The Presence of T Allele (rs35705950) of the MUC5B Gene Predicts Lower Baseline Forced Vital Capacity and Its Subsequent Decline in Patients with Hypersensitivity Pneumonitis.

Hypersensitivity pneumonitis (HP) is an exposure-related interstitial lung disease with two phenotypes-fibrotic and non-fibrotic. Genetic predisposition is an important factor in the disease pathogenesis and fibrosis development. Several genes are supposed to be associated with the fibrosing cascade in the lungs. One of the best-recognized and most prevalent is the common MUC5B gene promoter region polymorphism variant rs35705950. The aim of our study was to establish the frequency of the minor allele of the MUC5B gene in the population of patients with HP and to find the relationship between the MUC5B promoter region polymorphism and the development of lung fibrosis, the severity of the disease course, and the response to the treatment in patients with HP. Eighty-six consecutive patients with HP were tested for the genetic variant rs35705950 of the MUC-5B gene. Demographic, radiological, and functional parameters were collected. The relationship between the presence of the T allele and lung fibrosis, pulmonary function test parameters, and the treatment response were analyzed. The minor allele frequency in the study group was 17%, with the distribution of the genotypes GG in 69.8% of subjects and GT/TT in 30.2%. Patients with the GT/TT phenotype had significantly lower baseline forced vital capacity (FVC) and significantly more frequently had a decline in FVC with time. The prevalence of lung fibrosis in high-resolution computed tomography (HRCT) was not significantly increased in GT/TT variant carriers compared to GG ones. The patients with the T allele tended to respond worse to immunomodulatory treatment and more frequently received antifibrotic drugs. In conclusions: The frequency of MUC5B polymorphism in HP patients is high. The T allele may indicate a worse disease course, worse immunomodulatory treatment response, and earlier need for antifibrotic treatment.

New 6-Minute-Walking Test Parameter-Distance/Desaturation Index (DDI) Correctly Diagnoses Short-Term Response to Immunomodulatory Therapy in Hypersensitivity Pneumonitis.

The six-minute-walking test (6MWT) is an easy-to-perform, cheap and valuable tool to assess the physical performance of patients. It has been used as one of the endpoints in many clinical trials investigating treatment efficacy in pulmonary arterial hypertension and idiopathic pulmonary fibrosis. However, the utility of 6MWT in patients diagnosed with hypersensitivity pneumonitis (HP) is still under investigation. The aim of the present retrospective study was to assess the value of different 6MWT parameters, including the newly developed distance-desaturation index (DDI), to evaluate immunomodulatory treatment outcomes in HP patients. METHODS: 6MWT parameters (distance, initial saturation, final saturation, desaturation, distance-saturation product (DSP), and DDI) were analyzed at baseline and after 3 to 6 months of treatment with corticosteroids alone or in combination with azathioprine. RESULTS: 91 consecutive HP patients diagnosed and treated in a single pulmonary unit from 2005 to 2017 entered the study. There were 44 (48%) males and 52 (57%) patients with fibrotic HP (fHP). Sixty-three patients (69%) responded to treatment (responders) and 28 (31%) did not respond (non-responders). In the responders group, all parameters assessed during 6MWT significantly improved, whereas in non-responders, they worsened. Medians (95% CI) of best indices were post-treatment DDI/baseline DDI-1.67 (1.85-3.63) in responders versus 0.88 (0.7-1.73) in non-responders (p = 0.0001) and change in walking distance-51 m (36-72 m) in responders, versus 10.5 m (-61.2-27.9) in non-responders (p = 0.0056). The area under the curve (AUC) of receiver operating characteristics (ROC) for post-treatment DDI/baseline DDI was 0.74 and the optimal cut-off was 1.075, with 71% of specificity and 71% of sensitivity. CONCLUSIONS: 6MWT may be used as a tool to assess and monitor the response to immunomodulatory therapy in HP patients, especially if indices incorporating both distance and desaturation are used. Based on the present study results, we recommend 6MWD and DDI use, in addition to FVC and TL,co, to monitor treatment efficacy in patients with interstitial lung diseases.

Bronchoalveolar Lavage Cell Count and Lymphocytosis Are the Important Discriminators between Fibrotic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis.

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.

Factors Predictive for Immunomodulatory Therapy Response and Survival in Patients with Hypersensitivity Pneumonitis-Retrospective Cohort Analysis.

Hypersensitivity pneumonitis (HP) is one of the interstitial lung diseases with clearly established diagnostic criteria. Nevertheless, pharmacologic treatment recommendations are still lacking. Most specialists use steroids as first-line drugs, sometimes combined with an immunosuppressive agent. Aim: The aim of the present retrospective study was to establish predictive factors for treatment success and survival advantage in HP patients. Methods: We analyzed the short-term treatment outcome and overall survival in consecutive HP patients treated with prednisone alone or combined with azathioprine. Results: The study group consisted of 93 HP patients, 54 (58%) with fibrotic HP and 39 (42%) with non-fibrotic HP. Mean (± SD) VCmax % pred. and TL,co % pred. before treatment initiation were 81.5 (±20.8)% and 48.3 (±15.7)%, respectively. Mean relative VCmax and TL,co change after 3−6 months of therapy were 9.5 (±18.8)% and 21.4 (±35.2)%, respectively. The short-term treatment outcomes were improvement in 49 (53%) patients, stabilization in 16 (17%) patients, and progression in 28 (30%) patients. Among those with fibrotic HP, improvement was noted in 19 (35%) cases. Significant positive treatment outcome predictors were fever after antigen exposure, lymphocyte count in broncho-alveolar lavage fluid (BALF) exceeding 54%, RV/TLC > 120% pred., and ill-defined centrilobular nodules in high-resolution computed tomography (HRCT). An increased eosinophil count in BALF and fibrosis in HRCT were significant negative treatment outcome predictors. The presence of fibrosis in HRCT remained significant in a multivariate analysis. A positive response to treatment, as well as preserved baseline VCmax (% pred.) and TLC (% pred.), predicted longer survival, while fibrosis in HRCT was related to a worse prognosis. Conclusion: Immunomodulatory treatment may be effective in a significant proportion of patients with HP, including those with fibrotic changes in HRCT. Therefore, future trials are urgently needed to establish the role of immunosuppressive treatment in fibrotic HP.