Produção Nacional
Revisado por pares
Diagnosis and Evaluation of Hypersensitivity Pneumonitis
2021; Elsevier BV; Volume: 160; Issue: 2 Linguagem: Inglês
10.1016/j.chest.2021.03.066
ISSN1931-3543
AutoresEvans R. Fernández Pérez, William D. Travis, David A. Lynch, Kevin M. Brown, Kerri A. Johannson, Moisés Selman, Jay H. Ryu, Athol U. Wells, Yuh‐Chin T. Huang, Carlos A.C. Pereira, Mary-Beth Scholand, Ana Villar, Naohiko Inase, Richard B. Evans, Stephen A. Mette, Lindsy Frazer-Green,
Tópico(s)Inhalation and Respiratory Drug Delivery
ResumoBackgroundThe purpose of this analysis is to provide evidence-based and consensus-derived guidance for clinicians to improve individual diagnostic decision-making for hypersensitivity pneumonitis (HP) and decrease diagnostic practice variability.Study Design and MethodsApproved panelists developed key questions regarding the diagnosis of HP using the PICO (Population, Intervention, Comparator, Outcome) format. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion, and vetted evaluation tools were used to assess the quality of included studies, to extract data, and to grade the level of evidence supporting each recommendation or statement. The quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted and voted on using a modified Delphi technique to achieve consensus. A diagnostic algorithm is provided, using supporting data from the recommendations where possible, along with expert consensus to help physicians gauge the probability of HP.ResultsThe systematic review of the literature based on 14 PICO questions resulted in 14 key action statements: 12 evidence-based, graded recommendations and 2 ungraded consensus-based statements. All evidence was of very low quality.InterpretationDiagnosis of HP should employ a patient-centered approach and include a multidisciplinary assessment that incorporates the environmental and occupational exposure history and CT pattern to establish diagnostic confidence prior to considering BAL and/or lung biopsy. Criteria are presented to facilitate diagnosis of HP. Additional research is needed on the performance characteristics and generalizability of exposure assessment tools and traditional and new diagnostic tests in modifying clinical decision-making for HP, particularly among those with a provisional diagnosis. The purpose of this analysis is to provide evidence-based and consensus-derived guidance for clinicians to improve individual diagnostic decision-making for hypersensitivity pneumonitis (HP) and decrease diagnostic practice variability. Approved panelists developed key questions regarding the diagnosis of HP using the PICO (Population, Intervention, Comparator, Outcome) format. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion, and vetted evaluation tools were used to assess the quality of included studies, to extract data, and to grade the level of evidence supporting each recommendation or statement. The quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted and voted on using a modified Delphi technique to achieve consensus. A diagnostic algorithm is provided, using supporting data from the recommendations where possible, along with expert consensus to help physicians gauge the probability of HP. The systematic review of the literature based on 14 PICO questions resulted in 14 key action statements: 12 evidence-based, graded recommendations and 2 ungraded consensus-based statements. All evidence was of very low quality. Diagnosis of HP should employ a patient-centered approach and include a multidisciplinary assessment that incorporates the environmental and occupational exposure history and CT pattern to establish diagnostic confidence prior to considering BAL and/or lung biopsy. Criteria are presented to facilitate diagnosis of HP. Additional research is needed on the performance characteristics and generalizability of exposure assessment tools and traditional and new diagnostic tests in modifying clinical decision-making for HP, particularly among those with a provisional diagnosis. 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 facilitate 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 (eg, 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 (eg, 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 CT (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 or bronchiolectasis; 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 radiologic features may be seen only in patients with nonfibrotic 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 immunoassay 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 are 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 worldwide 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 nonfibrotic 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. The definition and proposed diagnostic criteria for hypersensitivity pneumonitis (HP) have evolved substantially since their first published description in the 18th century.1Ramazzini B. Diseases of Workers. Wright WC, trans., New York, NY1964Google Scholar, 2Fink J.N. Ortega H.G. Reynolds H.Y. et al.Needs and opportunities for research in hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2005; 171: 792-798Crossref PubMed Scopus (149) Google Scholar, 3Lacasse Y. Selman M. Costabel U. et al.Clinical diagnosis of hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2003; 168: 952-958Crossref PubMed Scopus (452) Google Scholar HP is now understood as an immunologically mediated form of lung disease resulting from inhalational exposure to a large variety of environmental and/or occupational organic (typically fungal, bacterial, and avian), and less often, nonorganic inciting antigens (IAs). HP is a complex lung disease that occurs in genetically susceptible individuals previously sensitized to the inhaled IA. HP can occur at any age, with most patients presenting after the fourth decade of life.4Fernandez Perez E.R. Kong A.M. Raimundo K. Koelsch T.L. Kulkarni R. Cole A.L. Epidemiology of hypersensitivity pneumonitis among an insured population in the United States: a claims-based cohort analysis.Ann Am Thorac Soc. 2018; 15: 460-469Crossref PubMed Scopus (51) Google Scholar Conservatively, the prevalence of HP is estimated to range from one to two cases per 100,000 per year in North America and Europe.4Fernandez Perez E.R. Kong A.M. Raimundo K. Koelsch T.L. Kulkarni R. Cole A.L. Epidemiology of hypersensitivity pneumonitis among an insured population in the United States: a claims-based cohort analysis.Ann Am Thorac Soc. 2018; 15: 460-469Crossref PubMed Scopus (51) Google Scholar, 5Duchemann B. Annesi-Maesano I. Jacobe de Naurois C. et al.Prevalence and incidence of interstitial lung diseases in a multi-ethnic county of Greater Paris.Eur Respir J. 2017; 50Crossref PubMed Scopus (76) Google Scholar, 6Rittig A.H. Hilberg O. Ibsen R. Lokke A. Incidence, comorbidity and survival rate of hypersensitivity pneumonitis: a national population-based study.ERJ Open Res. 2019; 5Crossref PubMed Google Scholar Both the incidence and prevalence increase with advancing age and are highly variable worldwide reflecting the complex interplay among host risk factors, the IA, and environmental factors.4Fernandez Perez E.R. Kong A.M. Raimundo K. Koelsch T.L. Kulkarni R. Cole A.L. Epidemiology of hypersensitivity pneumonitis among an insured population in the United States: a claims-based cohort analysis.Ann Am Thorac Soc. 2018; 15: 460-469Crossref PubMed Scopus (51) Google Scholar,7Fernández Pérez E.R. Sprunger D.B. Ratanawatkul P. et al.Increasing Hypersensitivity Pneumonitis-related Mortality in the United States from 1988 to 2016.Am J Respir Crit Care Med. 2019; 199: 1284-1287Crossref PubMed Scopus (9) Google Scholar, 8Singh S. Collins B.F. Sharma B.B. et al.Interstitial lung disease in India. Results of a prospective registry.Am J Respir Crit Care Med. 2017; 195: 801-813Crossref PubMed Scopus (80) Google Scholar, 9Iijima Y. Sugiyama Y. Suzuki E. Nakayama M. Yamasawa H. Bando M. The relationship between the incidence of summer-type hypersensitivity pneumonitis and environmental factors in Southern Tochigi Prefecture.Intern Med. 2017; 56: 1023-1027Crossref PubMed Scopus (3) Google Scholar More than one-half of subjects present with chronic respiratory symptoms and resultant pulmonary fibrosis.4Fernandez Perez E.R. Kong A.M. Raimundo K. Koelsch T.L. Kulkarni R. Cole A.L. Epidemiology of hypersensitivity pneumonitis among an insured population in the United States: a claims-based cohort analysis.Ann Am Thorac Soc. 2018; 15: 460-469Crossref PubMed Scopus (51) Google Scholar,8Singh S. Collins B.F. Sharma B.B. et al.Interstitial lung disease in India. Results of a prospective registry.Am J Respir Crit Care Med. 2017; 195: 801-813Crossref PubMed Scopus (80) Google Scholar,10Wang B.R. Edwards R. Freiheit E.A. et al.The Pulmonary Fibrosis Foundation Patient Registry. Rationale, design, and methods.Ann Am Thorac Soc. 2020; 17: 1620-1628Crossref PubMed Scopus (2) Google Scholar,11Wells A.U. Flaherty K.R. Brown K.K. et al.Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.Lancet Respir Med. 2020; 8: 453-460Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar While early diagnostic criteria required the presence of an identifiable IA,12Richerson H.B. Bernstein I.L. Fink J.N. et al.Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis.J Allergy Clin Immunol. 1989; 84: 839-844Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 13Schuyler M. Cormier Y. The diagnosis of hypersensitivity pneumonitis.Chest. 1997; 111: 534-536Abstract Full Text Full Text PDF PubMed Google Scholar, 14Ando 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: 765-769Crossref PubMed Google Scholar it is now widely acknowledged that the IA often goes unrecognized or has ceased prior to diagnosis.15Fernández Pérez E.R. Swigris J.J. Forssen A.V. et al.Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis.Chest. 2013; 144: 1644-1651Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Within this context, the elusiveness of the IA together with the array of clinically heterogeneous HP phenotypes in terms of presentation, imaging and pathologic patterns, outcome, and response to therapy frequently leads to misdiagnosis.16Churg A. Bilawich A. Wright J.L. Pathology of chronic hypersensitivity pneumonitis. What is it? What are the diagnostic criteria? Why do we care?.Arch Pathol Lab Med. 2018; 142: 109-119Crossref PubMed Scopus (0) Google Scholar, 17Mooney J.J. Hypersensitivity pneumonitis: lessons from the great imitator in interstitial lung disease.Ann Am Thorac Soc. 2017; 14: 1506-1507Crossref PubMed Scopus (1) Google Scholar, 18Vasakova M. Morell F. Walsh S. Leslie K. Raghu G. Hypersensitivity pneumonitis: perspectives in diagnosis and management.Am J Respir Crit Care Med. 2017; 196: 680-689Crossref PubMed Scopus (176) Google Scholar, 19Morell F. Villar A. Montero M. et al.Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study.Lancet Respir Med. 2013; 1: 685-694Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar HP has traditionally been classified based on clinical features and disease duration as acute, subacute, or chronic.12Richerson H.B. Bernstein I.L. Fink J.N. et al.Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis.J Allergy Clin Immunol. 1989; 84: 839-844Abstract Full Text PDF PubMed Scopus (238) Google Scholar Reliance on this classification framework has led to biased estimates of diagnostic test performance across these three broad categories hindering the impact of relevant HP subgroups on diagnostic test accuracy. Statements on the predictive value of specific HP diagnostic tests in the medical literature are often misleading when derived from highly selected individuals meeting these criteria for classification. Over the years, this HP diagnostic classification coupled with the requirement of strict traditional criteria has been unhelpful, even when accurate, when separated from a probabilistic diagnostic reasoning approach and multidisciplinary consensus. Diagnostic variability in HP is attributed to multiple factors. However, a central source of practice variation and diagnostic disagreement across multidisciplinary teams and among clinicians has been the absence of a comprehensive clinical practice guideline to optimize diagnostic consistency and decision-making in HP. Recently published guidelines offer clinical practice guidance in this area.20Raghu G. Remy-Jardin M. Ryerson C.J. et al.Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/JRS/ALAT clinical practice guideline.Am J Respir Crit Care Med. 2020; 202: e36-e69Crossref PubMed Scopus (80) Google Scholar Publication of these guidelines highlights the need for comprehensive guidance in HP diagnosis, and important distinctions between the guidance provided in that manuscript and in the present guidelines will be discussed further. The rationale for the development of this international evidence-based guideline and expert panel report is to provide rigorously developed contemporary guidance to clinicians on the HP diagnostic process to improve disease recognition, diagnostic accuracy, and individual care and outcomes of HP patients. A provisional HP diagnostic approach and criteria are provided, and a patient-centered and teamwork-oriented approach is emphasized. The Chair of the panel (E. R. F. P.) was reviewed for potential conflicts of interest (COIs) and approved by CHEST’s Professional Standards Committee. An international panel was nominated by the Chair based on their expertise relative to potential guideline questions. The panel consisted of the guideline chair, 13 panelists (A. V., A. U. W., C. A. C. P., D. A. L., J. H. R., K. A. J., K. K. B., M. B. S., M. S., N. I., R. B. E., W. D. T., and Y. C. T. H), representing seven countries, a methodologist (L. F. G), and an additional panelist (S. A. M.) serving as a liaison to CHEST’s Guidelines Oversight Committee. This multidisciplinary panel includes experts in interstitial lung diseases (ILDs), occupational and environmental medicine, chest radiology, and pulmonary pathology. A literature search for qualitative research on patients’ views regarding the acceptability of diagnostic procedures for HP was conducted to incorporate the patient perspective. All panel nominees were reviewed for potential COIs by the Professional Standards Committee. Nominees who were found to have no substantial COIs were approved, whereas nominees with potential intellectual and financial COIs that were manageable were “approved with management.” Panelists approved with management were prohibited from voting on recommendations in which they had substantial COIs. A grid used to track COIs was created for each key clinical question and used during voting to ensure management terms were observed (e-Appendix 1). The expert panel drafted 14 key clinical questions using the Population, Intervention, Comparator, Outcome (PICO) format. With the help of the methodologist, the panel reviewed the PICO questions to identify and finalize search terms, inclusion and exclusion criteria, and databases to be searched. The methodologist performed an initial systematic search of the literature for all PICO questions in March 2018 using MEDLINE (via PubMed) and the Cochrane Library. A combination of the National Library of Medicine’s medical subject headings and key words specific to the PICO elements of the key questions were used to identify studies. MEDLINE (via PubMed) search strategies are available (e-Appendix 2). A pragmatic search update was conducted in May 2020 using MEDLINE (via Pu
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