Role of Surgical Lung Biopsy in Separating Chronic Hypersensitivity Pneumonia From Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis*: Analysis of 31 Biopsies From 15 Patients

doi:10.1378/chest.08-0033

Chest

Volume 134, Issue 1, July 2008, Pages 126-132

https://doi.org/10.1378/chest.08-0033 Get rights and content

Background

Lung biopsy has been proposed as a criterion for diagnosis of chronic hypersensitivity pneumonia (HP), especially in patients without proven antigen exposure. Histologic findings in some suspected HP patients overlap with usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). We reviewed our experience to determine the specificity of histologic findings in surgical lung biopsies from patients with clinical diagnoses of HP.

Methods

Surgical lung biopsies from patients with chronic HP, idiopathic pulmonary fibrosis, and idiopathic NSIP were reviewed retrospectively without knowledge of the clinical diagnosis. Each specimen was assigned a histologic diagnosis, and selected histologic findings were tabulated. Clinical data were abstracted from medical records.

Results

Fifteen patients with clinical diagnoses of chronic HP underwent biopsy of one to three lobes. Ten showed features diagnostic of HP in all specimens. Two had discordant findings that included HP in one specimen and UIP or nonspecific changes in others. Biopsies from two showed only UIP, and one showed NSIP. Diagnostic features were present in all samples from 9 of the 11 patients with more than one biopsy site (81.8%). Three patients died of disease, including both patients from whom biopsies showed only UIP.

Conclusions

Most patients with a clinical diagnosis of chronic HP have supportive histologic findings in surgical lung biopsies. A subset of HP patients has findings indistinguishable from UIP. Sampling from more than one lobe may be helpful in separating HP from idiopathic pulmonary fibrosis.

Section snippets

Materials and Methods

We conducted a computer-assisted search of the Mayo Clinic database to identify patients with chronic HP who underwent surgical lung biopsy between January 1997 and June 2005. A clinical diagnosis of chronic HP required the following criteria: (1) presence of chronic respiratory symptoms (≥ 3 months), (2) inspiratory crackles, (3) radiologic evidence of diffuse lung disease by chest radiography or CT, (4) history of exposure or a positive serum precipitin test to an inciting antigen, and (5) no

Clinical Findings

Clinical findings in 15 study patients with HP are detailed in Table 1. Twelve patients were women (80%), with a mean age at diagnosis of 58.7 years (range, 46 to 79 years). Eleven were never smokers (73%), and 4 were ex-smokers (27%). Median duration of respiratory symptoms was 18 months (range, 4 to 130 months). Specific antigenic exposures were identified by history in nine patients and included birds (n = 5) household mold (n = 2), and thermophilic bacteria linked to a contaminated

Discussion

Our findings support previous observations3, 6, 9, 11, 13, 21, 22 that surgical lung biopsy is helpful in separating HP from other forms of diffuse lung disease, including the idiopathic interstitial pneumonias. Chronic interstitial pneumonia, bronchiolitis, and a distinctive form of peribronchiolar granulomatous inflammation is the most frequent combination of findings in surgical lung biopsies from patients with a clinical diagnosis of HP. The bronchiolitis often includes associated

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Cited by (106)

Integration and Application of Clinical Practice Guidelines for the Diagnosis of Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis
2022, Chest
Recent clinical practice guidelines have addressed the diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). These disease-specific guidelines were developed independently, without clear direction on how to apply their respective recommendations concurrently within a single patient, where discrimination between these two fibrotic interstitial lung diseases represents a frequent diagnostic challenge. The objective of this review, created by an international group of experts, was to suggest a pragmatic approach on how to apply existing guidelines to distinguish IPF and fHP. Key clinical, radiologic, and pathologic features described in previous guidelines are integrated in a set of diagnostic algorithms, which then are placed in the broader context of multidisciplinary discussion to guide the generation of a consensus diagnosis. Although these algorithms necessarily reflect some uncertainty wherever strong evidence is lacking, they provide insight into the current approach favored by experts in the field based on currently available knowledge. The authors further identify priorities for future research to clarify ongoing uncertainties in the diagnosis of fibrotic interstitial lung diseases.
Alternative Gene Expression by TOLLIP Variant Is Associated With Lung Function in Chronic Hypersensitivity Pneumonitis
2022, Chest
Chronic hypersensitivity pneumonitis (CHP) is a heterogeneous fibrotic interstitial pneumonia resulting from the immune response of susceptible individuals to inhaled antigens. Genetic predispositions have been suggested in CHP; however, the link between susceptibility genes and fibrotic progression has not been elucidated fully. Recent data suggest that variants in Toll-interacting protein gene (TOLLIP) are associated with lung diseases.
Can TOLLIP variants be associated with any clinical features in patients with CHP?
We genotyped rs5743899 and rs3750920 in TOLLIP and analyzed the association with clinical parameters in 101 patients with CHP (67 for the retrospective cohort and 34 for the prospective cohort). We evaluated the expression of TOLLIP and fibrogenic signals in affected lung tissues and periostin in sera. Furthermore, we performed immunologic analysis in the lungs and sera.
The rs5743899 GG genotype was associated with rapid deterioration in FVC over time, which demonstrated significant annual decline in the retrospective cohort (vs AA, P = .0006; vs AG, P < .0001), prospective cohort (vs AA, P < .0001; vs AG, P = .003), and combined cohort (both P < .0001). The patients with the GG genotype demonstrated lower transcription-translation levels of TOLLIP as well as increased phosphorylation of Smad2 and inhibitor of kappa B in the lung tissues and exhibited higher serum levels of periostin, IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor α, and IFN-γ.
The functional changes by TOLLIP variant were associated with rapid FVC decline through dysregulated Smad/transforming growth factor β and NF-κB signaling in CHP.
Disease pathology in fibrotic interstitial lung disease: is it all about usual interstitial pneumonia?
2021, The Lancet
The interstitial pneumonias comprise a diverse group of diseases that are typically defined by their cause (either idiopathic or non-idiopathic) and their distinct histopathological features, for which radiology, in the form of high-resolution CT, is often used as a surrogate. One trend, fuelled by the failure of conventional therapies in a subset of patients and the broad-spectrum use of antifibrotic therapies, has been the focus on the progressive fibrosing phenotype of interstitial lung disease. The histological pattern, known as usual interstitial pneumonia, is the archetype of progressive fibrosis. However, it is clear that progressive fibrosis is not exclusive to this histological entity. Techniques including immunohistochemistry and single-cell RNA sequencing are providing pathogenetic insights and, if integrated with traditional histopathology, are likely to have an effect on the pathological classification of interstitial lung disease. This review, which focuses on the histopathology of interstitial lung disease and its relationship with progressive fibrosis, asks the question: is it all about usual interstitial pneumonia?
Diagnosis and Evaluation of Hypersensitivity Pneumonitis: CHEST Guideline and Expert Panel Report
2021, Chest
Citation Excerpt :
Based on the presence or absence of an interstitial fibrotic pattern, lung biopsy findings are divided into “nonfibrotic HP” (cellular HP) and “fibrotic HP” patterns, with worse survival seen in the fibrosing cases (Tables 7 and 8).129,192-201 Surgical lung biopsies obtained from multiple lobes will have a higher diagnostic yield compared to approaches using more limited sampling of lung tissue, such as TBB or TCB, as the likelihood of identifying diagnostic features of HP is related to the biopsy sampling size.43,48,123,129,132,160,202-206 We suggest the use of four pathologic categories that reflect the level of confidence that a histopathological specimen is likely to represent HP in the appropriate clinical context (Tables 7 and 8): 1) Typical nonfibrotic HP or fibrotic HP; 2) Compatible with nonfibrotic HP or fibrotic HP; 3) Indeterminate for nonfibrotic or fibrotic HP; and 4) Alternative 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.
Executive Summary: Diagnosis and Evaluation of Hypersensitivity Pneumonitis: CHEST Guideline and Expert Panel Report
2021, Chest
The purpose of this summary is to provide a synopsis of 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, and 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.
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. 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.
Changes in serum KL-6 levels during short-term strict antigen avoidance are associated with the prognosis of patients with fibrotic hypersensitivity pneumonitis caused by avian antigens
2020, Respiratory Investigation
Bird-related hypersensitivity pneumonitis (BRHP) is the most common type of fibrotic hypersensitivity pneumonitis (HP). Antigen avoidance (AA) is a key step in the diagnosis and management of HP, but not all fibrotic HP patients improve through AA. Because of the poor prognosis of fibrotic HP, predictive biomarkers to identify patients showing rapid progression during AA are urgently needed.
From a retrospective review of the medical records of 1941 patients with interstitial lung disease, 75 cases of fibrotic BRHP confirmed by a provocation test or surgical lung biopsy were identified. To identify potential prognostic markers obtained at or around diagnosis, physiological and serological variables at diagnosis and the relative changes in those variables during strict AA were evaluated. Cox proportional hazards models with log-rank testing were used to compare the associations between these variables and survival.
Univariate analyses showed that gender, smoking status, and the relative change in the serum levels of Krebs von den Lungen-6 (KL-6) were associated with prognosis (P = 0.02, 0.04, and 0.02, respectively), but the presence of honeycombing and the forced vital capacity were not associated with survival. The relative change in KL-6 levels (greater than vs. less than a 10% decrease) was significantly associated with survival in a stratified analysis (73.9 vs. 34.9 months; P = 0.04).
The relative change in KL-6 levels is associated with the prognosis of patients with fibrotic BRHP independent of previously identified prognostic biomarkers. This finding could help pulmonologists identify fibrotic BRHP patients that are likely to show rapid progression.

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All work for this study was performed at the Mayo Clinic, Rochester, MN.

No conflicts of interest exist for any of the authors.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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Chest

Original ResearchInterstitial Lung DiseaseRole of Surgical Lung Biopsy in Separating Chronic Hypersensitivity Pneumonia From Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis*: Analysis of 31 Biopsies From 15 Patients

Background

Methods

Results

Conclusions

Section snippets

Materials and Methods

Clinical Findings

Discussion

J Allergy Clin Immun

Chest

Ann Diagn Pathol

Am J Med

Am J Med

J Allergy Clin Immun

Mayo Clin Proc

Chest

Needs and opportunities for research in hypersensitivity pneumonitis

Am J Respir Crit Care Med

Clinical diagnosis of hypersensitivity pneumonitis

Am J Respir Crit Care Med

Controversies in hypersensitivity pneumonitis

Am Rev Respir Dis

Histologic diagnosis of extrinsic allergic alveolitis

Am J Surg Pathol

Pathological diagnosis of granulomatous lung disease: a review

Histopathology

Original Research
Interstitial Lung Disease
Role of Surgical Lung Biopsy in Separating Chronic Hypersensitivity Pneumonia From Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis*: Analysis of 31 Biopsies From 15 Patients