Chronic Hypersensitivity Pneumonitis Patients Research Articles

Pulmonary vessel volume can help to differentiate fibrotic lung diseases

Objectives: Idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), and chronic hypersensitivity pneumonitis (CHP) are diffuse fibrosing lung diseases that are sometimes difficult to differentiate by only visual evaluation of CT images. We aimed to find if pulmonary vessel volume (PVV), a new quantitative CT measure, can help to differentiate these diseases at the time of diagnosis. Methods: We retrospectively measured PVV values of IPF, NSIP, and CHP patients diagnosed within the last five years in our institution, by using their CT images at the time of diagnosis. We used CALIPER-technology (Computer-Aided Lung Informatics for Pathology Evaluation and Rating) for the quantification of CT images. We compared the PVV values of disease groups by the Kruskal-Wallis test and performed ROC curve analysis to evaluate the ability of PVV to differentiate these diseases. Results: We measured the PVV values of 152 patients, 113 of them were diagnosed with IPF, 16 with NSIP, and 23 with CHP. The PVV value of the NSIP group was significantly lower than that of both IPF (p = 0.028) and CHP (p = 0.013) groups. However, there was no significant difference between IPF and CHP groups (p = 0.924). Selected cut-off values of PVV were found to differentiate NSIP from IPF with a specificity of 88%, and NSIP from CHP with a specificity of 91%. Conclusions: PVV measured by CALIPER at the time of diagnosis can help to differentiate NSIP from both IPF and CHP.

Impact of concomitant gastroesophageal reflux disease symptomology on prognosis and pulmonary function of chronic hypersensitivity pneumonitis.

Comorbid risk factors in chronic hypersensitivity pneumonitis (CHP) are poorly characterised. Gastroesophageal reflux disease (GERD) is linked to interstitial lung diseases like idiopathic pulmonary fibrosis (IPF), but its association and treatment in CHP is less understood. This study aims to understand the role and prevalence of GERD in CHP, plus the effect of GERD treatment on lung function and mortality. A tertiary referral centre panel was retrospectively reviewed for 214 patients diagnosed with CHP based on clinical history, bronchoalveolar lavage fluid analysis, imaging and histopathology. GERD diagnostic criteria included symptomology, acid suppressive therapy use and diagnostic testing. CHP patients with GERD (n = 89) and without GERD (n = 125) were compared via descriptive statistical analysis. Pulmonary function, GERD diagnosis plus treatment and other comorbidities were evaluated against CHP outcomes. Respective differences between diagnosis and study termination dates in the GERD population versus without GERD for functional vital capacity (FVC) were - 1 L vs - 2.5 L, diffusing capacity of the lungs for carbon monoxide (DLCO) were - 2 mL/min/mmHg versus - 1 mL/min/mmHg, per cent alive at the time of study 88% versus 81%, median date of survival 574.5 versus 850 and supplemental oxygen requirement 41% versus 37%. GERD prevalence was higher in CHP patients relative to the general population. No statistical significance was found between survival curves, oxygen requirement, smoking history, FVC, or DLCO. GERD could be a harmful comorbidity in CHP though may not necessarily affect survival or functional outcomes. This aligns with previous IPF studies, though remains controversial. Further research is needed regarding this association and treatment benefit.

Does avian antigen-induced chronic hypersensitivity pneumonitis lead to more severe PH than other causes of the same?

Sir, Chronic hypersensitivity pneumonitis (CHP) is a prominent aetiology of diffuse parenchymal lung disease (DPLD), contributing to over 47% of the inclusions in the ILD-India registry.[1] The diagnosis of CHP is difficult because the pathological description needs lung biopsy that remains mostly undone. The high-resolution computed tomography (HRCT) chest, however, can give some definite clues for the possibility.[2] In our series, the HRCT diagnosis of HP was done by a pulmonologist and a radiologist on an agreement for the probability of HP in their independent interpretation of HRCT chest pictures. The radiologically possible-HP diagnosis was supported by positive IgG precipitin titre for avian antigen by immunoCAP method.[3] A precipitin titre value >30 mg mgA/L was taken as significant.[3] The clinico-radio-serological positivity was further supported by history of exposure to pigeons/birds to build up a nearly definite avian antigen–induced diagnosis of CHP. However, the possible CHP cases from other causes could not be evaluated serologically as the panel with common antigens was not available to us at that point of time. The study did not essentially include subjects with features of CHP without any etiological confirmation and exclude other causes like connective tissue disease associated-interstitial lung disease (CTD-ILD) and sarcoidosis. The latter was done by a thorough clinical exercise (noting the American Rheumatology Association [ARA]) criteria for the common CTDs supported by the relevant serological tests whenever possible in the real-world situation. Sarcoidosis was diagnosed with demonstration of non-ceasing granuloma with exclusion of tuberculosis. All the patients underwent Doppler echo-cardiography by a single dedicated non-invasive cardiologist who looked systematically for evidence of pulmonary hypertension (PH) in addition to other parameters. Furthermore, we looked for the presence of clinical and radiological XRay -posterio-anterior (PA) view (chest X-ray [PA view] and HRCT) features of PH to satisfy the clinico-radio-echocardiographic screening criteria of the institute for the presence of PH.[4] We had 95 cases of suspected HP included in the evaluation from 2018 to 2019. These patients were sub-divided into two groups - CHP caused due to exposure to avian antigen and CHP likely from other possible etiologies. The above two groups were thus compared on the basis of demographic, spirometric, functional health status and echo-cardiographic variables [Table 1].Table 1: Demographic, spirometric, and functional health status and echocardiographic parameters between the two groups of chronic hypersensitivity pneumonitis (CHP) patientsThe results reflect that the two groups were similar on demographical and spirometric lung function variables, but the patients with CHP from avian antigen had significantly higher systolic pulmonary artery pressure (PAP). To appreciate the relative contribution of the variables for the difference between the two groups, we used the VIP plot that suggested the presence of PAP as the most effective discriminant between the two groups [Figure 1a]. However, the overlap between the clusters was very high, suggesting limited applicability of the information [Figure 1b]. In one of our previous observations, we found a very high frequency HRCT-chest that suggested PH in CHP patients induced by chronic exposure to avian antigen.[4] Such exposure of avian antigen has been found to be one of the common causes of CHP. Avian exposure was present in 21.4% of 513 HP patients in the ILD-India registry,[1] with the adjusted odds ratio of 3.52 (P < 0.001) for developing HP after exposure.[2] Pulmonary hypertension is found quite frequently in CHP[5] and is associated with poor survival prospect.[5] The subjects having CHP with history of exposure to avian antigen had a lesser but statistically insignificant mean duration of illness compared to the other group. The standard deviation in both the groups was very wide for the illness duration, making it unsuitable for interpretation through VIP plot [Figure 2]. Despite the weakness of having no biopsy-proven diagnosis of HP, a non-stringent exclusion of other aetiologies, non-inclusion of treatment history, and dearth of haemodynamic confirmation by right heart catheterisation, our observation demands attention. Furthermore, objective validation of our observation is, thus, warranted.Figure 1: (a) The VIP plot with the variables represents the relative contribution of the parameters to the variance between the study groups, (b) 2D score scatter plot of principal component analysis (PCA) to distinguish the two study groups [avian exposure related and other causes of CHP (chronic hypersensitivity pneumonitis)]showing a significant overlapFigure 2: Comparison of the disease duration between the two study groups [avian exposure related and other causes of CHP (chronic hypersensitivity pneumonitis)]Financial support and sponsorship The research was funded by the organization itself. Conflicts of interest There are no conflicts of interest.

Baseline peripheral T-cell composition in relation to radiographic phenotypes of immune-related pneumonitis.

2545 Background: Pneumonitis is one of the most morbid complications from immune checkpoint inhibitor (ICI) treatment, but pathogenic mechanisms are unclear and no biomarkers permit pre-treatment risk assessment. We sought to characterize peripheral T cell subsets of pneumonitis patients on the single cell level. Methods: Blood was collected before and during ICI treatment in 24 patients. Cells were processed for single cell RNA sequencing (scRNAseq) employing CITEseq methodology using multiplexed cell surface markers labelled with a cocktail of oligonucleotide-tagged Total-Seq anti-human antibodies against CD4, CD8, CD45RA and CD27 followed by Chromium 10X sequencing. Principal Component Analysis was performed with iCellR, K-nearest-neighbor-based Network graph drawing Layout, and PhenoGraph clustering to assign cell types. CT scans were performed per standard of care and were reviewed by an experienced thoracic radiologist. Results: Seven of 24 patients developed pneumonitis; 9 did not experience an immune-related adverse event, and the remainder experienced arthritis (4), thyroiditis (3), or neurotoxicity (1). Pneumonitis patients had expanded proportions of TH2 TCF7+ T cells at baseline as compared to the other patients. Radiographically, two patients’ pneumonitis manifested as Chronic Hypersensitivity Pneumonitis (CHP), and four had Organized Pneumonia (OP). At baseline, CHP patients had significantly lower levels of CD8+ TCM cells (CXCR3+), double-positive T cells, gamma-delta T cells, and higher levels of naïve-like CD4+ TN TCF7+LEF1+ and CD4+ TH1/2 CXCR3+GATA3+ cells compared to OP. Gene expression levels also distinguished between these radiographic phenotypes. Conclusions: The peripheral T cell composition of patients who developed pneumonitis was distinct from those who did not in our cohort and unique by radiographic manifestation, suggesting potential pathogenic mechanisms and a prelude to circulating predictive markers of ICI toxicity.

Chronic hypersensitivity pneumonitis is associated with an increased risk of venous thromboembolism: a retrospective cohort study

BackgroundIdiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis share commonalities in pathogenesis shifting haemostasis balance towards the procoagulant and antifibrinolytic activity. Several studies have suggested an increased risk of venous thromboembolism in IPF. The association between venous thromboembolism and chronic hypersensitivity pneumonitis has not been studied yet.MethodsA retrospective cohort study of IPF and chronic hypersensitivity pneumonitis patients diagnosed in single tertiary referral center between 2005 and 2018 was conducted. The incidence of symptomatic venous thromboembolism was evaluated. Risk factors for venous thromboembolism and survival among those with and without venous thromboembolism were assessed.ResultsA total of 411 (259 IPF and 152 chronic hypersensitivity) patients were included (mean age 66.7 ± 8.4 vs 51.0 ± 13.3 years, respectively). There were 12 (4.6%) incident cases of venous thromboembolism in IPF and 5 (3.3%) in chronic hypersensitivity pneumonitis cohort. The relative risk (RR) of venous thromboembolism in chronic hypersensitivity pneumonitis was not significantly different to that found in patients with IPF (7.1 vs 11.8/1000 person-years, RR 1.661 95% CI 0.545–6.019, respectively).The treatment with systemic steroids (OR 5.38; 95% CI 1.65–18.8, p = 0.006) and GAP stage 3 (OR 7.85; 95% CI 1.49–34.9; p = 0.037) were significant risk factors for venous thromboembolism in IPF. Arterial hypertension and pulmonary hypertension significantly increased risk of venous thromboembolism in chronic hypersensitivity pneumonitis. There were no significant differences in survival between patients with and without venous thromboembolism.ConclusionsThe patients with chronic hypersensitivity pneumonitis have a marked increase in the risk of venous thromboembolism, similar to the patients with IPF. Venous thromboembolism does not affect the survival of patients with IPF and chronic hypersensitivity pneumonitis.

Identification of Chronic Hypersensitivity Pneumonitis Biomarkers with Machine Learning and Differential Co-expression Analysis.

This study aims to identify the biomarkers for chronic hypersensitivity pneumonitis (CHP) and facilitate the precise gene therapy of CHP. Chronic hypersensitivity pneumonitis (CHP) is an interstitial lung disease caused by hypersensitive reactions to inhaled antigens. Clinically, the task of differentiating CHP and other interstitial lung diseases, especially idiopathic pulmonary fibrosis (IPF), was challenging. In this study, we analyzed the publically available gene expression profile of 82 CHP patients, 103 IPF patients, and 103 control samples to identify the CHP biomarkers. The CHP biomarkers were selected with advanced feature selection methods: Monte Carlo Feature Selection (MCFS) and Incremental Feature Selection (IFS). A Support Vector Machine (SVM) classifier was built. Then, we analyzed these CHP biomarkers through functional enrichment analysis and differential co-expression analysis. There were 674 identified CHP biomarkers. The co-expression network of these biomarkers in CHP included more negative regulations and the network structure of CHP was quite different from the network of IPF and control. The SVM classifier may serve as an important clinical tool to address the challenging task of differentiating between CHP and IPF. Many of the biomarker genes on the differential coexpression network showed great promise in revealing the underlying mechanisms of CHP.

Hypersensitivity Pneumonitis and (Idiopathic) Pulmonary Fibrosis Due to Feather Duvets and Pillows

IntroductionExposure to feather bedding may be an unnoticed cause of hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF). Thus, an in-depth clinical study of the diagnosis of patients with suspected HP and IPF is required in order to determine their etiologies. The objective of the present study is to raise awareness of HP and pulmonary fibrosis due to exposure to feather bedding, and to study the prevalence and describe long-term outcomes. MethodsWe describe a series of 33 patients diagnosed with HP and pulmonary fibrosis due to feather bedding exposure and followed over a 10-year period. The patients were from a subgroup of 127 individuals with HP undergoing in-depth evaluation using a diagnostic protocol at a regional referral center. ResultsEleven (33%) patients were clinically diagnosed with acute HP and 22 (67%) with chronic HP. Ten (45%) chronic HP patients showed a high resolution computed tomography (HRCT) pattern of usual interstitial pneumonia (UIP) with suspected IPF. The prevalence of HP was 6.2/100 000 feather bedding users (compared with 54.6 per 100 000 bird-breeders). The survival rates of patients over the 10-year period was 100% for acute HP and 64% for chronic HP. ConclusionsIn a series of HP patients, the diagnosis was attributed to feather bedding exposure in 26%. UIP pattern on HRCT was present in nearly half of the chronic cases. The survival of patients with chronic HP at ten years was 64%, despite avoiding further exposure.

Inhalation challenge test using pigeon eggs for chronic hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis (CHP) remains a diagnostic challenge. The process of collecting and extracting serum and droppings from causative animals for the inhalation challenge test is complicated and the risk of inducing disease progression exists. To investigate the utility and safety of an inhalation challenge test using pigeon eggs. Pigeon eggs were pasteurized and mixed with a saline solution to produce an inhalation fluid. An inhalation challenge test was conducted on 19 patients with bird-related CHP and 17 patients with interstitial lung disease other than bird-related CHP. To identify antigens in pigeon eggs, the antigen-antibody responses of the pigeon eggs and serum from patients were evaluated using Western blotting. The mean changes in C-reactive protein, alveolar-arterial oxygen difference, erythrocyte sedimentation rate, and lactate dehydrogenase significantly increased by 0.32mg/dL (P=.014), 7.8Torr (P=.002), 1.4mm/h (P=.012), and 5.4 U/mL (P=.0019), respectively, in bird-related CHP group compared to the control 24hours after the inhalation challenge test. Furthermore, within 24hours of the inhalation test, the mean forced vital capacity decreased by 2.3% in the bird-related CHP group compared with a decline of 0.05% in the control group (P=.035). Serum collected from seven bird-related CHP patients who underwent the inhalation challenge test and reacted to antigens with molecular weights of 37-75 KDa, and these molecular weights were consistent with egg albumin and globulin. Since a mild response was observed after the inhalation challenge test using pigeon eggs, this test was an obvious candidate for diagnosing bird-related CHP.

Disruption in the balance between apolipoprotein A-I and mast cell chymase in chronic hypersensitivity pneumonitis.

BackgroundApolipoprotein A‐I (apoA‐I) has an antifibrotic effect in idiopathic pulmonary fibrosis. Although pulmonary fibrosis is associated with poor prognosis of patients with hypersensitivity pneumonitis (HP), little is known regarding the role of apoA‐I in the pathogenesis of HP.MethodsTwo‐dimensional electrophoresis, immunoblotting, and enzyme‐linked immunosorbent assays were performed for the identification and quantification of apoA‐I in bronchoalveolar lavage fluid (BALF) from patients with acute and chronic HP. To investigate the degradation of apoA‐I, apoA‐I was incubated with BALF. Moreover, the role of apoA‐I in TGF‐β1‐induced epithelial–mesenchymal transition of A549 cells was examined.ResultsThe concentration of apoA‐I in the BALF was significantly lower in chronic HP (n = 56) compared with acute HP (n = 31). The expression level of apoA‐I was also low in the lung tissues of chronic HP. ApoA‐I was degraded by BALF from HP patients. The number of chymase‐positive mast cells in the alveolar parenchyma was inversely correlated with apoA‐I levels in the BALF of chronic HP patients. In vitro experiment using A549 cells, untreated apoA‐I inhibited TGF‐β1‐induced epithelial–mesenchymal transition, although this trend was not observed in the chymase‐treated apoA‐I.ConclusionsA decrease of apoA‐I was associated with the pathogenesis of chronic HP in terms of pulmonary fibrosis and mast cell chymase attenuated the protective effect of apoA‐I against pulmonary fibrosis. Furthermore, apoA‐I could be a crucial molecule associated with lung fibrogenesis of HP.

Hypersensitivity Pneumonitis and (Idiopathic) Pulmonary Fibrosis Due to Feather Duvets and Pillows

IntroductionExposure to feather bedding may be an unnoticed cause of hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF). Thus, an in-depth clinical study of the diagnosis of patients with suspected HP and IPF is required in order to determine their etiologies. The objective of the present study is to raise awareness of HP and pulmonary fibrosis due to exposure to feather bedding, and to study the prevalence and describe long-term outcomes. MethodsWe describe a series of 33 patients diagnosed with HP and pulmonary fibrosis due to feather bedding exposure and followed over a 10-year period. The patients were from a subgroup of 127 individuals with HP undergoing in-depth evaluation using a diagnostic protocol at a regional referral center. ResultsEleven (33%) patients were clinically diagnosed with acute HP and 22 (67%) with chronic HP. Ten (45%) chronic HP patients showed a high resolution computed tomography (HRCT) pattern of usual interstitial pneumonia (UIP) with suspected IPF. The prevalence of HP was 6.2/100 000 feather bedding users (compared with 54.6 per 100 000 bird-breeders). The survival rates of patients over the 10-year period was 100% for acute HP and 64% for chronic HP. ConclusionsIn a series of HP patients, the diagnosis was attributed to feather bedding exposure in 26%. UIP pattern on HRCT was present in nearly half of the chronic cases. The survival of patients with chronic HP at ten years was 64%, despite avoiding further exposure.

Chronic Hypersensitivity Pneumonitis (CHP), an Interstitial Lung Disease (ILD) with Distinct Molecular Signatures

Background: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by progressive pulmonary fibrosis. The histopathological and clinical features of CHP are variable, however, a subset of CHP patients have usual interstitial pneumonia and behave clinically similar to patients with idiopathic pulmonary fibrosis (IPF). To determine the common and unique molecular features of CHP and IPF, we conducted a transcriptome analysis of lung samples from CHP (N=82), IPF (N=103), and unaffected controls (N=103). Methods: Gene expression in lung tissue was determined adjusting for sex, race, age, explant site, and smoking history, and using false discovery rate (FDR) to control for multiple comparisons. Findings: When compared to controls, we identified 413 upregulated and 317 downregulated genes in CHP, and 861 upregulated and 322 downregulated genes in IPF. Concordantly up/down-regulated genes in CHP and IPF were related to collagen catabolic processes and epithelial development, whereas genes specific to CHP were related to chemokine-mediated signaling and immune responsiveness. Using weighted gene co-expression network analysis (WGCNA), we found that among subjects with CHP, genes involved in adaptive immunity or epithelial cell development were associated with improved or reduced lung function respectively, and that MUC5B expression was associated with epithelial cell development. MUC5B expression was also associated with lung fibrosis and honeycombing. Interpretation: Gene expression analysis of CHP and IPF identified signatures common to CHP and IPF, as well as genes uniquely expressed in CHP. Select modules of gene expression are characterized by distinct clinical and pathological features of CHP. Funding Statement: NHLBI (R01-HL097163, P01-HL092870, UH3-HL123442, and DoD W81XWH17-1-0597). Declaration of Interests: None of the authors report conflicts of interest relevant to this study. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis. D.A.S. has an awarded patent (US patent no: 8,673,565) for the treatment and diagnosis of fibrotic lung disease. Ethics Approval Statement: This study conformed to the Declaration of Helsinki and was approved by the Colorado Multiple Institution Board (COMIRB) 15-1147.

Impact of Azathioprine use in chronic hypersensitivity pneumonitis patients

IntroductionSystemic corticosteroids are widely used in chronic hypersensitivity pneumonitis (CHP); however, there is not much evidence to support their use, besides being associated with significant side effects. Azathioprine (AZA) use is common in CHP, although not prospectively tested in randomized controlled trials. Our objective was to evaluate the lung function trajectory of CHP patients after AZA initiation, as well as to assess the safety profile of this drug. MethodsRetrospective analysis of patients initiated on AZA following a multidisciplinary team diagnosis of CHP. The longitudinal trajectory of lung function in the first 2 years of treatment was assessed. ResultsThirty-five out of 62 patients (56.5%) remained on treatment after 2 years. AZA treatment was associated with a significant improvement in forced vital capacity (FVC) at 12 and 24 months (p = 0.015 and p < 0.001, respectively). A slight increase in total lung capacity (TLC) and 6-min walking test (6MWT) were also reported, although it did not reach statistical differences at the end of 2 years. No changes in diffusion capacity for carbon monoxide (DLCO) were observed. ConclusionsThis is the first study identifying an improvement in lung function (FVC) of CHP patients on AZA treatment for 2 years. Prospective studies are needed to confirm these results and to more adequately select CHP patients who may benefit from AZA.

CLINICAL EXPOSURE ASSESSMENT IN CHRONIC HYPERSENSITIVITY PNEUMONITIS: A DELPHI PROJECT

SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM PURPOSE: Chronic hypersensitivity pneumonitis (CHP) is an immune mediated form of interstitial lung disease, caused by inhalational exposure to an environmental antigens, resulting in parenchymal fibrosis. Guidelines suggest a detailed history is taken to identify exposures to inducing antigens, but presently there are no validated tools to facilitate an evidence-based approach to this task. Technical variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis. METHODS: A Delphi method was applied to an international panel of ILD experts, to obtain consensus regarding technique for the elicitation of exposure to relevant antigens from possible CHP patients. Items were derived from a systematic review of the literature. The consensus threshold was set at 80% agreement, and median ≥ 2 and IQR = 0. RESULTS: In two rounds, 36/40 experts participated. Themes included: possible CHP inducing exposures, features that contribute to an exposure’s relevance, quantification of a relevant exposure, and ancillary tests. Experts agreed on 21 exposure items to ask every patient with suspected CHP, including organic particulate matter: water damage/flooding, standing water, humidifiers/vaporisers/air conditioners, hot tubs/pools/spas, humid internal environment, visible and smelly mold, moldy hay/silage, moldy wood, organic matter (manure/compost), musical instruments (e.g. trombone/saxophone), metal working fluids; animal and plant proteins: birds, down or feather products, vegetable production including mushroom workers, food production (i.e. salami, cheese, popcorn, wheat, sugarcane, malt, other); and chemical exposures: isocyanates, and exposure to vapours, dusts, gases, mists, or fumes. A minimum relevant duration of exposure required was agreed to be 1-12 months, and a temporal relationship between exposure and onset of symptoms and improvement on exposure avoidance increased the likelihood the exposure was linked to disease. A positive antibody test was agreed to increase the diagnostic likelihood of CHP, but was not considered a requirement for diagnosis. Consensus was unable to be reached in the dose/quantification of exposure, nor the use of an occupational hygienist. CONCLUSIONS: This Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP. CLINICAL IMPLICATIONS: Ongoing research is required to validate these items in the clinical setting. DISCLOSURES: No relevant relationships by Hayley Barnes, source=Web Response No relevant relationships by Harold Collard, source=Web Response No relevant relationships by Ian Glaspole, source=Web Response No relevant relationships by Phil Molyneaux, source=Web Response No relevant relationships by Julie Morisset, source=Web Response No relevant relationships by Glen Westall, source=Web Response

C-C Motif Chemokine Ligand 15 May Be a Useful Biomarker for Predicting the Prognosis of Patients with Chronic Hypersensitivity Pneumonitis

Background: Chronic hypersensitivity pneumonitis (CHP) is characterized by lymphocytic inflammation and progressive fibrosis of the lung caused by a variety of inhaled antigens. Due to the difficulty of accurately diagnosing CHP, and the poor prognosis associated with the condition, a novel clinical biomarker is urgently needed. Objective: To investigate the usefulness of C-C motif chemokine ligand 15 (CCL15), which had been demonstrated to highly express in the lungs of CHP patients, as a clinical biomarker for CHP. Method: Immunohistochemical investigations were performed on lung tissue from CHP patients, and CCL15 levels in serum and bronchoalveolar lavage fluid (BALF) were measured via the enzyme-linked immunosorbent assay. Results: Immunohistochemistry investigations revealed high CCL15 expression in the lungs of CHP patients. Serum CCL15 levels in CHP patients (29.1 ± 2.1 μg/mL) were significantly higher than those of idiopathic pulmonary fibrosis patients (19.7 ± 1.3 μg/mL, p = 0.01) and healthy subjects (19.5 ± 1.7 μg/mL, p = 0.003). When BALF CCL15 level was divided by BALF albumin (Alb) level (BALF CCL15/Alb), it was significantly inversely correlated with forced vital capacity (β = –0.47, p = 0.0006), percentage of predicted carbon monoxide diffusion capacity of the lung (β = –0.41, p = 0.0048), and BALF lymphocyte count (β = –0.34, p = 0.01) in CHP patients. Multivariate Cox proportional hazards analysis revealed that high BALF CCL15/Alb and poor prognosis were statistically significantly independently correlated in CHP patients (HR 1.1, 95% CI 1.03–1.18, p = 0.004). Conclusion: The results of the current study suggest that CCL15 may be a useful prognostic biomarker for CHP. CCL15 was highly expressed in the lung tissue of CHP patients, and BALF CCL15/Alb was significantly associated with CHP prognosis.

Clinical characteristics and outcomes of hypersensitivity pneumonitis: a population-based study in China.

Backgrounds:Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) that develops in response to the inhalation of various antigens. The clinical pathologies are very complex and undetermined. The clinical features and outcomes of HP have not been fully elucidated. The aim of this study was to analyze the incidence, clinical features, and outcomes of HP patients and construct a simple clinical model for diagnosing chronic HP (CHP).Methods:The cohort study included 101 patients with HP admitted to the Nanjing Drum Tower Hospital from January 2009 to December 2017. The patients were categorized into acute HP (AHP, n = 72) and CHP (n = 29) groups according to the updated international criteria. The clinical, imaging, treatment, and follow-up data were retrospectively reviewed. All patients were followed up until December 31, 2017. Statistical analysis was performed, and a clinical scoring system for CHP was constructed by SPSS 20.0 software.Results:The incidence of HP was 2.4% in ILD inpatients in our center. Patients in the CHP group were older (t = −2.212, P = 0.029), had more smokers (χ2 = 8.428, P = 0.004), and longer duration of symptoms (t = −4.852, P < 0.001) than those in the AHP group. Weight loss, crackles, digital clubbing, and cyanosis were more common in the CHP group than those in the AHP group (χ2 = 5.862, P < 0.001; χ2 = 8.997, P = 0.003; χ2 = 11.939, P = 0.001; and χ2 = 4.025, P = 0.045, respectively). On chest high-resolution computed tomography (HRCT), reticular patterns, traction bronchiectasis, and accompanying honeycombing were more common in CHP cases than those in AHP cases (χ2 = 101.000, P < 0.001; χ2 = 32.048, P < 0.001; and χ2 = 36.568, P < 0.001, respectively). The clinical scoring system for CHP was established based on the clinical variables (age [A], duration of symptoms [D], smoking history [S], unidentified exposure [U], and chest HRCT [C]; ADSUC) (area under the curve 0.935, 95% confidence interval: 0.883–0.987, P < 0.001). Eleven patients (15.3%) in the AHP group developed CHP, and unidentified exposure was an independent risk factor for the progression of disease (P = 0.038). The survival of patients with CHP, smoking history, unidentified antigens and fibrosis on Chest HRCT were significantly worse (P = 0.011, P = 0.001, P = 0.005, and P = 0.011, respectively) by Kaplan-Meier analysis. Cox multivariate regression analysis revealed that unidentified exposure and total lung volume (TLC pred%) were independent prognostic predictors for HP patients (P = 0.017 and P = 0.017, respectively).Conclusions:The clinical features and outcomes of the CHP patients differ from those of the AHP patients. ADSUC is a simple and feasible clinical model for CHP. Unidentified exposure is an independent risk factor for the progression of AHP to CHP. Unidentified exposure and a low baseline TLC pred% are independent predictors for survival in HP patients.

Clinical behaviour of patients exposed to organic dust and diagnosed with idiopathic pulmonary fibrosis.

Although idiopathic pulmonary fibrosis (IPF) patients experience a worse survival compared with chronic hypersensitivity pneumonitis (CHP), organic dust exposure is a known risk factor for both IPF and CHP. We divided patients diagnosed with IPF, based on their exposure to moulds/birds (absent: group A; present: group B). We retrospectively compared pulmonary function and survival between groups A and B, and a separate CHP cohort (group C). A total of 293 patients were included (group A: n = 171, group B: n = 73, group C: n = 49). Demographics and baseline pulmonary function did not differ between groups A and B, but significant differences were seen between groups B and C. Median survival of group B was 84 months, which was longer than group A (43 months, P = 0.002), but lower than group C (157 months, P = 0.04), in both univariate and multivariate analyses. Antifibrotic treatment resulted in a better outcome in group A (hazard ratio (HR): 0.44) and group B (HR: 0.12) without interaction between exposure and antifibrotic use (P = 0.20). Forced vital capacity (FVC) decline was not associated with mould/bird exposure in this cohort. Group B patients experienced a better outcome compared with (non-exposed) IPF patients, although worse compared with CHP patients. Antifibrotic treatment in group B resulted in a similar beneficial effect compared with group A. Further research is needed to ascertain the diagnostic designation in this exposed usual interstitial pneumonia (UIP) patient group without other CHP features.

Autoimmune Hypothyroidism As a Predictor of Mortality in Chronic Hypersensitivity Pneumonitis

Chronic hypersensitivity pneumonitis (CHP) is a fibrotic parenchymal lung disease that occurs when inhalation of environmental antigens leads to immune dysregulation. Autoimmune features have recently been identified as potentially important among patients with CHP. However, the relationship between hypothyroidism (HT) and CHP is unknown. In this study, we investigate the prevalence and impact of HT among patients with CHP. We conducted a retrospective, case-control analysis. We identified 121 patients at the University of Chicago Interstitial Lung Disease Center with a multidisciplinary diagnosis of CHP. These patients were matched 3:1 according to age, sex, and race to 363 control subjects with asthma from 2006 to 2015. We analyzed demographics, clinical characteristics, and survival between both groups and assessed the relationship of HT with CHP. Survival analysis was performed using Cox proportional hazards modeling. Patients with CHP had higher prevalence of HT (25.6%, n = 31) compared to controls (10.7%, n = 39; OR, 2.86; 95% CI, 1.62-4.99; P < 0.0001). Compared to CHP alone, patients with CHP/HT were more likely to be female (80.6 vs 51.1%, P = 0.004), have increased incidence of autoimmune disease (19.4 vs 3.3%, P = 0.009), antinuclear antibody seropositivity (80.6 vs 57.0%, P = 0.019), and higher TSH levels (4.0 vs 1.9 mIU/L, P < 0.0001). HT was a significant independent predictor of mortality among CHP patients with seropositive ANA (HR, 3.39; 95% CI, 1.31-8.80; P = 0.012). HT is common in patients with CHP and may carry prognostic significance in patients with features of autoimmunity. Further research exploring common pathogenic pathways between autoimmune HT and CHP may illuminate the association of HT with survival.

Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis.

In chronic hypersensitivity pneumonitis (CHP), lack of improvement or declining lung function may prompt use of immunosuppressive therapy. We hypothesised that use of azathioprine or mycophenolate mofetil with prednisone reduces adverse events and lung function decline, and improves transplant-free survival.Patients with CHP were identified. Demographic features, pulmonary function tests, incidence of treatment-emergent adverse events (TEAEs) and transplant-free survival were characterised, compared and analysed between patients stratified by immunosuppressive therapy. A multicentre comparison was performed across four independent tertiary medical centres.Among 131 CHP patients at the University of Chicago medical centre (Chicago, IL, USA), 93 (71%) received immunosuppressive therapy, and had worse baseline forced vital capacity (FVC) and diffusing capacity, and increased mortality compared with those who did not. Compared to patients treated with prednisone alone, TEAEs were 54% less frequent with azathioprine therapy (p=0.04) and 66% less frequent with mycophenolate mofetil (p=0.002). FVC decline and survival were similar between treatment groups. Analyses of datasets from four external tertiary medical centres confirmed these findings.CHP patients who did not receive immunosuppressive therapy had better survival than those who did. Use of mycophenolate mofetil or azathioprine was associated with a decreased incidence of TEAEs, and no difference in lung function decline or survival when compared with prednisone alone. Early transition to mycophenolate mofetil or azathioprine may be an appropriate therapeutic approach in CHP, but more studies are needed.

Mycophenolate Mofetil Is Well Tolerated and May Stabilize Lung Function in Chronic Hypersensitivity Pneumonitis Patients

Mycophenolate Mofetil Is Well Tolerated and May Stabilize Lung Function in Chronic Hypersensitivity Pneumonitis Patients

Th2-Biased Immune Responses Are Important in a Murine Model of Chronic Hypersensitivity Pneumonitis

Background: Chronic hypersensitivity pneumonitis (HP) can lead to irreversible pulmonary fibrosis. A good animal model is essential to elucidate the mechanisms of this disease. We previously reported that a Th2 predominance may play an important role in the fibrogenesis in chronic HP patients. A study was undertaken to evaluate whether Th2-biased immune responses were crucial during the processes of lung fibrosis in a murine model of chronic HP. Methods: Instillation of pigeon dropping extracts (PDE) was conducted 3 days a week for 6 or 12 weeks in C57BL/6, BALB/c and A/J mice to establish models of chronic HP. We evaluated the histopathological features, immunohistochemistry, collagen content, bronchoalveolar lavage fluid (BALF) profiles and Th1/Th2 cytokines in BALF or lung tissue with RT-PCR and ELISA. Results: Thickening of the alveolar walls and structural alterations were observed only in the A/J mice after 12 weeks of exposure to PDE. The fibrosis scores were significantly increased in 12-week A/J mice compared to those in the other strains. Immunohistochemistry evaluation showed that PDE was engulfed by alveolar macrophages that were incorporated into the alveolar septa of 12-week A/J mice. Interleukin (IL)-4 mRNA increased significantly in 6- and 12-week A/J mice. IL-13 mRNA showed a significant increase in 12-week A/J mice compared with 6-week A/J mice. TGF-β1 mRNA at 12 weeks was significantly increased in A/J mice compared with the other groups. Conclusion: Th2-biased genetic backgrounds may play an important role in fibrosing processes in the present chronic HP model.