BACKGROUND AND OBJECTIVE:The available evidence on the effects of ambulatory oxygen on exercise impairment in patients with fibrotic interstitial lung diseases (F-ILD) is of limited quality. METHODS:We conducted a randomised, double-blind, placebo-controlled crossover trial with 32 normoxaemic F-ILD patients, desaturating to ≤ 88% during a baseline 6-minute walk test (6MWT) on ambient air. After determining the oxygen flow needed to prevent desaturation, patients completed two double-blind 6MWTs with either oxygen or placebo (compressed medical air) at the same personalised flow. Objective measures included oxygen saturation, pulse rate, and distance walked. Patient-reported outcomes, assessed via visual analogue scales, included end-of-test dyspnoea, fatigue, and preferences for walking with oxygen or placebo versus each other and ambient air. RESULTS:Ambulatory oxygen, compared to placebo, prevented desaturation, reduced tachycardia, increased walking distance by 37 m (95% CI: 10-74, p = 0.008), and lessened dyspnoea and fatigue. The mean preference score for oxygen over placebo was 2.6 (95% CI: 1.9-3.2, p < 0.0005), significantly greater than equivalence. The preference score for placebo over ambient air was -1.5 (-2.4 to 0.64, p = 0.005), significantly lower than equivalence, while the score for oxygen over ambient air was 0.4 (-0.7 to 1.5), not significantly different from equivalence. CONCLUSIONS:Our data confirm that ambulatory oxygen provides significant benefits beyond a placebo effect; although in some patients it is associated with a negative perception that may hinder treatment acceptance. This strengthens the evidence supporting current recommendations and suggests that incorporating patient preferences recorded at the time of the 6MWT into clinical discussions can aid shared decision making regarding ambulatory oxygen. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02668029.

Background:Suspected interstitial lung disease (ILD) patients may be referred to an ILD-specialist centre or a non-ILD-specialist centre for diagnosis and treatment. Early referral and management of patients at ILD-specialist centres has been shown to improve survival and reduce hospitalisations. The COVID-19 pandemic has affected the ILD patient diagnostic pathway and prompted centres to adapt. This study investigates and contrasts ILD patient pathways in ILD-specialist and non-ILD-specialist centres, focusing on referrals, caseloads, diagnostic tools, multi-disciplinary team (MDT) meeting practices and resource accessibility. Methods:Conducted as a cross-sectional study, a global self-selecting survey ran from September 2022 to January 2023. Participants included ILD specialists and healthcare professionals (HCPs) from ILD-specialist centres and non-ILD-specialist centres. Results:Of 363 unique respondents from 64 countries, 259 were from ILD-specialist centres and 104 from non-ILD-specialist centres. ILD centres had better resource availability, exhibiting higher utilisation of diagnostic tests (median: 12 tests) than non-ILD centres (nine tests) and better access to specialist professions attending MDT meetings (median: six professions at meeting) in specialist centres than non-ILD centres (three professions at meeting). Transitioning to virtual MDT meetings allowed HCPs from other locations to join meetings in nearly 90% of all centres, increasing regular participation in 60% of specialist centres and 72% of non-ILD centres. For treatment of patients, specialist centres had better access to antifibrotic drugs (91%) compared to non-ILD centres (60%). Conclusions:Diagnostic pathways for ILD patients diverged between specialist centres and non-ILD centres. Disparities in resource and specialist availability existed between centres.

IntroductionSarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures.MethodsAfter obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations.ResultsIn the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement.DiscussionThe observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene–environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.

Obstructive sleep apnea (OSA) is often observed in subjects with interstitial lung disease (ILD). It may have a negative impact on the course of ILD, but its prognostic significance in relation to other known indicators of poor outcome is unclear. After a detailed work-up, including overnight unattended type III polygraphy, all subjects newly diagnosed with ILDs referred to our clinics were followed-up for at least 1.5 years or until death or progression of disease [> 10% decline in forced vital capacity (FVC) below baseline]. We analyzed relationships between some prespecified variables of interest, including sleeping results, to establish parameters predictive of progressive course. Our population consisted of 46 subjects (mean age 59.6 years; males 61%); 23.9% and 41% had idiopathic pulmonary fibrosis and ILD associated with systemic diseases, respectively. Mean baseline forced vital capacity and diffusion capacity of carbon monoxide were 83% and 57% of predicted, respectively. Mean (± SE) Apnea–Hypopnea Index (AHI) was 17 (± 3) events/h. AHI in the ranges 5–14.9, 15–29.9, and ≥ 30 was recorded in 14 (31%), 6 (13%), and 9 (20%) subjects, respectively. Mean distance covered in the 6-MWG walk test (6MWT) was 302 (± 19) m and 26 subjects (57%) showed exertional oxyhemoglobin desaturation. The median follow-up was about 18 months. Multivariate logistic regression analysis showed that exertional desaturation (HR 8.2; 1.8–36.5 95% CI; p = 0.006) and AHI ≥ 30, namely the threshold of severe OSA (HR 7.5; 1.8–30.6; p = 0.005), were the only independent variables related to progressive disease course. We conclude that exertional desaturation and elevated AHI had independent negative prognostic significance in our ILD population.

Background: Individuals with self-declared sarcoidosis are at increased risk of COVID-19 related morbidity and mortality for which vaccination can be lifesaving. Despite this, vaccine hesitancy remains a large barrier to global acceptance of vaccination against COVID-19. We aimed to identify individuals with sarcoidosis who had and had not been vaccinated against COVID-19 vaccine to 1) establish a safety profile of COVID-19 vaccination in those with sarcoidosis and 2) to elucidate factors that contribute to COVID-19 vaccine hesitancy. Methods: A questionnaire inquiring about COVID-19 vaccination status, vaccination side effects, and willingness for future vaccination was distributed from December 2020 to May 2021 to individuals with sarcoidosis living in the US and European countries. Details regarding sarcoidosis manifestations and treatment were solicited. Vaccine attitudes were classified as pro or anti-COVID-19 vaccination for subgroup analysis. Results: At the time of questionnaire administration, 42% of respondents had already received a COVID-19 vaccination, most of whom either denied side effects or reported a local reaction only. Those not on sarcoidosis therapy were more likely to report systemic side effects. Among subjects who had not yet received a COVID-19 vaccine, 27% of individuals reported they would not receive one once available. Reasons against vaccination were overwhelmingly related to the lack of confidence in vaccine safety and/or efficacy and less related to concerns associated with convenience or complacency. Black individuals, women, and younger adults were more likely to decline vaccination. Conclusions: Among individuals with sarcoidosis, COVID-19 vaccination is well-accepted and well-tolerated. Subjects on sarcoidosis therapy reported significantly less vaccination side effects, and thus the correlation between side effects, vaccine type, and vaccine efficacy requires further investigation. Strategies to improve vaccination should focus on improving knowledge and education regarding vaccine safety and efficacy, as well as targeting sources of misinformation, particularly in young, black, and female subpopulations.

Introduction: Multidisciplinary team (MDT) meetings are recommended as the gold standard for interstitial lung disease (ILD) diagnosis. However, the COVID-19 pandemic has made face-to-face MDTs challenging, forcing teams to adapt. ILD diagnosis in the post-COVID era will likely involve virtual MDTs (vMDTs), improving collaboration between specialists and centres. Aims: The study, funded by Boehringer Ingelheim, aimed to identify key characteristics of ILD caseload and changes to MDTs in the post-COVID era. Methods: Physicians involved in the diagnosis of ILDs were invited to participate in a standardised international survey from September 2022 to January 2023. 363 centres from 64 countries participated. Results: 57.9% of centres reported a change in MDT format since the pandemic. 59.2% had virtual or hybrid meetings. Changing MDT format did not increase the frequency of meetings (57.9%), however, 89.6% of respondents found a virtual platform allowed healthcare professionals from outside of their centre to regularly participate in MDTs. 71.3% of centres reported an increase in referrals after/during the pandemic. Of total ILD cases/year, median [IQR] 30% [24%] were IPF referrals, 30% [20%] were PF-ILD, 5% [7%] were post-COVID ILD, and 20% [33%] were other ILDs. 73.8% of respondents had seen a change to the risk in exacerbation, progression, or death in patients with pre-existing ILD after COVID-19 infection. Conclusions: Most centres are facing increased ILD referrals and have adapted their ILD MDT format to a virtual platform. The move to vMDTs may aid ILD diagnosis and management, especially improve delayed assessment in regional non-ILD centres.

BACKGROUND:Krebs von den Lungen-6 (KL-6) is a high molecular weight (MW) glycoprotein mainly secreted by type II pneumocytes because of lung damage or during regeneration. Neurosarcoidosis (NS), where sarcoid granulomas involve the nervous system, occurs in 5-20% of patients with sarcoidosis. No data is currently available on KL-6 in serum or CSF of NS patients. The present study compared KL-6 concentrations in serum and CSF of NS patients versus others with neurodegenerative (ND) or chronic inflammatory demyelinating (DM) diseases.MATERIALS AND METHODS:Nine NS patients (mean age 46.2 years, range 16-61 years, M/F 5/4), nine patients with a chronic neurodegenerative disease (mean age 53.1 years, range 37-65 years, M/F 5/4) and nine patients with a chronic demyelinating disease (mean age 46.3 years, range 18-65 years, M/F 5/4) were retrospectively enrolled.RESULTS:Measurable CSF concentrations of KL-6 were detected in 7/9 NS patients but in no ND or DM patients. No significant differences in CSF concentrations of ACE were observed between the three groups (p=0.0819). In NS patients, CSF concentrations of KL-6 were directly correlated with CSF albumin index (r=0.98; p<0.0001), albumin (r=0.979, p=0.0001), IgG (r=0.928, p=0.0009) and total protein concentrations (r=0.945, p=0.0004).DISCUSSION:KL-6 is a high MW protein, under physiological conditions it is unlikely to cross the blood-brain barrier. We found KL-6 in CSF from NS and not from ND and DM patients. The finding sustains the specificity of changes in KL-6 in this granulomatous disease, suggesting it as a candidate biomarker for recognition of NS.

BACKGROUND: Given the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another. RESEARCH QUESTION: Do IPF endotypes exist and are they associated with outcome? STUDY DESIGN AND METHODS: Using a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples. RESULTS: One hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score- corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotypespecific survival-associated genes. INTERPRETATION: Gene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.

Introduction: Cytomegalovirus (CMV) is the leading opportunistic infection in lung transplant (LTx) recipients. CMV is associated with graft failure and decreased survival. Recently, new antiviral therapies have been proposed. The present study aimed to investigate NK and T cell subsets of patients awaiting LTx. We analyzed the cellular populations between reactive and non-reactive QuantiFERON (QF) CMV patients for the prediction of immunological response to infection. Methods: Seventeen pre-LTx patients and 15 healthy controls (HC) have been enrolled. QF and IFN-γ ELISA assay detections were applied. NK cell subsets and T cell and proliferation assay were detected before and after stimulation with pp-65 and IE-1 CMV antigens after stratification as QF+ and QF−. Furthermore, we quantified the serum concentrations of NK− and T-related cytokines by bead-based multiplex analysis. Results: CD56brCD16lowNKG2A+KIR+ resulted in the best discriminatory cellular subsets between pre-LTx and HC. Discrepancies emerged between serology and QF assay. Better proliferative capability emerged from patients who were QF+, in particular in CD8 and CD25-activated cells. CD56brCD16low, adaptive/memory-like NK and CD8Teff were highly increased only in QF+ patients. Conclusions: QF more than serology is useful in the detection of patients able to respond to viral infection. This study provides new insights in terms of immunological responses to CMV in pre-LTX patients, particularly in NK and T cells biology.

Rationale Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course of the disease. Underlying genetic associations with sarcoidosis phenotypes are largely unknown but genetic disease susceptibility suggests the existence of genetic signatures.

Lung Cancer (LC) is the first cause of death worldwide. Recently increased interest in interstitial lung diseases (ILD) has highlighted an association with lung cancer, offering interesting insights into the pathogenesis of the latter. Describe the association between lung cancer and ILD and evaluate the impact of LC on survival in these populations. We collected clinical, radiological, histologic data of 53 cases of advanced pulmonary fibrosis with lung cancer: 17 with UIP pattern (usual interstitial pneumonia, UIP/IPF-LC) and 36 with non-UIP pattern (ILD-LC). Adenocarcinoma was the most frequent histological subtype of lung cancer in all three groups and in UIP/IPF-LC developed in the lung periphery and in an advanced fibrosis context. Patients with DLCO% < 38% showed survival < 10 months, irrespective of group and development of carcinoma in UIP/IPF does not necessarily affect survival, unlike in SR-ILD. Our results confirm that the oncogenic mechanism is closely linked to fibrotic and inflammatory processes and that the development of carcinoma affects survival in SR-ILD but not in IPF.

Background: The immune mechanisms occurring during acute rejection (AR) and chronic lung allograft dysfunction are a challenge for research and the balance between effector and regulatory cells has not been defined completely. In this study, we aimed to elucidate the interaction of effector cells, mainly Th17, Th1 and Th2, and regulatory cells including (CD4+CD25+CD127low/−) T reg cells and phenotypes of B regs, CD19+CD24hiCD38hi, CD19+CD24hiCD27hi and CD19+CD5+CD1d+. Methods: Bronchoalveolar lavage cells (BAL) and peripheral blood mononuclear cells (PBMCs) from stable lung transplanted (LTx )subjects (n = 4), AR patients (n = 6) and bronchiolitis obliterans syndrome (BOS) (n = 6) were collected at the same time. Cellular subsets were detected through flow cytometry. Results: A predominance of Th17 cells subtypes in the PBMCs and BAL and a depletion of Tregs, that resulted in decrease Treg/Th17 ratio, was observed in the AR group. CD19+CD24hiCD38hi Bregs resulted increased in BAL of AR patients. Th1 cells predominance and a reduction of Tregs cells was observed in BAL from AR patients. Moreover, multivariate analysis showed interdependences within studied variables revealing that effector cells and regulatory cells can effectively discriminate patients’ immunological status. Conclusions: In AR, BOS and stable lung transplant, regulatory and effector cells clearly demonstrated different pathways of activation. Understanding of the balance of T cells and T and B regulatory cells can offers insights into rejection.

Background: Granulomatous interstitial nephritis in sarcoidosis (sGIN) is generally clinically silent, but in <1% causes acute kidney injury (AKI). Methods: This Italian multicentric retrospective study included 39 sarcoidosis-patients with renal involvement at renal biopsy: 31 sGIN-AKI, 5 with other patterns (No-sGIN-AKI), 3 with nephrotic proteinuria. We investigate the predictive value of clinical features, laboratory, radiological parameters and histological patterns regarding steroid response. Primary endpoint: incident chronic kidney disease (CKD) beyond the 1 degrees follow-up (FU) year; secondary endpoint: response at 1 degrees line steroid therapy; combined endpoint: the association of initial steroid response and outcome at the end of FU. Results: Complete recovery in all 5 No-sGIN-AKI-patients, only in 45% (13/29) sGIN-AKI-patients (p=0.046) (one lost in follow-up, for another not available renal function after steroids). Nobody had not response. Primary endpoint of 22 sGIN-AKI subjects: 65% (13/20) starting with normal renal function developed CKD (2/22 had basal CKD; median FU 77 months, 15-300). Combined endpoint: 29% (6/21) had complete recovery and final normal renal function (one with renal relapse), 48% (10/21) had partial recovery and final CKD (3 with renal relapse, of whom one with basal CKD) (p=0.024). Acute onset and hypercalcaemia were associated to milder AKI and better recovery than subacute onset and patients without hypercalcaemia, women had better endpoints than men. Giant cells, severe interstitial infiltrate and interstitial fibrosis seemed negative predictors in terms of endpoints. Conclusions: sGIN-AKI-patients with no complete recovery at 1 degrees line steroid should be treated with other immunosuppressive to avoid CKD, in particular if males with subacute onset and III stage-not hypercalcaemic AKI.

Background Galectins are proteins that bind β-galactosides such as N -acetyllactosamine present in N-linked and O-linked glycoproteins and that seem to be implicated in inflammatory and immune responses as well as fibrotic mechanisms. This preliminary study investigated serum galectins as clinical biomarkers in lung transplant patients with chronic lung allograft dysfunction (CLAD), phenotype bronchiolitis obliterans syndrome (BOS). Materials and Methods Nineteen lung transplant patients [median age (IQR), 55 (45–62) years; 53% males] were enrolled in the study. Peripheral blood concentrations of galectins-1, 3 and 9 were determined with commercial ELISA kits. Results Galectin-1 concentrations were higher in BOS than in stable LTX patients ( p = 0.0394). In logistic regression analysis, testing BOS group as dependent variable with Gal-1 and 3 as independent variables, area under the receiver operating characteristics (AUROC) curve was 98.9% (NPV 90% and PPV 88.9%, p = 0.0003). With the stable LTX group as dependent variable and Gal-1, 3 and 9 as independent variables, AUROC was 92.6% (NPV 100% and PPV 90%, p = 0.0023). In stable patients were observed an inverse correlation of Gal-3 with DLCO% and KCO%, and between Gal-9 and KCO%. Conclusion Galectins-1, 3 and 9 are possible clinical biomarkers in lung transplant patients with diagnostic and prognostic meaning. These molecules may be directly implicated in the pathological mechanisms of BOS. The hypothesis that they could be new therapeutic targets in BOS patients is intriguing and also worth exploring.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure-activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF.

Acute exacerbations (AEs) are among the main causes of death in idiopathic pulmonary fibrosis (IPF) patients. In this study proteomic comparative analysis of bronchoalveolar lavage (BAL) fluid samples was performed in stable IPF patients versus AEs IPF group to identify AE pathogenetic mechanisms and novel potential predictive biomarkers. A functional proteomic analysis of BAL fluid samples from stable and AE-IPF patients was conducted in a population of 27 IPF patients. Fifty-one differentially abundant spots were observed and identified by mass spectrometry. Enrichment analysis found proteins of interest involved in the regulation of macrophages and lipid metabolism receptors. In acute exacerbation IPF group, differentially abundant proteins were involved in propagation of the β-catenin WNT transduction signal, and proteins up-regulated in lung carcinogenesis (IGKC, S100A9, PEDF, IGHG1, ALDOA, A1AT, HPT, CO3 and PIGR) and acute phase proteins involved in protease-antiprotease imbalance (such as A1AT fragments). Dot-blot analysis of A1AT C-36 peptide allowed validating our findings, confirming up-regulation in AE IPF patients and suggesting its potential pathogenetic role. A crucial role of protease/antiprotease imbalance, clathrin-mediated endocytosis signalling and carcinogenesis emerged in IPF patients developing acute exacerbations.

Objective Familial pulmonary fibrosis (FPF) is defined as an idiopathic interstitial lung disease affecting two or more members of the same family; poor outcome with high risk of death and chronic lung allograft dysfunction (CLAD) after lung transplant has been reported in these patients. The present study aimed to compare the short- and long-term outcome of lung transplants in patients with FPF and patients transplanted because of other interstitial lung diseases. Method Clinical pre- and post-transplant data from 83 consecutive patients with pulmonary fibrosis who underwent lung transplant at our centre were collected retrospectively. Patients were divided into those with familial (n=9 FPF group) and those with non-familial pulmonary fibrosis (n=74 controls). Results The FPF group was composed of 4 females and 5 males; 44.5% were ex-smokers. The majority presented their CT scan and pathology evidence of usual interstitial pneumonia. Patients with FPF had significantly lower pre-transplant levels of haemoglobin and haematocrit. No other differences in pre- and post-transplant characteristics were observed concerning controls. The clinical post-operative course was similar in the two groups. No significant difference in one-year CLAD-free survival and overall survival was observed. Conclusion The post-transplant course of patients with FPF was similar to patients with non-familial pulmonary fibrosis, although more patients with FPF had pre-transplant anaemia. Short- and long-term outcome was comparable in both groups. Lung transplant proved to be a valid option for patients with FPF as it was for patients with other types of pulmonary fibrosis.

Over the past few months, the novel coronavirus disease 2019 (COVID-19) pandemic has posed many challenges for practicing physicians. Patients with sarcoidosis may have an increased risk of a poor outcome and death from COVID-19 infection for several reasons. First, sarcoidosis involves the lung in approximately 90% of patients,1Baughman R.P. Teirstein A.S. Judson M.A. et al.Clinical characteristics of patients in a case control study of sarcoidosis.Am J Respir Crit Care Med. 2001; 164: 1885-1889Crossref PubMed Scopus (1355) Google Scholar many of whom have diminished baseline lung function with reduced pulmonary reserve should they develop respiratory failure. Second, although the etiology of sarcoidosis is unknown, it is postulated that immunologic dysfunction and dysregulation play essential roles in the development of the disease.2Grunewald J. Grutters J.C. Arkema E.V. Saketkoo L.A. Moller D.R. Müller-Quernheim J. Sarcoidosis.Nat Rev Dis Primers. 2019; 5: 45Crossref PubMed Scopus (230) Google Scholar Third, African-American race and many comorbidities associated with glucocorticoid (GC) therapies such as hypertension, diabetes, and obesity have been identified by the Centers for Disease Control and Prevention as independent risk factors for COVID-19-related death and are more prevalent in sarcoidosis cohorts.3Garg S. Kim L. Whitaker M. et al.Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 states, March 1-30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 458-464Crossref PubMed Scopus (3) Google Scholar Finally, and most pertinent to the treating clinician, immunosuppressive medications are the primary agents used for the treatment of sarcoidosis, particularly GCs, which are often the first-line agent.4Judson M.A. Corticosteroids in sarcoidosis.Rheum Dis Clin North Am. 2016; 42: 119-135, ixAbstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Little is known about the impact of sarcoidosis treatments on susceptibility to and disease expression of COVID-19 infection; however, because of the lethality of COVID-19 infection, there is concern that the risk-benefit ratio of effective immunosuppressive therapies for sarcoidosis may be altered in the current climate. The goal of the present article was to provide clinicians with practical guidance on how to adjust immunosuppressive therapy for the treatment of sarcoidosis during the COVID-19 pandemic. This guidance does not reflect a change in the standard of care of sarcoidosis but rather stresses the importance of minimizing the dose of immunosuppression, which is the accepted practice in the management of sarcoidosis. Given the current COVID-19 pandemic and the increased risk of a poor outcome in individuals receiving immunosuppression who become infected, these guidelines emphasize adherence to this principle. This document should be considered an opinion statement to provide guidance to the clinician based on expert opinion. Whenever possible, the authors have attempted to extrapolate the outcomes of infections in patients with sarcoidosis from what is known in other populations who receive similar medications. Many of the immunosuppressive agents used to treat sarcoidosis are used in rheumatic diseases. Based on systematic reviews and meta-analyses, it is known that these drugs, notably systemic GCs and biologic agents (eg, tumor necrosis factor inhibitors), increase the risk for serious infections.5Doran M.F. Crowson C.S. Pond G.R. O'Fallon W.M. Gabriel S.E. Predictors of infection in rheumatoid arthritis.Arthritis Rheum. 2002; 46: 2294-2300Crossref PubMed Scopus (472) Google Scholar,6Singh J.A. Cameron C. Noorbaloochi S. et al.Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis.Lancet. 2015; 386: 258-265Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar Traditional steroid-sparing agents, most importantly methotrexate, are also associated with an increased risk of infection, but the degree of risk depends on the nature of the underlying illness, dosage, treatment duration, and infection in question.7Ibrahim A. Ahmed M. Conway R. Carey J.J. Risk of infection with methotrexate therapy in inflammatory diseases: a systematic review and meta-analysis.J Clin Med. 2018; 8Crossref PubMed Scopus (57) Google Scholar This degree of risk is generally considered to be lower than that with GCs and biologic agents.7Ibrahim A. Ahmed M. Conway R. Carey J.J. Risk of infection with methotrexate therapy in inflammatory diseases: a systematic review and meta-analysis.J Clin Med. 2018; 8Crossref PubMed Scopus (57) Google Scholar,8Judson M.A. Baughman R.P. Costabel U. et al.Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis.Eur Respir J. 2014; 44: 1296-1307Crossref PubMed Scopus (160) Google Scholar Although lowering immunosuppression might improve the outcome of a patient with sarcoidosis who becomes exposed to COVID-19, it is also associated with the risk of worsening sarcoidosis. In practice, treating physicians are confronted with two general scenarios: first, a patient who is clinically quiescent maintained on a stable medical regimen; or second, a patient with active, organ-threatening disease. If a patient with stable sarcoidosis is receiving GC therapy alone, an attempt can be made in most cases to slowly reduce the corticosteroid dose. Notably, in a randomized trial with GC tapering, a high proportion of patients receiving placebo were successfully able to taper their prednisone dosage by > 50% without flares of the disease over several months.8Judson M.A. Baughman R.P. Costabel U. et al.Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis.Eur Respir J. 2014; 44: 1296-1307Crossref PubMed Scopus (160) Google Scholar In one study of 36 patients with pulmonary sarcoidosis who had a pulmonary exacerbation, none was receiving more than 10 mg/d of prednisone at the time of their exacerbation.9McKinzie B.P. Bullington W.M. Mazur J.E. Judson M.A. Efficacy of short-course, low-dose corticosteroid therapy for acute pulmonary sarcoidosis exacerbations.Am J Med Sci. 2010; 339: 1-4Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Even exacerbations of pulmonary disease usually do not result in significant respiratory distress and typically respond to modest increases in corticosteroid dosages for just a few weeks. Skin sarcoidosis is a specific, non-life-threatening form of the disease in which it may be prudent to attempt to taper therapy. In patients with stable disease who are currently on disease-modifying antisarcoid drugs (DMASDs) such as methotrexate, mycophenolate mofetil, azathioprine, and others, de-escalation of therapy should be considered. This can be achieved by reducing the dose or prolonging the dosing interval. For example, if a patient is stable on weekly methotrexate, a dose reduction or dosing every other week instead of every week are reasonable options. An outright drug holiday for several weeks, while risk-benefit is continually reassessed, may be considered for some patients, but this approach could increase the chance for more abrupt sarcoidosis flares that may be more refractory to control and prompt additional GC therapy. It is re-emphasized that DMASDs may present lower risk of infections than GCs. In patients who are receiving antimalarial agents such as chloroquine or hydroxychloroquine, we suggest continuing therapy. Unfortunately, because of preliminary, inconclusive reports suggesting a potential benefit of hydroxychloroquine in the treatment of COVID-19,10Gautret P. Lagier J.C. Parola P. et al.Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.Int J Antimicrob Agents. 2020; : 105949Crossref PubMed Scopus (3654) Google Scholar widespread shortages have ensued. Patients who receive immunosuppressive biologic agents may be at increased risk of COVID-19 infection. However, because of concern for rebound sarcoidosis flares, which may be problematic to control if these medications are discontinued abruptly, a gradual dose reduction could be considered. For example, infliximab may be given less frequently (eg, every 6 to 8 weeks instead of monthly) or at a lower weight-based dose (eg, 3 mg/kg instead of 5 mg/kg of body weight). In addition, premedication with GC could be reduced significantly or eliminated from the infusion protocol. When DMASDs are used for prevention of antibody formation in patients taking tumor necrosis factor inhibitors, a low dose (eg, methotrexate 10 mg weekly) is considered effective.11Schaeverbeke T. Truchetet M.E. Kostine M. Barnetche T. Bannwarth B. Richez C. Immunogenicity of biologic agents in rheumatoid arthritis patients: lessons for clinical practice.Rheumatology (Oxford). 2016; 55: 210-220Crossref PubMed Scopus (82) Google Scholar If immunosuppression is reduced, clinicians should instruct patients with sarcoidosis to be vigilant for any changes in their condition that are suggestive of active disease. The clinician should establish facile methods of communication with their patients, including rapid consultation systems (eg, telemedicine) and other appropriate safeguards. In patients with sarcoidosis and organ or life-threatening disease, a significant dose reduction or discontinuation of therapy may be contraindicated because of the risk of severe unfavorable outcomes. Such patients include those with progressive pulmonary disease, cardiac disease, uveitis, or neurosarcoidosis. Patients who are on GC therapy alone should be managed with the lowest possible dose to achieve disease control. If very high doses of GC (eg, > 40-60 mg/d of prednisone) are necessary, the addition of a DMASD may be prudent to enable a reduction in GC requirements, because GC therapy is associated with a high risk of infection in patients with sarcoidosis.12Baughman R.P. Lower E.E. Fungal infections as a complication of therapy for sarcoidosis.QJM. 2005; 98: 451-456Crossref PubMed Scopus (62) Google Scholar Such patients who have been stabilized on DMASDs should probably be maintained on current dosages. In patients on biologic therapies such as infliximab and adalimumab, therapy also should probably be continued because of the consequences of disease relapse. Due to logistic concerns (eg, potential closure of infusion units), switching to home infusion of infliximab or to subcutaneous adalimumab may be considered in carefully selected patients. In patients with active disease who cannot receive biologic therapies for logistic or clinical reasons, alternative treatments such as tofacitinib, repository corticotropin, or others may be considered on a case-by-case basis. However, convincing evidence of their efficacy in severe disease from clinical trials is not yet available. We also suggest that the assessment of symptoms in patients with sarcoidosis should involve the judicious use of objective testing such as pulmonary function tests and chest imaging to avoid unnecessary evaluations in the clinic and hospital. Again, this approach is a standard practice that we emphasize during this pandemic. The correlations between flares of sarcoidosis and changes in pulmonary function and chest imaging are known to be poor, and the determination of whether a patient with sarcoidosis is developing worsening disease may often be made on clinical grounds alone. The management of sarcoidosis during the current COVID-19 pandemic poses many challenges for treating physicians. The present article offers a generalized approach to this issue (Fig 1). The risk of a poor outcome from COVID-19 infection must be factored into the clinician's treatment algorithm. This may result in an adjustment of the immunosuppressive regimen of the patient with sarcoidosis depending on the stability of his or her disease and consequences of disease reactivation. If immunosuppression is reduced, a clear-cut plan to monitor and treat exacerbations of sarcoidosis should be in place. We acknowledge that our understanding of COVID-19 infection is currently meager, and we expect that more evidence-based recommendations will be developed over time. Treating physicians should remain vigilant in their decision-making to the changing landscape of the available COVID-19 testing, the high variability in local and regional prevalence of the virus, and the evolving COVID-19 treatments.

Pulmonary hypertension (PH) is defined as an elevated mean pulmonary artery pressure at rest (mPAP ≥ 25 mmHg), evaluated by right heart catheterization (RHC). The aim of the present study was to evaluate HRCT findings in relation to transthoracic echocardiographic data to better characterize PH in IPF patients and to identify a non-invasive composite index with high predictive value for PH in these patients. 37 IPF patients were enrolled in this retrospective study. All patients underwent a complete assessment for PH, including transthoracic Doppler echocardiography, HRCT scan and right heart catheterization. Right heart catheterization was done in 19 patients (51.3%) as pre-lung transplant assessment and in 18 patients (48.6%) to confirm PH, suspected on the basis of echocardiography. Twenty out of 37 patients (54%) were confirmed to have PH by RHC. Multivariate regression showed that the combination of sPAP, PA area measured by HRCT and the ratio of the diameter of the segmental artery to that of the adjacent bronchus in the apicoposterior segment of the left upper lobe was strongly correlated with mPAP (R2 = 0.53; p = 0.0009). The ROC analysis showed that 931.6 was the ULN for PA area, with 86% sensitivity and 61% specificity (0.839 AUC); 20.34 was the ULN for the ratio of PA area to ascending aorta diameter, with 100% sensitivity and 50% specificity (0.804 AUC). The composite index proposed in the present study could help early detection of IPF patients suspected of PH requiring confirmation by RHC (if deemed clinically necessary).