Assessment of clinical relevance of antigen improves diagnostic accuracy of hypersensitivity pneumonitis.

BACKGROUND: Exposure assessment is integral to the diagnosis of hypersensitivity pneumonitis (HP). Although the clinical relevance of exposed antigens is essential for the assessment, many of the previous guidelines or reports have only evaluated simple exposure histories or immunological tests. To overcome this problem, the Exposure Assessment Form (EAF) was developed as an assessment tool for classifying the exposure grade from G0 to G4. The EAF was modified from the description in the Japanese clinical practice guide 2022 for HP published by the Japanese Respiratory Society. METHODS: One hundred and seventy-two consecutive patients with interstitial lung disease who underwent multidisciplinary discussion (MDD) at our hospital were retrospectively examined. We assessed whether the use of the EAF improved the diagnostic performance of the international guideline of HP. We also evaluated whether the exposure grade affected the prognosis of HP. RESULTS: Even when a HP diagnosis was made with a confidence of 70% or higher according to the international guideline, less than half of these cases resulted in a final diagnosis of HP when the exposure grades were lower than G3. When the result of the EAF was integrated into the exposure definition of the international guideline, the specificity of the diagnostic performance improved, while sensitivity was maintained. Furthermore, HP patients with an exposure grade of G3 or higher showed a tendency to take a longer time to initiate medication. CONCLUSIONS: This is the first study to evaluate the clinical relevance of possible antigens using the EAF. Assessing the exposure grade prevents overdiagnosis and improves the diagnostic performance of the international guideline.

IL-17A-Secreting Memory γδ T Cells Play a Pivotal Role in Sensitization and Development of Hypersensitivity Pneumonitis.

Hypersensitivity pneumonitis (HP) typically presents with interstitial inflammation and granulomas induced by an aberrant immune response to inhaled Ags in sensitized individuals. Although IL-17A is involved in the development of HP, the cellular sources of IL-17A and the mechanisms by which IL-17A contributes to granuloma formation remain unclear. Recent studies report that γδ T cells produce IL-17A and exhibit memory properties in various diseases. Therefore, we focused on IL-17A-secreting memory γδ T cells in the sensitization phase and aimed to elucidate the mechanisms by which IL-17A contributes to granuloma formation in HP. We induced a mouse model of HP using pigeon dropping extract (PDE) in wild-type and IL-17A knockout (IL-17A-/-) mice. IL-17A-/- mice exhibited reduced granulomatous areas, attenuated aggregation of CD11b+ alveolar macrophages, and reduced levels of CCL2, CCL4, and CCL5 in the bronchoalveolar lavage fluid. Among IL-17A+ cells, more γδ T cells than CD4+ cells were detected after intranasal PDE administration. Interestingly, the expansion of IL-17A-secreting Vγ4+ or Vγ1-Vγ4- cells of convalescent mice was enhanced in response to the sensitizing Ag. Additionally, coculture of macrophages with PDE and Vγ4+ cells purified from PDE-exposed convalescent mice produced significantly more IL-17A than coculture with Vγ4+ cells from naive mice. Our findings demonstrate that in the sensitization phase of HP, IL-17A-secreting memory γδ T cells play a pivotal role. Furthermore, we characterized the IL-17A/CCL2, CCL4, CCL5/CD11b+ alveolar macrophage axis, which underlies granuloma formation in HP. These findings may lead to new clinical examinations or therapeutic targets for HP.

Efficacy of treatment with corticosteroids for fibrotic hypersensitivity pneumonitis: a propensity score-matched cohort analysis.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (HP) is a chronic interstitial lung disease caused by allergic responses to repeated exposures to a causative antigen. Therapeutic evidence of the use of corticosteroids to treat fibrotic HP remains lacking, although corticosteroids are recognized as a major treatment option. The purpose of this study was to evaluate the efficacy of corticosteroid treatment in patients with fibrotic HP in a propensity score-matched cohort. METHODS: A retrospective review of the medical records from 2005 to 2019 in a single center was conducted, and 144 patients with fibrotic HP were identified. Semiquantitative scores for lung abnormalities on HRCT were evaluated. Patients who received (PDN group) and did not receive (non-PDN group) corticosteroid treatment were matched using a propensity score method. Survival rates, serial changes in pulmonary function and annual changes in HRCT scores were compared in the matched cohort. RESULTS: In the matched analysis, 30 individuals in the PDN group were matched with 30 individuals in the non-PDN group, the majority of whom had ILD without extensive fibrosis. The survival rate was significantly better in the PDN group (P = 0.032 for the stratified Cox proportional hazards model; HR, 0.250). The absolute changes in FVC at 6, 12, and 24 months from baseline were significantly better in the PDN group. Fewer patients in the PDN group experienced annual deterioration, as reflected in the HRCT score, due to ground-glass attenuation, consolidation, reticulation, traction bronchiectasis and honeycombing. CONCLUSION: We demonstrated that corticosteroids improved survival and slowed fibrotic progression in a matched cohort, the majority of whom had ILD without extensive fibrosis. Fibrotic HP with less severe fibrosis may benefit from corticosteroid treatment. We propose that the early initiation of corticosteroids should be considered for fibrotic HP when worsening fibrosis is observed.

[A Case of Pulmonary Enteric Adenocarcinoma with Soleus Muscle Metastasis].

Pulmonary enteric adenocarcinoma is a unique pulmonary adenocarcinoma subtype and has histopathological findings that are similar to those of colorectal adenocarcinoma. A man in his 50s visited our hospital because of discomfort in his right lower leg for the last 9 months. Imaging studies revealed a mass in his right soleus muscle, and needle biopsy was performed. Histological findings revealed adenocarcinoma, and immunohistochemical staining showed that the tumor cells were positive for CK20 and CDX-2. The tumor was first suspected to be metastasis of gastrointestinal malignant tumors. FDG-PET/CT showed increased FDG uptake in the right soleus muscle mass and presented with increased FDG uptake in a right upper lobe mass and right mediastinum lymphadenopathy. There were no findings in other organs. Scraping cytology of a transbronchial biopsy indicated adenocarcinoma. Upper and lower gastrointestinal endoscopy showed no findings of malignancy. He was finally diagnosed with pulmonary enteric adenocarcinoma(cT3N2M1b, Stage ⅣA). Treatment with cisplatin(CDDP), pemetrexed( PEM), and bevacizumab(BEV) was initiated. After 4 courses of the regimen, the tumor was partially reduced, and the patient showed stable disease(SD).

Role of serum surfactant protein-D as a prognostic predictor in fibrotic hypersensitivity pneumonitis.

BACKGROUND: Serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are candidate diagnostic and activity markers for fibrotic hypersensitivity pneumonitis (HP), although their correlation with prognosis remains unclear. We aimed to evaluate the prognostic usefulness of serum KL-6 and SP-D in patients with fibrotic HP. METHODS: This was a retrospective medical record review of 185 patients with fibrotic HP at a single center from 2005 to 2019. The baseline and minimum serum KL-6 and SP-D levels over two years were recorded. The contribution of KL-6 and SP-D levels to the incidence of progressive fibrosing interstitial lung disease (PF-ILD) and mortality were evaluated using multivariate analysis. RESULTS: The respective baseline and minimum levels were 1441 and 808 U/ml for KL-6 and 254 and 132 ng/mL for SP-D. A high minimum SP-D level was significantly associated with a high incidence of PF-ILD by logistic regression, independent of baseline forced vital capacity and honeycombing. Similarly, a high minimum SP-D level was significantly associated with high mortality by Cox proportional hazard model analysis. The stratified minimum SP-D levels of <100, 100-200, and >200 revealed significantly distinct groups in the entire cohort, with PF-ILD incidence rates of 28%, 48%, and 74% and median survival times of 120, 74, and 45 months, respectively. CONCLUSIONS: High minimum SP-D levels over two years were correlated with an unfavorable prognosis in our cohort. Patient with consistently high SP-D levels during the clinical course may have a poor prognosis and be a candidate for early treatment intensification.

Successful diagnosis of humidifier lung by individual provocation test to a responsible environment, a case report.

A 52-year-old woman presented with repeating episodes of pneumonia which spontaneously resolved after hospitalization. Hypersensitivity pneumonitis was suspected, but the causative antigen was not determined whether the parakeets she kept or the humidifier she owned was causative exposure. To identify which exposure is culprit, individual provocation test to a responsible environment was sequentially conducted. First, a home-returning provocation test to the parakeet was negative. Contrarily, the humidifier provocation test to her own humidifier was positive for symptoms, radiological changes, and inflammatory responses in blood test. Finally, she was diagnosed as having humidifier lung. When several antigens are suspected to be the causative agents for hypersensitivity pneumonitis, a step-by-step provocation tests is useful.