Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Update on sarcoidosis guidelines.

PURPOSE OF REVIEW: The current review summarizes recent guidance in the diagnosis and management of sarcoidosis. Until recently, the main guidelines were the 1999 International Statement on Sarcoidosis. However, in 2020 two new guidelines were published by the American and British Thoracic Societies. They have a number of key updates and this review aims to summarize these. RECENT FINDINGS: The key findings from 2020 revolve around several themes. First, the need for a histological diagnosis should be supported by a multidisciplinary team approach. When a histological biopsy is needed of the lungs, thought is given to the approach taken for this and to whether an endobronchial ultrasound, endoscopic ultrasound or transbronchial biopsy is needed. Second, information regarding supporting tests including blood biomarkers, lung function and imaging. Third, a section specific to cardiac sarcoidosis. Finally, a summary of guidance for treating sarcoidosis including the need to treat fatigue. SUMMARY: The recent guidance suggests that a histological biopsy is only needed in cases of diagnostic uncertainty or in patients with typical long standing features on imaging. The guidelines also provide a clear pathway on the type of lung biopsy needed depending on the extent of mediastinal or parenchymal involvement. Support is given to steroid regimens and indication for second-line immunosuppression.

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Use of mycophenolate mofetil and azathioprine for the treatment of chronic hypersensitivity pneumonitis-A single-centre experience.

INTRODUCTION: The optimal pharmacological management of chronic hypersensitivity pneumonitis (cHP) is unknown. Corticosteroids are often used as first line therapy but can be associated with side effects. There is a paucity of data examining the role of steroid-sparing agents in cHP. We aimed to determine the effect of mycophenolate mofetil (MMF) and azathioprine (AZA) on lung function and prednisolone dose in cHP patients. METHODS: Retrospective analysis of patients initiated on either MMF or AZA following a multidisciplinary team diagnosis of cHP. Changes in lung function and prednisolone dose up to 12 months before and after MMF/AZA initiation were analysed. RESULTS: Twenty two out of 30 patients remained on treatment at 12 months (18 MMF, 4 AZA). Steroid-sparing therapy resulted in a significant reduction in prednisolone dose from 16.2 ± 9.7 to 8.2 ± 4.2 mg daily (P = 0.002). Treatment with MMF or AZA for 12 months was associated with a significant improvement in carbon monoxide diffusing capacity (TLCO) (-0.55 ± 0.96 vs. +0.31 ± 0.58 mmol/kPa/min, P = 0.02). Although treatment reduced the rate of forced vital capacity decline (-111 ± 295 vs. +2.3 ± 319 mL), it was not significant (P = 0.22). CONCLUSION: MMF or AZA therapy in cHP is associated with an improvement in TLCO and reduction in prednisolone dose. There is a need for prospective trials.

The Aminopeptidase CD13 Induces Homotypic Aggregation in Neutrophils and Impairs Collagen Invasion.

Aminopeptidase N (CD13) is a widely expressed cell surface metallopeptidase involved in the migration of cancer and endothelial cells. Apart from our demonstration that CD13 modulates the efficacy of tumor necrosis factor-α-induced apoptosis in neutrophils, no other function for CD13 has been ascribed in this cell. We hypothesized that CD13 may be involved in neutrophil migration and/or homotypic aggregation. Using purified human blood neutrophils we confirmed the expression of CD13 on neutrophils and its up-regulation by pro-inflammatory agonists. However, using the anti-CD13 monoclonal antibody WM-15 and the aminopeptidase enzymatic inhibitor bestatin we were unable to demonstrate any direct involvement of CD13 in neutrophil polarisation or chemotaxis. In contrast, IL-8-mediated neutrophil migration in type I collagen gels was significantly impaired by the anti-CD13 monoclonal antibodies WM-15 and MY7. Notably, these antibodies also induced significant homotypic aggregation of neutrophils, which was dependent on CD13 cross-linking and was attenuated by phosphoinositide 3-kinase and extracellular signal-related kinase 1/2 inhibition. Live imaging demonstrated that in WM-15-treated neutrophils, where homotypic aggregation was evident, the number of cells entering IL-8 impregnated collagen I gels was significantly reduced. These data reveal a novel role for CD13 in inducing homotypic aggregation in neutrophils, which results in a transmigration deficiency; this mechanism may be relevant to neutrophil micro-aggregation in vivo.