Hypersensitivity pneumonitis (HP) is a complex form of interstitial lung disease (ILD) characterized by immune-mediated inflammation following an inciting antigen exposure in a susceptible individual.1 Chronic exposure leads to progression of inflammation with evolution of fibrotic response in the lung and progressive pulmonary fibrosis (PPF). Knowledge of key features of disease presentation is critical in distinguishing HP from other idiopathic interstitial pneumonias, allowing for subsequent appropriate interventions including exposure avoidance and treatment. Recently, two anticipated guidelines have emerged, one published by the American Thoracic Society/Japanese Respiratory Society/Asociación Latinoamericana de Tórax (ATS/JRS/ALAT) and the second by the American College of Chest Physicians (ACCP), establishing standardized diagnostic approaches to HP.2, 3 These guidelines provide similar diagnostic algorithms, in addition to establishing clinical, radiographic and histopathologic features of two clinical phenotypes known as fibrotic and nonfibrotic HP, with separate recommendations for each. Both guidelines emphasize the importance of classification of diagnosis of fibrotic HP (fHP) or nonfibrotic HP (nfHP), the distinction of which is made by the presence or absence of radiographic or histopathologic fibrosis. Prior time-based classification (acute, subacute, chronic) was deemed inferior by both working groups due to unreliable association with clinical outcomes. The new approach was adapted to objectively define disease presentation and to allow for more consistent association with disease prognostication, as well as to better inform treatment decisions. Diagnosis of HP is often challenging given the heterogeneity in clinical presentation, in addition to overlap with other non-fibrotic and fibrotic ILDs. Establishing a clinical profile may help inform pre-test probability when distinguishing between fibrotic ILDs, though an indeterminate clinical profile with overlapping features that may be compatible with both idiopathic pulmonary fibrosis (IPF) and fHP (such as male >60 years of age, former smoker with a possible exposure) can make distinction difficult.4 As a result, misdiagnosis is not infrequent, as a proportion of patients labelled as having IPF are often found to have fHP on explant studies or case re-evaluation.5-7 Furthermore, a causative antigen exposure is not identified in up to 60% of patients with HP, despite thorough evaluation.2, 8-10 Nonetheless, the index of suspicion for HP must remain high in a clinician's mind during evaluation of ILD, and an integrated approach implementing multidisciplinary discussion is particularly important in cases with clinical overlap. The diagnosis of HP requires an integrative approach with collaboration among expert pulmonologists, radiologists and pathologists in order to optimize diagnostic accuracy (Figure 1A). Both guidelines highlight the importance of three primary clinical domains including (1) exposure identification, (2) high resolution computed tomography (HRCT) imaging and (3) BAL lymphocytosis. The need for histopathology should be limited to patients in whom the confidence of the clinical diagnosis of HP is low and in whom risks for obtaining surgical lung biopsy are low.2 Antigen identification can be investigated initially through a comprehensive patient history. Regrettably, there is no validated recommended questionnaire available to date, and as a result, the clinician must approach patients with a detailed environmental exposure history with awareness of usual and unusual HP inducers.1 Serum-specific IgG testing detects immunologic sensitization without establishing causality, though can be helpful in generating supportive data in cases with some diagnostic uncertainty.5 Exposure tests such as the specific inhalation challenge can only be performed at centres with the appropriate expertise and have limited widespread implementation.3, 5 The importance of recognizing the distribution and patterns of HRCT chest imaging is emphasized in both guidelines. These are categorized as ‘typical’ or ‘compatible with HP’, for both nonfibrotic and fHP and include ‘indeterminate for HP’ for fHP.2, 3 The indeterminate category is used when any pattern of pulmonary fibrosis is present without specific features of HP.3 The distinction between fibrotic and nfHP has clinical significance, as there is clear demonstration that the presence of radiographic or histopathological fibrosis are associated with worse outcomes.11-19 While the specific radiographic features of the ‘typical’ nfHP and fHP patterns are described in the guidelines and have an upper lobe predominance, the three-density pattern is highly specific for fHP. This pattern is a combination of three attenuations on inspiratory CT images: normal appearing lung, high attenuation (GGO) corresponding to infiltrative disorder and regions of decreased attenuation related to the obstructive abnormality seen in small airway disease (Figure 1B).2 BAL lymphocytosis raises the probability of HP, with thresholds of 30% or greater demonstrating a high specificity for fHP.2, 20 This can help to distinguish fHP from other forms of fibrotic ILD such as IPF, though the absence of BAL lymphocytosis does not exclude a diagnosis of HP (Figure 1A). In patients in whom a confident diagnosis of HP cannot be made despite multidisciplinary review of clinical, radiographic and BAL findings (typically in patients with indeterminate imaging pattern for HP), the diagnosis of HP can only be ascertained with histopathology features found on lung biopsy (Figure 1A). The guidelines emphasize that lung biopsy must be considered as a last resort only in patients whose risk for the procedure are relatively low and all other diagnostic evaluation/intervention has been exhausted. The ATS/JRS/ALAT guideline suggests that transbronchial lung cryobiopsy (TBLC) be considered by capable medical centres with expertise in performing TBLC to patients with suspected fHP.2 Both guidelines offer similar criteria for histopathologic findings in fibrotic and nfHP.2, 3 Typical features of nfHP are accentuated around airways (‘bronchiolocentric’), with lymphocyte predominance, and poorly formed nonnecrotizing granulomas and/or multinucleated giant cells. Histopathologic features typical for fHP are (1) chronic fibrosing interstitial pneumonia with fibrotic NSIP or UIP-like pattern, (2) airway-centred fibrosis with or without peribronchiolar metaplasia, (3) poorly formed non-necrotizing granulomas and (4) absence of features to suggest alternative diagnosis. In cases where an inciting antigen is identified, avoidance and remediation are essential aspects of HP management. Importantly, lack of clinical improvement following antigen avoidance does not exclude a diagnosis of HP or rule out the antigen as causal. Currently, there are no established guidelines for pharmacologic management of HP. Immunomodulating medications such as prednisone, mycophenolate mofetil (MMF) or azathioprine are commonly used, though without the support of clinical trials. Although limited data does suggest the strongest benefit of corticosteroid (CS) in patients with nfHP, evidence to support long-term benefit of CS is lacking. Few retrospective studies have shown improvement in forced vital capacity (FVC) or diffusion capacfity for carbon monoxide (DLCO) with the use of MMF and azathioprine with significant reduction in prednisone dose and decreased incidence of treatment-emergent adverse effects when compared with prednisone alone.21-24 A retrospective study of rituximab in 20 patients with chronic HP suggested that rituximab may lead to stabilization of lung function in some patients.25 The 2022 ATS/ERS/JRS/ALAT guideline on PPF suggests therapeutic benefit with the antifibrotic nintedanib for patients with PPF, irrespective of the specific ILD diagnosis. Thus, nintedanib may be tried for patients with fHP manifesting PPF.26 Despite the lack of standardized treatment guidelines for HP, a reasonable approach based on limited data may be a trial of immunomodulating medications (i.e., CSs in addition to steroid-sparing agent such as MMF) in symptomatic patients with nf/fHP, with consideration of the addition of nintedanib as either combination or monotherapy without immunosuppression in cases of fHP with progressive disease. Collectively, the available data (largely from observational studies) suggest that clinical improvement is more common in nfHP than fHP, however, clinicians should not rely solely on clinical improvement (or lack of) with medical therapy to confirm or exclude a diagnosis of HP as suggested in the ACCP guideline.3 HP is a complex disease with a heterogeneous presentation and clinical course, often leading to diagnostic challenges. Guidelines published by both the ATS/JRS/ALAT and ACCP provide clinicians with similar diagnostic algorithms to aid in the diagnostic approach to patients with newly recognized ILD. Research is needed to improve diagnostic certainty in various aspects including genetic predisposition, validated regionally relevant exposure questionnaires, establishing BAL thresholds and specific antibody testing, in addition to differentiating histopathologic similarities of UIP and UIP-like patterns and genomic classifiers of UIP in patients with fHP and IPF. The possibility of HP as a primary entity or ‘cryptogenic HP’ when an antigen is not identified in the patient's environment despite thorough investigation (including inspection and microbiology testing by an environmental hygienist) will need to be pursued. Finally, data to guide treatment of HP is limited, with a strong need for clinical trials and other research to address treatment of both fHP and nfHP. None declared.
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Apr 24, 2024
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