Everolimus Treatment for Chronic Lung Allograft Dysfunction in Lung Transplantation.

Our study aims to evaluate the effect of everolimus treatment on lung function in lung transplant (LT) patients with established chronic lung allograft dysfunction (CLAD). METHODS: This retrospective study included LT patients in two reference LT units who started everolimus therapy to treat CLAD from October 2008 to October 2016. We assessed the variation in the maximum forced expiratory volume in the first second (FEV1) before and after the treatment. RESULTS: Fifty-seven patients were included in this study. The variation in the FEV1 was -102.7 (149.6) mL/month before starting everolimus compared to -44.7 (109.6) mL/month within the first three months, +1.4 (63.5) mL/month until the sixth month, and -7.4 (46.2) mL/month until the twelfth month (p < 0.05). Glomerular filtrate remained unchanged after everolimus treatment [59.1 (17.5) mL/min per 1.73 m2 at baseline and 60.9 (19.6) mL/min per 1.73 m2, 57.7 (20.5) mL/min per 1.73 m2, and 57.3 (17.8) mL/min per 1.73 m2, at 1, 3, and 6 months, respectively] (p > 0.05). Everolimus was withdrawn in 22 (38.6%) patients. The median time to withdrawal was 14.1 (5.5-25.1) months. CONCLUSIONS: This study showed an improvement in FEV1 decline in patients with CLAD treated with everolimus. However, the drug was withdrawn in a high proportion of patients.

Inflammasome-Related Genetic Polymorphisms as Severity Biomarkers of COVID-19.

The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, IL18, NFKB1, ATG16L1, and MIF) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, and ATG16L1 were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19.

E-Selectin, ICAM-1, and ET-1 Biomarkers Address the Concern of the Challenging Diagnosis of Interstitial Lung Disease in Patients with Autoimmune Diseases.

Interstitial lung disease (ILD) constitutes the most critical comorbidity in autoimmune diseases (ADs) and its early diagnosis remains a challenge for clinicians. Accordingly, we evaluated whether E-selectin, ICAM-1, and ET-1, key molecules in endothelial damage, could be useful biomarkers for the detection of AD-ILD+. We recruited patients with rheumatoid arthritis (RA)-ILD+ (n = 21) and systemic sclerosis (SSc)-ILD+ (n = 21). We included comparison groups of patients: RA-ILD- (n = 25), SSc-ILD- (n = 20), and idiopathic pulmonary fibrosis (IPF) (n = 21). Serum levels of these proteins were determined by ELISA. E-selectin, ICAM-1, and ET-1 serum levels were increased in RA-ILD+ and IPF patients in comparison to RA-ILD- patients. Additionally, SSc-ILD+ and IPF patients exhibited higher ICAM-1 levels than those with SSc-ILD-. The ability of E-selectin, ICAM-1, and ET-1 to discriminate RA-ILD+ from RA-ILD- patients, and ICAM-1 to distinguish SSc-ILD+ from SSc-ILD- patients was confirmed using ROC curve analysis. Furthermore, elevated levels of ET-1 and E-selectin correlated with lung function decline in RA-ILD+ and SSc-ILD+ patients, respectively. In conclusion, our findings support the relevant role of E-selectin, ICAM-1, and ET-1 in RA-ILD+ patients as well as of ICAM-1 in SSc-ILD+ patients, constituting potential screening blood biomarkers of ILD in AD. Moreover, this study suggests ET-1 and E-selectin as possible indicators of worsening lung function in RA-ILD+ and SSc-ILD+ patients, respectively.

Angiogenic T Cells: Potential Biomarkers for the Early Diagnosis of Interstitial Lung Disease in Autoimmune Diseases?

(1) Background: We explored, for the first time, the contribution of angiogenic T cells (TAng) in interstitial lung disease associated to autoimmune disease (AD-ILD+) as potential biomarkers of the disease, evaluating their role in the underlying vasculopathy and lung fibrosis. Additionally, the relationship of TAng with clinical manifestations and cellular and molecular endothelial dysfunction-related biomarkers was assessed. (2) Methods: We included 57 AD-ILD+ patients (21 with rheumatoid arthritis (RA)-ILD+, 21 with systemic sclerosis (SSc)-ILD+ and 15 with other AD-ILD+) and three comparative groups: 45 AD-ILD- patients (25 RA-ILD- and 20 SSc-ILD-); 21 idiopathic pulmonary fibrosis (IPF) patients; 21 healthy controls (HC). TAng were considered as CD3+CD184+CD31+ by flow cytometry. (3) Results: A similar TAng frequency was found between AD-ILD+ and IPF, being in both cases lower than that observed in AD-ILD- and HC. A lower TAng frequency was associated with negative Scl-70 status and lower FEV1/FVC ratio in SSc-ILD+, as well as with men in RA-ILD+ and non-specific interstitial pneumonia radiological pattern in other AD-ILD+. No relationship between TAng and endothelial progenitor cells, endothelial cells and vascular endothelial growth factor gene expression and protein levels was disclosed. (4) Conclusions: Our findings suggest TAng as potential biomarkers for the early diagnosis of ILD in AD.

Elevated VCAM-1, MCP-1 and ADMA serum levels related to pulmonary fibrosis of interstitial lung disease associated with rheumatoid arthritis.

Introduction: Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD+. Methods: We included 21 RA-ILD+ patients and two comparative groups: 25 RA-ILD- patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR. Results: VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD+ patients in relation to RA-ILD- and IPF patients. Additionally, RA-ILD+ patients exhibited increased CCL2 (gene encoding MCP-1) and decreased PRMT1 (gene related to ADMA synthesis) mRNA expression in relation to RA-ILD- patients. A lower expression of VCAM1, CCL2, and PRMT1 was observed in RA-ILD+ patients when compared with those with IPF. Furthermore, MCP-1 serum levels and PRMT1 mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD+ patients. Conclusion: Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD+ from IPF, contributing to the early diagnosis of RA-ILD+.

Evaluation of Two Different CMV-Immunoglobulin Regimens for Combined CMV Prophylaxis in High-Risk Patients following Lung Transplant.

BACKGROUND: The clinical benefits of the common off-label use of cytomegalovirus (CMV)-specific immunoglobulin (CMV-Ig) combined with antivirals in organ transplantation have not been previously assessed. The objective was to compare the risk of CMV infection and other post-transplantation outcomes between two CMV-Ig prophylaxis regimens in lung transplant recipients; Methods: Retrospective study of 124 donor CMV positive/recipient negative (D+/R-) patients receiving preventive ganciclovir/valganciclovir for 12 months, of whom 62 received adjunctive CMV-Ig as per label indication (short regimen [SR-Ig]; i.e., 7 doses over 2.5 months) and were compared to 62 who received an extended off-label regimen (ER-Ig) consisting of 17 doses over one year after transplantation. RESULTS: The incidence of CMV infection or disease, acute rejection, chronic lung allograft dysfunction, and survival did not differ between the two CMV-Ig schedules. Although the time to the first CMV infection after transplantation was shorter in the ER-Ig than in the SR-Ig adjunctive group (log-rank: p = 0.002), the risk was independently predicted by antiviral cessation (odds ratio = 3.74; 95% confidence interval = 1.04-13.51; p = 0.030), whereas the CMV-Ig schedule had no effect. CONCLUSIONS: Extending the adjunctive CMV-Ig prophylaxis beyond the manufacturer's recommendations up to one year does not confer additional clinical benefits regarding lung post-transplantation outcomes.

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome.

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

Endothelial Progenitor Cells: Relevant Players in the Vasculopathy and Lung Fibrosis Associated with the Presence of Interstitial Lung Disease in Systemic Sclerosis Patients.

Endothelial progenitor cells (EPC), which are key effectors in the physiologic vascular network, have been described as relevant players in autoimmune diseases. We previously showed that EPC frequency may help to identify the presence of interstitial lung disease (ILD) in rheumatoid arthritis patients. Given that ILD constitutes the main cause of mortality in systemic sclerosis (SSc) patients, we aimed to determine the EPC contribution to the pathogenic processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC quantification was performed by flow cytometry on blood from 83 individuals: 21 SSc-ILD+ patients and subjects from comparative groups (20 SSc-ILD- and 21 idiopathic pulmonary fibrosis (IPF) patients and 21 healthy controls (HC)). EPC were considered as CD34+, CD45low, CD309+, and CD133+. A significant increase in EPC frequency was found in SSc-ILD+ patients when compared to HC (p < 0.001). SSc-ILD+ patients exhibited a higher EPC frequency than SSc-ILD- patients (p = 0.012), whereas it was markedly reduced compared to IPF patients (p < 0.001). EPC frequency was higher in males (p = 0.04) and negatively correlated to SSc duration (p = 0.04) in SSc-ILD+ patients. Our results indicate a role of EPC in the processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC frequency may be considered as a biomarker of ILD in SSc patients.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

Coexisting sarcoidosis and systemic lupus erythematosus: a case report and literature review.

The coexistence of sarcoidosis and SLE in the same patient has uncommonly been reported. Information on the epidemiology, clinical presentation, and management of this rare association is scarce. We report a 46-year-old Hispanic man who was recently diagnosed with concomitant SLE and sarcoidosis at our institution. A diagnosis of sarcoidosis was established due to the presence of dyspnea, fever, and malaise along with bilateral hilar lymphadenopathy and histological evidence of non-caseating granuloma. In addition, he fulfilled the American Rheumatism Association (ACR) criteria for SLE due to a history of photosensitivity, polyarthritis, lymphocytopenia, and positivity of ANA and anti-dsDNA antibodies. He was successfully treated with a combination of oral glucocorticoids, hydroxychloroquine, and methotrexate. In a further step, we conducted an extensive literature review to further investigate into the association of sarcoidosis and SLE. We identified 25 additional published cases. The concurrence of these two conditions may be more common than previously reported, mainly affecting young female adults in the fourth decade of life. The most common manifestation of sarcoidosis was mild pulmonary symptoms whereas SLE presentation was highly variable. Most patients were positive for anti-dsDNA antibodies. Different therapeutic strategies included oral glucocorticoids, hydroxychloroquine, conventional immunosuppressive drugs and, cyclophosphamide in severe cases. Our study reinforces the need of considering the potential concurrence of sarcoidosis and SLE. Clinicians should be aware of the potential presence of SLE in patients with a diagnosis of sarcoidosis presenting with cutaneous manifestations, cytopenia, renal involvement, and/or positivity for ANA and anti-dsDNA antibodies.

Methylprednisolone in adults hospitalized with COVID-19 pneumonia : An open-label randomized trial (GLUCOCOVID).

PURPOSE: To determine whether a 6-day course of methylprednisolone (MP) improves outcome in patients with severe SARS-CoV­2 (Corona Virus Disease 2019 [COVID-19]). METHODS: The study was a multicentric open-label trial of COVID-19 patients who were aged ≥ 18 years, receiving oxygen without mechanical ventilation, and with evidence of systemic inflammatory response who were assigned to standard of care (SOC) or SOC plus intravenous MP (40 mg bid for 3 days followed by 20 mg bid for 3 days). The primary outcome was a composite of death, admission to the intensive care unit, or requirement for noninvasive ventilation. Both intention-to-treat (ITT) and per protocol (PP) analyses were performed. RESULTS: A total of 91 patients were screened, and 64 were randomized (mean age70 ± 12 years). In the ITT analysis, 14 of 29 patients (48%) in the SOC group and 14 of 35 (40%) in the MP group suffered the composite endpoint (40% versus 20% in patients under 72 years and 67% versus 48% in those over 72 years; p = 0.25). In the PP analysis, patients on MP had a significantly lower risk of experiencing the composite endpoint (age-adjusted risk ratio 0.42; 95% confidence interval, CI 0.20-0.89; p = 0.043). CONCLUSION: The planned sample size was not achieved, and our results should therefore be interpreted with caution. The use of MP had no significant effect on the primary endpoint in ITT analysis; however, the PP analysis showed a beneficial effect due to MP, which consistent with other published trials support the use of glucocorticoids in severe cases of COVID-19.

HLA association with the susceptibility to anti-synthetase syndrome.

OBJECTIVE: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). METHODS: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. RESULTS: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P=1.56E-09, odds ratio-OR [95% confidence interval-CI]=2.54 [1.84-3.50] and 21.4% versus 5.5%, P=18.95E-18, OR [95% CI]=4.73 [3.18-7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P=0.0003, OR [95% CI]=0.48 [0.31-0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P=0.001, OR [95% CI]=2.54 [1.39-4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. CONCLUSIONS: Our results support the association of the HLA complex with the susceptibility to ASSD.

Endothelial Progenitor Cells as a Potential Biomarker in Interstitial Lung Disease Associated with Rheumatoid Arthritis.

Interstitial lung disease (ILD) increases morbidity and mortality in patients with rheumatoid arthritis (RA). Although the pathogenesis of ILD associated with RA (RA-ILD+) remains poorly defined, vascular tissue is crucial in lung physiology. In this context, endothelial progenitor cells (EPC) are involved in endothelial tissue repair. However, little is known about their implication in RA-ILD+. Accordingly, we aimed to investigate the potential role of EPC related to endothelial damage in RA-ILD+. EPC quantification in peripheral blood from 80 individuals (20 RA-ILD+ patients, 25 RA-ILD- patients, 21 idiopathic pulmonary fibrosis (IPF) patients, and 14 healthy controls) was performed by flow cytometry. EPC were considered as CD34+, CD45low, CD309+ and CD133+. A significant increase in EPC frequency in RA-ILD+ patients, as well as in RA-ILD- and IPF patients, was found when compared with controls (p < 0.001, p = 0.02 and p < 0.001, respectively). RA-ILD+ patients exhibited a higher EPC frequency than the RA-ILD- ones (p = 0.003), but lower than IPF patients (p < 0.001). Our results suggest that EPC increase may represent a reparative compensatory mechanism in patients with RA-ILD+. The degree of EPC frequency may help to identify the presence of ILD in RA patients and to discriminate RA-ILD+ from IPF.

Influence of MUC5B gene on antisynthetase syndrome.

MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.

Pulmonary Langerhans cell histiocytosis "de novo" after lung transplantation.

A pulmonary Langerhans cell histiocytosis is presented in a 40 year-old woman two years after bilateral lung transplantation for emphysema without any signs of Langerhans cells proliferation in the explanted lungs. A microsatellite molecular analysis showed the proliferating cells were generated in a recipient cellular clone. The patient did not quit smoking after transplantation. No signs of disease were detected in the implanted lungs before surgery. Strict control of immunosupressive drug levels stabilized the disease. A "de novo" monoclonal origin of stem cells, probably from the bone marrow is suggested. The reason she did not develop disease in the native lungs is unknown, although we suggest an interaction between tobacco or some other antigens and local cellular receptors.

Golimumab in uveitis previously treated with other anti-TNF-alpha drugs: a retrospective study of three cases from a single centre and literature review.

OBJECTIVES: The aim of this paper is to assess the clinical response to golimumab (GLM) in patients with non-infectious uveitis from a single centre that had previously been treated with other anti-TNF-α drugs. METHODS: A retrospective chart review was carried out of patients with immune-mediated uveitis refractory to standard synthetic immunosuppressive drugs who were treated with GLM at Hospital Universitario Marqués de Valdecilla, Santander (Spain). Patients were included in this study if they had previously been treated with other anti-TNF-α drugs. A literature review of patients with immune-mediated uveitis undergoing GLM therapy was conducted. RESULTS: Three patients (2 men and 1 woman) were included in this study. Two of them were refractory to other anti-TNF-α drugs. The median age of patients was 26 years (range 20-42). Uveitis was bilateral in two patients. The underlying diseases were uveitis associated with HLA-B27 and psoriasis in one case and sarcoidosis in the other two cases. Improvement of the main ocular parameters following GLM therapy was achieved in all cases. After a median follow-up of 3 (range 1-9) months using GLM therapy, none of the patients had experienced new relapses of uveitis. None of them had side effects during treatment with this drug. A literature review disclosed that our observations were in keeping with other reports that showed good response to GLM in 13 of 16 patients with immune-mediated uveitis refractory to other biologic agents. CONCLUSIONS: Although the follow-up was too short in our series, GLM could be an effective and safe therapy for the management of patients with uveitis previously treated with other anti-TNF-α drugs.