Korean Guidelines for the Diagnosis and Management of Interstitial Lung Diseases: Hypersensitivity Pneumonitis

1. Identification of exposure

The initial step in diagnosing HP involves identifying the inciting antigen. Since nonfibrotic HP typically exhibits a clear temporal association with antigen exposure, pinpointing the triggers may be relatively straightforward [20]. In contrast, a substantial number of fibrotic HP cases [1,21] do not have identified causative antigens; thus, a comprehensive medical history is crucial. Al-though the American Thoracic Society/Japaness Respiratory Society (ATS/JRS) guidelines neither endorse nor recommend a questionnaire, they do suggest serum immunoglobulin G (IgG) antibody testing, though with low confidence [1]. Despite the sensitivity and specificity concerns of the test, and the unavailability of serum specific IgG tests in Korea, there is a need for further research to design a systematic questionnaire to aid in identifying potential etiologic agents. Recent data from a tertiary ILD referral center in Korea identified mold as the most common inciting antigen [22]. It is essential to understand the regional and cultural differences concerning causative antigens [23].

2. High-resolution computed tomography

In patients suspected of having HP, high-resolution computed tomography (HRCT) is the primary and most crucial modality for diagnosing and detecting lung fibrosis [1,2,11]. According to current guidelines, HRCT patterns are categorized into nonfibrotic and fibrotic HP (Table 1). Given that air trapping due to small airway diseases is commonly present irrespective of fibrosis, two imaging series—deep inspiration and prolonged expiration—should be acquired in patients with HP, as detailed in Table 1. Nonfibrotic HP, as depicted in HRCT, includes at least one feature of diffuse parenchymal infiltration, such as ground-glass opacity (GGO) or mosaic attenuation (Figure 1A), accompanied by at least one sign of small airway disease, such as ill-defined small centrilobular nodules or air trapping (Figure 1B) [1,24]. Mosaic attenuation involves geographic regions of differing attenuation, wherein irregularities exhibit higher attenuation. Conversely, air trapping, stemming from small airway disease, leads to prominent areas of lower attenuation during expiration [25]. Fibrotic HP shown on HRCT presents evidence of lung fibrosis, with a pattern either random or predominant in mid lung zones (Figure 2A) [1,24]. Features indicative of small airway disease are also evident in typical HP patterns. The three-density sign, specific for fibrotic HP, is characterized by decreased attenuation, GGO, and surrounding normal lobules (Figure 2B) [26]. HRCT patterns for both fibrotic and nonfibrotic HP types are provided in Table 1, offering differing levels of diagnostic confidence.

Table 1.

High-resolution computed tomography features of hypersensitivity pneumonitis

Fig. 1.

High-resolution computed tomography (HRCT) patterns of nonfibrotic hypersensitivity pneumonitis. (A) Axial HRCT scans show diffuse and heterogeneous bilateral ground-glass opacities with mosaic attenuation. (B) Diffuse bilateral poorly defined centrilobular nodules with ground-glass opacities, suggestive of a small airway disease pattern.

Fig. 2.

High-resolution computed tomography patterns of fibrotic hypersensitivity pneumonitis. (A) Fibrosis with areas of honeycombing with upper lung predominance, traction bronchiectasis, and architectural distortion. (B) Heterogeneous bilateral ground-glass opacity with minimal reticulation, and the three different densities: high attenuation (ground-glass opacity) (red stars), lucent lung (regions of decreased attenuation and decreased vascular sections) (red arrows), and normal lung (black arrows).

3. Bronchoalveolar lavage/histopathologic findings

BAL plays a pivotal role in patients with uncertain HP [1,2,27-29]. Typically, BAL lymphocytosis is commonly observed in nonfibrotic HP. Although no definite cutoff for BAL lymphocytosis exists, the diagnosis of HP can be established when there is a history of relevant exposure, compatible HRCT patterns, and a lymphocyte level of 20% to 40% in BAL fluids [28,30]. In contrast, BAL fluid analysis in fibrotic HP often shows variable results [4], and the absence of BAL lymphocytosis does not exclude the diagnosis of HP [11,31]. The guideline panel has selected key questions addressing the use of BAL for diagnosing HP.

Key question 1: Is BAL necessary for the diagnosis of nonfibrotic HP?

Key question 2: Is BAL necessary for the diagnosis of fibrotic HP?

Previous studies have compared the proportion of BAL lymphocytes in patients with HP to those with IPF or sarcoidosis. In our meta-analysis, we found that HP demonstrated a significantly higher proportion of lymphocytes in BAL fluid compared to IPF and sarcoidosis, with a much greater difference observed in nonfibrotic HP (Supplementary Figures S1, S2). Therefore, we strongly recommend performing BAL in nonfibrotic HP (low confidence) and conditionally recommend it in fibrotic HP (low confidence).

Patients with ILD, who have limited lung function and are at risk of exacerbation or death following invasive diagnostic procedures [32,33], should be diagnosed using the least invasive methods [1]. In this scenario, while lung biopsy plays a crucial role in cases of undiagnosed ILD, clinicians must carefully consider whether to conduct a biopsy. We have developed PICOs (Population, Intervention, Comparison, and Outcomes) to determine which biopsy methods are most appropriate for diagnosing HP.

Key question 3: Between transbronchial lung biopsy (TBLB) and transbronchial lung cryobiopsy (TBLC), which modality is more suitable for the diagnosis of nonfibrotic HP?

Key question 4: Between TBLB and TBLC, which modality is more suitable for the diagnosis of fibrotic HP?

Although numerous studies on the diagnostic yield of bronchoscopic TBLB for nonfibrotic HP were reviewed, the results of our meta-analysis (Supplementary Figure S3) confirm previous findings [34]. Nonnecrotizing granuloma is a critical feature for diagnosing nonfibrotic HP [1,2], leading us to conditionally recommend TBLB for its diagnosis (low confidence). Conversely, due to a lack of recent studies on TBLC for diagnostic purposes, we offer no recommendations for or against its use in diagnostic procedures, conforming to ATS/JRS guidelines (low confidence) [1]. However, considering TBLC is not common in Korea, its implementation should be limited to experienced specialists and specialized institutions.

Histopathologic findings are subdivided into three categories: HP, probable HP, and indeterminate for HP. In nonfibrotic HP, a high level of diagnostic confidence is reached when the following three criteria are all met: (1) airway-centered cellular interstitial pneumonia, (2) peribronchiolar cellular infiltration, and (3) poorly formed nonnecrotizing granuloma (Figure 3) [1,35]. Of these, the presence of nonnecrotizing granuloma is particularly critical for the diagnosis of nonfibrotic HP. In fibrotic HP, achieving all three of the following criteria in at least one biopsy specimen provides a high level of diagnostic confidence: (1) chronic fibrosing interstitial pneumonia, (2) airway-centered fibrosis, and (3) poorly formed nonnecrotizing granulomas (Figure 4) [1]. The level of diagnostic confidence is reduced when criterion (3) is not fulfilled or when only criteria (1) or (2) are present (Table 2). In both subtypes of HP, the granulomas observed consist of loosely clustered epithelioid cells, distinguishing them from the well-formed granulomas typical of sarcoidosis [36,37].

Fig. 3.

Histopathologic findings of nonfibrotic hypersensitivity pneumonitis. (A) Airway-centered cellular interstitial pneumonia (x10). (B) Peribronchiolar cellular infiltration with extension to adjacent lung parenchyma (x50). (C) Lymphocyte infiltration with poorly formed nonnecrotizing granuloma (x200). Hematoxylin and eosin staining was used.

Fig. 4.

Histopathologic findings of fibrotic hypersensitivity pneumonitis. (A) Centrilobular interstitial fibrosis with cellular infiltration (x20). (B) Poorly formed nonnecrotizing granuloma (x200). Hematoxylin and eosin staining was used.

Table 2.

Histopathologic features of hypersensitivity pneumonitis

Current ATS/JRS guidelines recommend considering fibrotic HP as a differential diagnosis in patients with newly identified fibrotic ILD due to the many similarities between HP and other ILDs [1]. Comprehensive inte-gration of clinical, radiological, and in some instances, BAL and/or histopathologic findings is essential for the accurate diagnosis of HP. If the inciting antigen is identified and HRCT patterns show characteristic HP features, the diagnostic probability is considered moderate to high according to current guidelines [1,2]. Therefore, diagnosis of HP is primarily based on the identification of antigen exposure and typical HRCT patterns. However, in cases where evidence is insufficient, additional tests of BAL and/or histopathological confirmation are recommended in sequential order. Multidisciplinary discussion should be incorporated into the final diagnosis (Figure 5).

Fig. 5.

Diagnostic algorithm for hypersensitivity pneumonitis (HP). HRCT: high-resolution computed tomography; BAL: bronchoalveolar lavage; TBLB: transbronchial lung biopsy; TBLC: transbronchial lung cryobiopsy; SLB: surgical lung biopsy.

1. Antigen avoidance and immunosuppressants

Key question 5: Is antigen avoidance recommended for all patients with HP?

The guideline panel strongly recommends the avoidance and elimination of the inciting antigen (strong recommendation, expert opinion). The standard treatment for HP has not been established through randomized controlled trials. However, substantial evidence supports that the most essential treatment strategy involves identifying the inciting antigen and avoiding exposure to it [6,21,38]. For this reason, clinicians should be vigilant in reevaluating any additional exposure, even though a significant proportion of patients with HP may not have identifiable triggering antigens.

Key question 6: Is corticosteroid therapy recommended for patients with nonfibrotic HP based on symptom and radiological severity?

Key question 7: Is corticosteroid therapy recommended for patients with fibrotic HP based on symptom and radiological severity?

The treatment strategies—antigen avoidance, corticosteroid therapy with or without immunosuppressants, and supplementary oxygen—are similar for both nonfibrotic and fibrotic HP. However, despite appropriate identification and elimination of antigens, clinical-radiological worsening may still occur [39], indicating that various factors contribute to disease progression. The initiation of corticosteroids is a common practice in a real-world setting; however, evidence supporting their efficacy in improving long-term outcomes or decelerating functional decline, particularly in fibrotic HP, remains sparse [11]. Thus, the guideline panel recommends considering corticosteroids in nonfibrotic HP patients experiencing disease progression (strong recommendation, expert opinion). Corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day until clinical-radiological improvement is observed, followed by gradual tapering [7]. In contrast, for fibrotic HP, solely relying on antigen avoidance and corticosteroid treatment may be insufficient to prevent the progression of lung fibrosis. Hence, the panel also advises considering corticosteroids in patients with fibrotic HP experiencing progression (conditional recommendation, expert opinion). Several retrospective studies have investigated the efficacy of immunosuppressants, such as azathioprine, mycophenolate mofetil, rituximab, and leflunomide [40-43]. However, caution is essential when interpreting these findings, due to the inherent limitations of retrospective studies. Considering the potential side effects of long-term corticosteroid usage, a careful assessment of risks and benefits is crucial. We advise starting prednisolone at a dose of 0.5 to 1 mg/kg/day, tapering slowly to below 20 mg/day within 3 months [5]. If the treatment proves suboptimal, or if corticosteroid-related side effects occur, addition of immunosuppressants may be warranted.

2. Antifibrotics and further management

Key question 8: Is antifibrotic therapy recommended for patients with a progressive phenotype of fibrotic HP?

Despite efforts to avoid inciting antigens and utilizing pharmacological treatments such as corticosteroids and/or immunosuppressants, some patients with fibrotic HP experience worsening conditions, progressing to progressive pulmonary fibrosis (PPF) [43,44]. Criteria for diagnosing PPF include lung function decline, increasing symptoms, and advancing radiologic findings, although these criteria have not yet been firmly established [45-48]. In the INBUILD trial, nintedanib reduced the rate of lung function decline by approximately 50% in patients with PPF [45]. Although the INBUILD trial was not originally designed to assess the effectiveness of antifibrotics in disease-specific subgroups, subgroup analyses showed that nintedanib significantly decreased the rate of lung function decline over 52 weeks in patients with fibrotic HP [49]. Pirfenidone, another antifibrotic agent widely used in Korea, has also demonstrated potential in managing fibrotic HP with a PPF phenotype [50]. The guideline panel advocates for the use of antifibrotics in fibrotic HP cases with PPF, although this is a conditional recommendation based on low confidence levels. Further research is necessary to establish the optimal timing for initiating antifibrotic therapy.