BACKGROUND: According to international diagnostic guidelines for hypersensitivity pneumonitis (HP), cases with both nonfibrotic and fibrotic lesions are classified by the predominant feature. Therefore, some cases with nonfibrotic HP, have inflammatory lesions alone, while others have a mixture of fibrosis and inflammation. We investigated the impact of slight fibrotic lesions in nonfibrotic HP.
METHODS: This retrospective study included nonfibrotic HP cases with <10% of lung distortion on high-resolution CT. We divided the cases into two groups: those with pure ground glass opacities (GGOs) without lung distortion and those with slight lung distortion of <10%.
RESULTS: In this study, 37 cases were included. The mean baseline forced vital capacity (FVC) was 109% in the pure GGO group and 96% in the slight lung distortion group (p = 0.038). After 1 year, the reticular shadows appeared or increased more in the slight lung distortion group than in the pure GGO group (16% vs. 8%, p = 0.030). The time to medication initiation was significantly shorter in the slight lung distortion group than in the pure GGO group (p = 0.044). %FVC decreased by ≥ 5% from diagnosis in no cases with the pure GGO and in two cases with the slight lung distortion (-11.0% for 9.5 years and -10.7% for 1.3 years, respectively).
CONCLUSIONS: The slight distortion group exhibited a higher rate of worsening and new appearance of reticular shadows after 1 year and a shorter time to first medication compared to the pure GGO group.

BACKGROUND: Although transbronchial lung cryobiopsy (TBLC) is widely used in diagnostic algorithms for various interstitial lung diseases (ILDs), its real-world utility in the therapeutic decision-making strategy for ILD patients remains unclear, in particular, when judging the time to start antifibrotic agents.
METHODS: We analyzed medical records of 40 consecutive patients with idiopathic or fibrotic hypersensitivity pneumonitis who underwent TBLC. A TBLC-based usual interstitial pneumonia (UIP) score was used to assess three morphologic descriptors: patchy fibrosis, fibroblastic foci, and honeycombing.
RESULTS: In our 40 patients with ILD, the most frequent radiological feature was indeterminate for UIP (45.0%). Final diagnosis included idiopathic pulmonary fibrosis (22.5%), fibrotic nonspecific interstitial pneumonia (5.0%), fibrotic hypersensitivity pneumonitis (35.0%), and unclassifiable ILD (37.5%). Linear mixed-effects analysis showed that declines in the slopes of %FVC and %DLCO in patients with TBLC-based UIP \"Score ≥ 2\" were significantly steeper than those of patients with \"Score ≤ 1.\" During follow-up of patients with Score ≥ 2 (n = 24), more than half of them (n = 17) received an antifibrotic agent, with most patients (n = 13) receiving early administration of the antifibrotic agent within 6 months after the TBLC procedure.
CONCLUSIONS: TBLC-based UIP Score ≥ 2 indicated the increased possibility of a progressive fibrosis course that may prove helpful in predicting progressive pulmonary fibrosis/progressive fibrosing ILD even if disease is temporarily stabilized due to anti-inflammatory agents. Patients may benefit from early introduction of antifibrotic agents by treating clinicians.

BACKGROUND: The optimal treatment of fibrosing hypersensitivity pneumonitis (fHP) is not well understood. The aim of the study was to obtain information about the usefulness of mycophenolate mofetil (MMF) in its treatment.
METHODS: Quasi-experimental analysis of patients diagnosed with fHP and treated with MMF for one year, in a single centre. From the start of treatment, data collection was prospective.
RESULTS: 73 were included and 58 completed the study. FVC% and DLCO% decreased until starting MMF (year -1 to year 0). After completion of treatment (year 1), FVC% stabilised (p=0.336) and DLCO% improved significantly (p=0.004) compared to year 0. Dyspnoea, number of patients without corticosteroids and mean corticosteroid dose also improved significantly (p<0.001 in all cases). Being male and having a history of tuberculosis were predictors of poor drug response [AUC = 0.89 (95% CI: 0.80-0.98)]. 45 adverse effects were observed in 34 patients (46.6%). In 4 cases (5.5%), the adverse effect was severe and required discontinuation of treatment.
CONCLUSIONS: In patients with fHP, MMF improves lung function and dyspnoea and reduces both the number of patients requiring oral corticosteroids and their mean dose in those who completed 1 year of treatment. The model constructed predicts which patients will respond poorly to treatment, with good discriminative ability and only a small percentage of patients will not tolerate treatment. Further prospective, randomised clinical trials are needed to define the role of this treatment in fHP.

BACKGROUND: The diagnosis of fibrotic hypersensitivity pneumonitis (fHP) from other interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), is often difficult. This study aimed to examine computed tomography (CT) findings that were useful for differentiating between fHP and IPF and to develop and validate a radiological diagnostic model.
METHODS: In this study, 246 patients (fHP, n = 104; IPF, n = 142) from two institutions were included and randomly divided into the test (n = 164) and validation (n = 82) groups (at a 2:1 ratio). Three radiologists evaluated CT findings, such as pulmonary fibrosis, small airway disease, and predominant distribution, and compared them between fHP and IPF using binomial logistic regression and multivariate analysis. A prognostic model was developed from the test group and validated with the validation group.
RESULTS: Ground-glass opacity (GGO) with traction bronchiectasis (TB), honeycombing, hypoattenuation area, three-density pattern, diffuse craniocaudal distribution, peribronchovascular opacities in the upper lung, and random distribution were more common in fHP than in IPF. In multivariate analysis, GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were significant features. The area under the curve of the fHP diagnostic model with the three aforementioned CT features was 0.733 (95% confidence interval [CI], 0.655-0.811, p < 0.001) in the test group and 0.630 (95% CI, 0.504-0.755, p < 0.047) in the validation group.
CONCLUSIONS: GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were important CT features for differentiating fHP from IPF.

Rationale: Fibrotic hypersensitivity pneumonitis is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in fibrotic hypersensitivity pneumonitis in single-cell resolution. Methods: Single-cell 5\' RNA sequencing was conducted on peripheral blood mononuclear cells and bronchoalveolar lavage cells obtained from 45 patients with fibrotic hypersensitivity pneumonitis, 63 idiopathic pulmonary fibrosis, 4 non-fibrotic hypersensitivity pneumonitis, and 36 healthy controls in the United States and Mexico. Analyses included differential gene expression (Seurat), transcription factor activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3/Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and controls and 88,336 bronchoalveolar lavage cells from 19 patients were profiled. Compared to controls, fibrotic hypersensitivity pneumonitis has elevated classical monocytes (adjusted-p=2.5e-3) and are enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-p<2.2e-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared to both controls and idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis patient cells are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit transcription factor activities indicative of TGFβ and TNFα/NFκB pathways. These results are publicly available at https://ildimmunecellatlas.org. Conclusions: Single-cell transcriptomics of fibrotic hypersensitivity pneumonitis patients uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells - reflecting this disease\'s unique inflammatory T-cell driven nature - as well as increased S100Ahi and CCL3hi/CCL4hi classical monocytes also observed in idiopathic pulmonary fibrosis. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Interstitial lung disease (ILD) encompasses a diverse group of disorders characterized by chronic inflammation and fibrosis of the pulmonary interstitium. Three ILDs, namely idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (fHP), and connective tissue disease-associated ILD (CTD-ILD), exhibit similar progressive fibrosis phenotypes, yet possess distinct etiologies, encouraging us to explore their different underlying mechanisms.
Transcriptome data of fibrotic lung tissues from patients with IPF, fHP, and CTD-ILD were subjected to functional annotation, network, and pathway analyses. Additionally, we employed the xCell deconvolution algorithm to predict immune cell infiltration in patients with fibrotic ILDs and healthy controls.
We identified a shared progressive fibrosis-related module in these diseases which was related to extracellular matrix (ECM) degradation and production and potentially regulated by the p53 family transcription factors. In IPF, neuron-related processes emerged as a critical specific mechanism in functional enrichment. In fHP, we observed that B cell signaling and immunoglobulin A (IgA) production may act as predominant processes, which was further verified by B cell infiltration and the central role of CD19 gene. In CTD-ILD, active chemokine processes were enriched, and active dendritic cells (aDCs) were predicted to infiltrate the lung tissues.
This study revealed shared and specific molecular and cellular pathways among IPF, fHP, and CTD-ILD, providing a basis for understanding their pathogenesis and identifying potential therapeutic targets.

BACKGROUND: Patients with fibrotic hypersensitivity pneumonitis (f-HP) have varied clinical and radiologic presentations whose associated phenotypic outcomes have not been previously described. We conducted a study to evaluate mortality and lung transplant (LT) outcomes among clinical clusters of f-HP as characterized by an unsupervised machine learning approach.
METHODS: Consensus cluster analysis was performed on a retrospective cohort of f-HP patients diagnosed according to recent international guideline. Demographics, antigen exposure, radiologic, histopathologic, and pulmonary function findings along with comorbidities were included in the cluster analysis. Cox proportional-hazards regression was used to assess mortality or LT risk as a combined outcome for each cluster.
RESULTS: Three distinct clusters were identified among 336 f-HP patients. Cluster 1 (n = 158, 47%) was characterized by mild restriction on pulmonary function testing (PFT). Cluster 2 (n = 46, 14%) was characterized by younger age, lower BMI, and a higher proportion of identifiable causative antigens with baseline obstructive physiology. Cluster 3 (n = 132, 39%) was characterized by moderate to severe restriction. When compared to cluster 1, mortality or LT risk was lower in cluster 2 (hazard ratio (HR) of 0.42; 95% CI, 0.21-0.82; P = 0.01) and higher in cluster 3 (HR of 1.76; 95% CI, 1.24-2.48; P = 0.001).
CONCLUSIONS: Three distinct phenotypes of f-HP with unique mortality or transplant outcomes were found using unsupervised cluster analysis, highlighting improved mortality in fibrotic patients with obstructive physiology and identifiable antigens.

OBJECTIVE: The acute-phase protein C-reactive protein (CRP) is known to be associated with poor outcomes in cancer and cardiovascular disease, but there is limited evidence of its prognostic implications in interstitial lung diseases (ILDs). We therefore set out to test whether baseline serum CRP levels are associated with mortality in four different ILDs.
METHODS: In this retrospective study, clinically measured CRP levels, as well as baseline demographics and lung function measures, were collected for ILD patients first presenting to the Royal Brompton Hospital between January 2010 and December 2019. Cox regression analysis was used to determine the relationship with 5-year mortality.
RESULTS: Patients included in the study were: idiopathic pulmonary fibrosis (IPF) n = 422, fibrotic hypersensitivity pneumonitis (fHP) n = 233, rheumatoid arthritis associated ILD (RA-ILD) n = 111 and Systemic Sclerosis associated ILD (SSc-ILD) n = 86. Patients with a recent history of infection were excluded. Higher CRP levels were associated with shorter 5-year survival in all four disease groups on both univariable analyses, and after adjusting for age, gender, smoking history, immunosuppressive therapy and baseline disease severity (IPF: HR (95% CI): 1.3 (1.1-1.5), p = 0.003, fHP: 1.5 (1.2-1.9), p = 0.001, RA-ILD: 1.4 (1.1-1.84), p = 0.01 and SSc-ILD: 2.7 (1.6-4.5), p < 0.001).
CONCLUSIONS: Higher CRP levels are independently associated with reduced 5-year survival in IPF, fHP, RA-ILD and SSc-ILD.

Transbronchial cryobiopsy (TBCB) is increasingly used for the diagnosis of fibrosing interstitial pneumonias, but there are few detailed descriptions of the pathologic findings in such cases. It has been proposed that a combination of patchy fibrosis and fibroblast foci with an absence of alternative features is diagnostic of usual interstitial pneumonia (UIP; ie, idiopathic pulmonary fibrosis [IPF]) in TBCB. In this study, we reviewed 121 TBCB in which a diagnosis of fibrotic hypersensitivity pneumonitis (FHP; n = 83) or IPF (n = 38) was made by multidisciplinary discussion and evaluated a range of pathologic features. Patchy fibrosis was found in 65 of 83 (78%) biopsies from FHP and 32of 38 (84%) biopsies from UIP/IPF cases. Fibroblast foci were present in 47 of 83 (57%) FHP and 27 of 38 (71%) UIP/IPF cases. Fibroblast foci/patchy fibrosis combined did not favor either diagnosis. Architectural distortion was seen in 54 of 83 (65%) FHP and 32 of 38 (84%) UIP/IPF cases (odds ratio [OR] for FHP, 0.35; P = .036) and honeycombing in 18 of 83 (22%) and 17 of 38 (45%), respectively (OR, 0.37; P = .014). Airspace giant cells/granulomas were present in 13 of 83 (20%) FHP and 1 of 38 (2.6%) UIP/IPF cases (OR for FHP, 6.87; P = .068), and interstitial giant cells/granulomas in 20 of 83 (24%) FHP and 0 of 38 (0%) UIP/IPF (OR, 6.7 x 106; P = .000). We conclude that patchy fibrosis plus fibroblast foci can be found in TBCB from both FHP and UIP/IPF. The complete absence of architectural distortion/honeycombing favors a diagnosis of FHP, as does the presence of airspace or interstitial giant cells/granulomas, but these measures are insensitive, and many cases of FHP cannot be separated from UIP/IPF on TBCB.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (fHP) shares many features with other fibrotic interstitial lung diseases (ILD), and as a result it can be misdiagnosed as idiopathic pulmonary fibrosis (IPF). We aimed to determine the value of bronchoalveolar lavage (BAL) total cell count (TCC) and lymphocytosis in distinguishing fHP and IPF and to evaluate the best cut-off points discriminating these two fibrotic ILD.
METHODS: A retrospective cohort study of fHP and IPF patients diagnosed between 2005 and 2018 was conducted. Logistic regression was used to evaluate the diagnostic utility of clinical parameters in differentiating between fHP and IPF. Based on the ROC analysis, BAL parameters were evaluated for their diagnostic performance, and optimal diagnostic cut-offs were established.
RESULTS: A total of 136 patients (65 fHP and 71 IPF) were included (mean age 54.97 ± 10.87 vs. 64.00 ± 7.18 years, respectively). BAL TCC and the percentage of lymphocytes were significantly higher in fHP compared to IPF (p < 0.001). BAL lymphocytosis >30% was found in 60% of fHP patients and none of the patients with IPF. The logistic regression revealed that younger age, never smoker status, identified exposure, lower FEV1, higher BAL TCC and higher BAL lymphocytosis increased the probability of fibrotic HP diagnosis. The lymphocytosis >20% increased by 25 times the odds of fibrotic HP diagnosis. The optimal cut-off values to differentiate fibrotic HP from IPF were 15 × 106 for TCC and 21% for BAL lymphocytosis with AUC 0.69 and 0.84, respectively.
CONCLUSIONS: Increased cellularity and lymphocytosis in BAL persist despite lung fibrosis in HP patients and may be used as important discriminators between IPF and fHP.