for quantitative IgG assays, and validation of serum antigen-specific IgG test performance in limited population settings.
Remarks: When there is a questionable exposure based on the history (eg, indoor musty odor but no visible mold or the occasional exposure to mold with the significance of exposure uncertain), the detection of serum antigen-specific IgG/IgA may suggest a putative exposure and in the setting of other supporting diagnostic tests (eg, typical HRCT) or environmental assessment data (eg, indoor visual inspection, surface sampling, and culture), may raise the likelihood of HP. However, there is a lack of data consistently supporting the test as a reproducible and accurate diagnostic tool.

8. For patients with suspected HP, we suggest not performing antigen-specific inhalation challenge testing to support the diagnosis of HP (Weak Recommendation, Very Low-Quality Evidence).
Remarks: Major limitations to the diagnostic utility of antigen-specific inhalation challenge testing in HP are the lack of standardized and validated antigen preparations for most IAs, the lack of standardized challenge techniques (eg, challenge chamber, nebulization of suspected IA), and the absence of validated criteria for defining a positive response. Also, there is limited world-wide availability of appropriate facilities to perform the test and absence of studies evaluating the additional value of antigen-specific inhalation challenge in modifying the likelihood of suspected HP (eg, unidentified IA) during the multidisciplinary diagnostic process.

9. For patients with suspected HP, we suggest not performing antigen-specific lymphocyte proliferation testing to support the diagnosis of HP (Weak Recommendation, Very Low-Quality Evidence).
Remarks: Major limitations to the diagnostic utility of antigen-specific lymphocyte proliferation testing in HP include: the lack of standardized and validated antigen preparations for most IAs, the lack of standardized lymphocyte proliferation techniques, absence of validated criteria for defining a positive response, and the absence of studies evaluating the additional value of antigen-specific lymphocyte proliferation testing in modifying the likelihood of HP during the diagnostic process.

10. For patients with suspected HP, we suggest the integration of HRCT findings characteristic of HP with clinical findings to support the diagnosis of HP, but not using the CT findings in isolation to make a definite diagnosis (Weak Recommendation, Very Low-Quality Evidence).
Remarks: High-resolution CT findings characteristic of HP include profuse centrilobular nodules of ground glass attenuation, inspiratory mosaic attenuation and air-trapping, and the three-density sign.
Remarks: Assessment of the overall probability of HP should consider the prevalence of the disease in the particular setting (eg, referral center or primary care clinic, farming region), the clinical context, the exposure history, and the information contributed by the HRCT.

11. For patients with suspected HP, we suggest using a multidisciplinary discussion (MDD) for diagnostic decision-making (Weak Recommendation, Very Low-Quality Evidence).
Remarks: If a high confidence diagnosis cannot be established by combining the history and clinical context, consider case discussion in the setting of an MDD.
Remarks: The inter-observer agreement for HP diagnosis between MDD and individual clinicians for typical HP cases (respiratory symptoms, known temporal relationship with a specific IA exposure, characteristic CT chest and histopathological findings) is unknown. However, in uncertain cases, MDD may increase diagnostic confidence and/or guide the appropriate use of subsequent tests such as bronchoscopy or surgical lung biopsy (SLB).

12. For patients with suspected HP who have a compelling exposure history within the appropriate clinical context and a chest HRCT pattern typical for HP, we suggest not routinely using BAL fluid analysis to confirm a diagnosis of HP (Weak Recommendation, Very Low-Quality Evidence).
Remarks: BAL fluid analysis can narrow the differential diagnosis by excluding competing causes, particularly in nonfibrotic HP (eg, infection). However, in patients with a high pretest probability of HP, the BAL cellular differential generally does not significantly alter the post-test probability and as a result adds little additional diagnostic information. In the appropriate clinical context, a history of clinically relevant exposure to a compelling IA with a typical high-resolution CT pattern allows for a confident diagnosis of HP.
Remarks: Lymphocytic alveolitis is not consistently present in patients with fibrotic HP and BAL fluid lymphocytosis is not sufficiently sensitive or specific to rule in or rule out the diagnosis of fibrotic HP. However, BAL fluid lymphocytosis may increase diagnostic confidence when the IA is identified and HRCT findings are compatible with HP. It may also increase diagnostic confidence and should be considered when the exposure history and imaging data are discordant (eg, unidentified exposure and typical CT for HP-provisional diagnosis), and may exclude common alternative diagnoses, such as IPF, when the lymphocyte differential count is high (eg, =40%).

13. In patients with suspected HP, we suggest considering histological lung biopsy for additional diagnostic evaluation when all available data such as clinical, laboratory and radiologic findings along with bronchoscopic results do not yield a confident diagnosis and results may help guide management (Weak Recommendation, Very Low-Quality Evidence).
Remarks: When possible, a consensus MDD should be considered before an SLB or TBC. SLB, TBC, and transbronchial biopsies (TBBs) have different diagnostic yields and benefit-risk profiles. The harm from the procedure must be weighed against the potentially useful information that can be gained, particularly in suspected non-fibrotic or advanced fibrotic HP cases.
Remarks: Some patients with fibrotic HP may show histopathologic findings of nonspecific interstitial pneumonia or usual interstitial pneumonia (UIP) pattern. Samples should be carefully examined for findings consistent with HP (eg, poorly formed non-necrotizing granulomas and/or multinucleated giant cells and fibrotic bronchiolocentric accentuation). Thus, when lung biopsy is performed, the histopathological information requires multidisciplinary reconciliation with the clinical and radiological information.

14. For patients with suspected HP, we suggest integrating biopsy findings with clinical and radiological findings to support the diagnosis of HP in the context of the MDD (Weak Recommendation, Very Low-Quality Evidence).
Remarks: Pathologic findings characteristic of HP typically include a combination of cellular and/or fibrosing interstitial pneumonia with bronchiolocentric accentuation, poorly formed non-necrotizing granulomas with or without giant cells, with or without peribronchiolar metaplasia, and/or small foci of organizing pneumonia. Isolated histopathological findings such as non-necrotizing granulomas or inconspicuous foci of organizing pneumonia can occasionally be seen in other ILDs and are not specific enough for a diagnosis of HP. Potential limitations of lung biopsy include interobserver variation in the pathologic interpretation, biopsy size and number of specimens affecting the diagnostic yield of the biopsy procedure, sampling error, and the occasional presence of atypical findings such as NSIP or UIP-like patterns. Biopsy findings of HP or occasional isolated atypical patterns produced by HP require MDD to confirm the diagnosis.

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Comments

A largely negative evidence based review of hypersensitivity pneumonitis, hampered by the lack of high quality evidence. Does not address specific treatment or the consequences (or lack of them) of allergen avoidance. More data needed

8/13/2021