Remission of hypersensitivity pneumonitis after allogeneic hematopoietic stem cell transplantation.

A 50-year-old man was diagnosed with hypersensitivity pneumonitis caused by the environment of his bar owing to worsening symptoms, laboratory test results, and computed tomography images after an environmental inhalation challenge test. His hypersensitivity pneumonitis exacerbated despite receiving prednisolone 20 mg/day. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor for myelodysplastic syndrome. No exacerbation of hypersensitivity pneumonitis was observed after HSCT. An environmental inhalation challenge test involving exposure to his bar confirmed the remission of hypersensitivity pneumonitis after HSCT. This case demonstrates that hypersensitivity pneumonitis can be remitted by HSCT.

Diffusely distributed centrilobular micronodules and branching opacities as the main chest computed tomography manifestations in a patient with humidifier lung.

We report a 60-year-old man with humidifier lung showing diffusely distributed centrilobular micronodules and branching opacities on chest computed tomography (CT). Fever and dyspnea occurred 2 months after using an ultrasonic humidifier. KL-6 and SP-D were within normal ranges. Bronchoalveolar lavage showed elevated lymphocytes (53 %) and histological findings of transbronchial lung biopsy demonstrated organizing pneumonia. His condition improved after cessation of the humidifier. A provocation test exhibited a positive response to the humidifier. Humidifier lung should be considered as a differential diagnosis in patients with these CT findings. Detailed clinical, pathological and microbiological examinations are needed to exclude other diseases.

Usefulness of Transbronchial Lung Cryobiopsy When Starting Antifibrotic Treatment and Predicting Progressive Fibrosing Interstitial Lung Disease: Descriptive Research.

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.

Validation of a computed tomography diagnostic model for differentiating fibrotic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis.

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. CONCLUSION: GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were important CT features for differentiating fHP from IPF.

Hypersensitivity Pneumonitis on Thin-Section Chest CT Scans: Diagnostic Performance of the ATS/JRS/ALAT versus ACCP Imaging Guidelines.

Purpose To compare the diagnostic performance of the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) versus the American College of Chest Physicians (ACCP) imaging classifications for hypersensitivity pneumonitis (HP). Materials and Methods Patients in the institutional review board-approved Interstitial Lung Disease (ILD) registry referred for multidisciplinary discussion (MDD) at the authors' institution (January 1, 2006-April 1, 2021) were included in this retrospective study when ILD was diagnosed at MDD. MDD diagnoses included HP, connective tissue disease-ILD, and idiopathic pulmonary fibrosis. Retrospective review of thin-section CT images was performed in consensus by two cardiothoracic radiologists blinded to the diagnosis. Diagnostic patterns were determined for thin-section CT images using both classifications. Discordance rates were determined. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were assessed using MDD diagnosis as the reference standard. Results A total of 297 patients were included in the study: 200 (67%) with HP, 49 (16%) with connective tissue disease-ILD, and 48 (16%) with idiopathic pulmonary fibrosis at MDD. The discordance rate between the two classifications was 21%. Assuming low HP prevalence (10%), ATS/JRS/ALAT classification outperformed ACCP classification, with greater accuracy (92.3% vs 87.6%) and greater positive predictive value (60.7% vs 42.9%). Assuming high prevalence (50%), accuracy and negative predictive value were superior using ACCP classification (81.7% vs 79.7% and 77.7% vs 72.6%, respectively), and positive predictive value was superior using ATS/JRS/ALAT classification (93.3% vs 87.1%). Conclusion Accuracy of the ATS/JRS/ALAT and ACCP HP classifications was greater in settings with low and high HP prevalence, respectively. Diagnostic performance of both classifications was discordant in a minority of cases. Keywords: CT, Thorax, Hypersensitivity Pneumonitis, Interstitial Lung Disease Supplemental material is available for this article. © RSNA, 2024.

Use of Mycophenolate mofetil for the treatment of fibrotic hypersensitivity pneumonitis.

INTRODUCTION: 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. MATERIAL AND 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: Seventy-three patients 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)]. Forty-five 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.

Single Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis.

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 TGFß 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.

[Morphology of hypersensitivity pneumonitis]. / Morfologiya giperchuvstvitel'nogo pnevmonita.

Hypersensitivity pneumonitis (HP) is one of the most common interstitial lung diseases, the manifestations of which are diverse, and the diagnosis is complex and requires a multidisciplinary approach. HP is an immunologically determined disease in response to inhaled antigens. The main feature of the disease is terminal bronchiole's involvement accompanied by interstitial inflammation and/or fibrosis together with the presence of non-necrotizing granulomas in the interalveolar septa and bronchioles. The article presents the histological features of non-fibrous and fibrotic variants of the disease. Well-defined diagnostic criteria were formulated on the basis of published international recommendations and the authors' own experience.

Cell-Based Therapy for Fibrosing Interstitial Lung Diseases, Current Status, and Potential Applications of iPSC-Derived Cells.

Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells.

Update on Interstitial Pneumonias.

The American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Asociación Latinoamericana de Tórax 2018 clinical practice guideline and 2022 update provide recommendations to define and diagnose idiopathic pulmonary fibrosis (IPF) in patients with newly diagnosed interstitial lung disease. The guideline emphasizes recognition of usual interstitial pneumonia (UIP) and probable UIP patterns of fibrosis on high-resolution CT, which can obviate the need for surgical lung biopsy and allow timely initiation of antifibrotic pharmacotherapy citing a high correlation with UIP on histopathology. This article reviews the recent 2022 IPF clinical practice guideline with a focus on the imaging updates.

Hypersensitivity pneumonitis: application of a new diagnostic algorithm to a time series of the disease.

BACKGROUND: The diagnostic criteria for Hypersensitivity pneumonitis (HP) have changed over time. Our aim is to apply a recent diagnostic algorithm to a historical series of patients diagnosed with HP to assess its distribution according to current diagnostic criteria and the diagnostic confidence achieved. RESEARCH DESIGN AND METHODS: Application to each patient the algorithm criteria. The diagnosis was HP (≥90%), provisional high (70-89%) or low confidence (51-69%) or non-HP (unlikely) (≤50%); or HP, provisional or non-HP, if they had lung biopsy. RESULTS: 129 patients [mean age 64 ± 12 years; 79 (61.2%) women] were included of which 16 (12.4%) were diagnosed on the basis of high clinical suspicion. After applying the algorithm, 106 patients (82.2%) could be evaluated and 83 (78.3%) had a diagnosis of HP or high confidence. Lung biopsy was able to establish a diagnosis of certainty in another 21 patients and a provisional diagnosis in 9 more [total, 113 (87.6%)]. The 16 patients without strict diagnostic criteria for HP had a low confidence diagnosis. A total of 56 lung biopsies (64.4%) could have been avoided according to the new guidelines. CONCLUSIONS: The application of this algorithm achieves a high diagnostic yield in HP, significantly reducing the number of lung biopsies required.

Interstitial lung disease: a review of classification, etiology, epidemiology, clinical diagnosis, pharmacological and non-pharmacological treatment.

Interstitial lung diseases (ILDs) refer to a heterogeneous and complex group of conditions characterized by inflammation, fibrosis, or both, in the interstitium of the lungs. This results in impaired gas exchange, leading to a worsening of respiratory symptoms and a decline in lung function. While the etiology of some ILDs is unclear, most cases can be traced back to factors such as genetic predispositions, environmental exposures (including allergens, toxins, and air pollution), underlying autoimmune diseases, or the use of certain medications. There has been an increase in research and evidence aimed at identifying etiology, understanding epidemiology, improving clinical diagnosis, and developing both pharmacological and non-pharmacological treatments. This review provides a comprehensive overview of the current state of knowledge in the field of interstitial lung diseases.

Dominant Circulating Cell-free Mycobacterial Proteins in in-use Machining Fluid and their Antigenicity Potential.

BACKGROUND: Occupational exposure to industrial Metalworking Fluid (MWF) colonized by Mycobacterium immunogenum (MI) has been associated with immune lung disease hypersensitivity pneumonitis (HP) in machinists. This warrants regular fluid monitoring for early detection of mycobacterial proteins, especially those with antigenic potential. OBJECTIVE: To detect and identify dominant MI proteins and antigens directly from the field-drawn in-use MWF using an integrated immunoproteomic and immunoinformatic approach. METHODS: An MI-positive MWF selected by DNA-based screening of several field-drawn MWF samples were cultured to isolate the colonizing strain and profiled for dominant circulating cell- free (ccf) MI proteins, including antigens using an integrated immunoproteomic (1D- and 2Dgel fractionation of seroreactivity proteins combined with shotgun proteomic analysis using LC-MS/ MS) and immunoinformatic strategy. RESULTS: A new MI strain (MJY-27) was identified. The gel fractionated MI protein bands (1Dgel) or spots (2D-gel) seroreactive with anti-MI sera probes (Rabbit and Patient sera) yielded 86 MI proteins, 29 of which showed peptide abundance. T-cell epitope analysis revealed high (90-100%) binding frequency for HLA-I& II alleles for 13 of the 29 proteins. Their antigenicity analysis revealed the presence of 6 to 37 antigenic determinants. Interestingly, one of the identified candidates corresponded to an experimentally validated strong B- and T-cell antigen (AgD) from our laboratory culture-based studies. CONCLUSION: This first report on dominant proteins, including putative antigens of M. immunogenum prevalent in field in-use MWF, is a significant step towards the overall goal of developing fluid monitoring for exposure and disease risk assessment for HP development in machining environments.

Survival and Lung Function Changes in Hypersensitivity Pneumonitis According to Radiological Phenotypes Compared With Idiopathic Pulmonary Fibrosis.

INTRODUCTION: The main objective of this study was to estimate survival and changes in lung function in patients with chronic hypersensitivity pneumonitis (HP), both fibrotic (f-HP) and nonfibrotic (nf-HP), and to compare them with those in patients with idiopathic pulmonary fibrosis (IPF). METHODS: HP was diagnosed based on antigen exposure, HRCT (high-resolution CT scan), BAL (bronchoalveolar lavage), and histology. According to HRCT, HP was classified into fibrotic and non-fibrotic phenotypes. In most cases, IPF was diagnosed based on HRCT findings. RESULTS: We identified 84 patients: 46 with IPF, 18 with f-HP, and 20 with nf-HP. Five-year survival was 23.9% in IPF, 72% in f-HP, and 100% in nf-HP (p <0.0001). Honeycombing was associated with decreased survival in IPF (p <0.001) and in f-HP (p <0.0001). The mean loss of FVC (forced vital capacity) % pred. (percent predicted) was -18.3% in IPF (p =0.001), -4.8% in f-HP, and -6.0% in nf-HP. The mean change in DLCO (diffusion capacity for carbon monoxide) % pred. was -10.2% in IPF (p <0.002), -0.5% in f-HP, and +1.9% in nf-HP. The agreement between radiological phenotypes and histology in HP was 89.6%. CONCLUSIONS: We found shorter survival in IPF, followed by f-HP, and nf-HP. Over time, we did not find significant changes in FVC% pred. or DLCO% pred. in HP, while a significant decline in IPF was noted. In HP, we found strong agreement between radiological phenotypes and histology. Radiological signs suggestive of lung fibrosis in HP were reliable for the diagnosis of f-HP and seem to have intrinsic prognostic value.

Compatible with fibrotic hypersensitivity pneumonitis on high-resolution computed tomography: from the ATS/JRS/ALAT 2020 hypersensitivity pneumonitis guidelines.

Background: In compatible with fibrotic hypersensitivity pneumonitis (HP) of the computed tomography (CT) classification using the American Thoracic Society (ATS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) HP guidelines, the lung fibrosis pattern was classified as either a usual interstitial pneumonia (UIP) pattern or a diffuse ground-glass opacity (GGO) pattern with subtle fibrosis. We investigated whether patients with the same imaging classification had different disease progression. We also attempted to reclassify these patients using the CHEST HP guidelines. Methods: Patients with fibrotic HP who had compatible CT pattern in the ATS/JRS/ALAT classification were investigated retrospectively. Results: With 62 patients in the UIP pattern group and 25 patients in the diffuse GGO pattern group, 87 patients with fibrotic HP had compatible pattern on CT. Annual forced vital capacity changes in the UIP pattern group and diffuse GGO pattern group were -2.7% and +3.3% (P=0.004), respectively. The 5-year survival rates in the UIP pattern group and diffuse GGO pattern group were 86% and 100% (P=0.02). In UIP pattern group in the ATS/JRS/ALAT classification, 27% patients were classified as typical fibrotic HP pattern in the CHEST guidelines. In the diffuse GGO pattern group, 52% patients were classified as typical pattern of fibrotic HP. In the CHEST guidelines, more patients in the GGO pattern were classified as typical pattern compared with those in the UIP pattern (P=0.02). Conclusions: The two patterns in compatible with fibrotic HP of CT classification using the ATS/JRS/ALAT HP guidelines had different disease progression. Typical patterns were more frequent in the CHEST guidelines than the ATS/JRS/ALAT guidelines.

Longitudinal changes in serum immunoglobulin G testing in patients with fibrotic avian hypersensitivity pneumonitis.

BACKGROUND: Evaluation of the antigen responsible for fibrotic hypersensitivity pneumonitis (HP) is challenging. Serum immunoglobulin (Ig) G testing against HP-associated antigens is performed. Although single-serum IgG testing has been investigated, multiple-serum IgG testing has not yet been studied. METHODS: This study included patients who underwent histopathological examination and positive inhalation challenge test as well as those with moderate or high HP guideline confidence level. Serum IgG testing against pigeon serum was conducted twice using two methods: enzyme linked-immunosorbent assay (ELISA) and ImmunoCAP. The association between changes in serum IgG antibody titers and changes in forced vital capacity (FVC) and other parameters was investigated. RESULTS: In this study, 28 patients (mean age, 64.5 years; mean FVC, 85.3%) with fibrotic avian HP were selected, of whom 20 and 8 underwent surgical lung biopsy and transbronchial lung cryobiopsy, respectively. Of the 28 patients, 19 had been keeping birds for more than 6 months. A correlation was observed between the annual changes in serum IgG antibody titers by ELISA and changes in relative FVC (r = - 0.6221, p < 0.001). Furthermore, there was a correlation between the annual changes in serum IgG antibody titers by ImmunoCAP and changes in relative FVC (r = - 0.4302, p = 0.022). Multiple regression analysis revealed that the change in serum IgG antibody titers by both ELISA and ImmunoCAP also influenced the relative FVC change (p = 0.012 and p = 0.015, respectively). Moreover, 13 patients were given additional treatments between the first and second blood test; however, the additional treatment group was not significantly different in relative FVC change compared to the group with no additional treatment (p = 0.982). CONCLUSIONS: In patients with fibrotic avian HP, the annual changes in serum IgG testing were correlated with FVC changes, highlighting the importance of serum IgG testing over time.

A Case of Immunomodulator-Responsive Hypersensitivity Pneumonitis Secondary to Chronic Passive Smoke Inhalation.

Hypersensitivity pneumonitis (HP) is a pulmonary disease characterized by inflammation and fibrosis of the lung parenchyma following chronic exposure to immunogenic antigens. The pathophysiology of HP involves type 3 and type 4 hypersensitivity reactions leading to acute and chronic manifestations, respectively. Clinically, it manifests as exertional dyspnea and wheezing. Pulmonary function tests display a pattern of restrictive lung disease, and high-resolution CT scans display a pattern of ground glass opacities, centrilobular nodules, and mosaic attenuation. Antigen avoidance remains the only method for primary prevention. Alternative therapy may be needed due to either the inability to avoid antigens or the lack of antigen identification. Prednisone 0.5 mg/kg per day is the first-line treatment for acute non-fibrotic forms of HP. In chronic or fibrotic HP, the immunomodulator mycophenolate mofetil (MMF) was shown to be an effective treatment in improving the diffusing capacity of the lungs for carbon monoxide and forced vital capacity, but not overall survival. The following study aims to bring to attention the need for additional prospective multicenter clinical trials to clarify the role of MMF as an immunomodulator in fibrosing HP.

Risk of hypersensitivity pneumonitis and other interstitial lung diseases following organic dust exposure.

BACKGROUND: Organic dust is associated with hypersensitivity pneumonitis, and associations with other types of interstitial lung disease (ILD) have been suggested. We examined the association between occupational organic dust exposure and hypersensitivity pneumonitis and other ILDs in a cohort study. METHODS: The study population included all residents of Denmark born in 1956 or later with at least 1 year of gainful employment since 1976. Incident cases of hypersensitivity pneumonitis and other ILDs were identified in the Danish National Patient Register 1994-2015. Job exposure matrices were used to assign individual annual levels of exposure to organic dust, endotoxin and wood dust from 1976 to 2015. We analysed exposure-response relations by different exposure metrics using a discrete-time hazard model. RESULTS: For organic dust, we observed increasing risk with increasing cumulative exposure with incidence rate ratios (IRR) per 10 unit-years of 1.19 (95% CI 1.12 to 1.27) for hypersensitivity pneumonitis and 1.04 (95% CI 1.02 to 1.06) for other ILDs. We found increasing risk with increasing cumulative endotoxin exposure for hypersensitivity pneumonitis and other ILDs with IRRs per 5000 endotoxin units/m3-years of 1.55 (95% CI 1.38 to 1.73) and 1.09 (95% CI 1.00 to 1.19), respectively. For both exposures, risk also increased with increasing duration of exposure and recent exposure. No increased risks were observed for wood dust exposure. CONCLUSION: Exposure-response relations were observed between organic dust and endotoxin exposure and hypersensitivity pneumonitis and other ILDs, with lower risk estimates for the latter. The findings indicate that organic dust should be considered a possible cause of any ILD. TRIAL REGISTRATION NUMBER: j.no.: 1-16-02-196-17.