New-onset systemic lupus erythematosus following BNT162b2 mRNA COVID-19 vaccine: a case series and literature review.

Emerging data evaluated the possible link between the Coronavirus 19 (COVID-19) vaccine and acute flares of rheumatic autoimmune diseases. However, the association between the COVID-19 vaccine and the development of de-novo rheumatic autoimmune diseases remained unclear. We report the first case series of three male patients who developed new-onset systemic lupus erythematosus following receiving Pfizer BNT162b2 mRNA vaccination. The clinical characteristics share some similarities with drug-induced lupus. More patients with SLE following COVID-19 may be diagnosed in the future. Additional studies will provide more significant insights into the possible immunogenic influence of the COVID-19 vaccine.

Validation of Lung EpiCheck, a novel methylation-based blood assay, for the detection of lung cancer in European and Chinese high-risk individuals.

AIM: Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples. METHODS: A case-control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case-control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively). RESULTS: The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942. CONCLUSIONS: Lung EpiCheck demonstrated strong performance in lung cancer prediction in case-control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations.

Routine comprehensive Aspergillus screening of bronchoalveolar lavage samples in lung transplant recipients.

BACKGROUND: Invasive aspergillosis is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). Early diagnosis may improve outcome, yet is challenging. We assessed the diagnostic yield of a routine, comprehensive, prospectively employed Aspergillus screening strategy in LTRs. METHODS: During a 6-month period, all bronchoalveolar lavage (BAL) samples (including post-transplant surveillance) obtained from LTRs at our center were routinely tested for Aspergillus PCR, galactomannan (GM), and fungal culture. Invasive aspergillosis (IA) was defined using EORTC/MSG and ISHLT criteria for proven and probable aspergillosis. RESULTS: Ninety-five consecutive BAL samples were tested. PCR, GM, and fungal culture were positive in 28.4%, 30.6%, and 7.4%, respectively. Five cases of IA (two proven, three probable) were identified. Fungal culture failed to detect 40% of IA cases, which were detected by a positive PCR and/or GM. However, the majority of positive PCR samples represented colonization (59.3%). Sensitivity of PCR, GM, and culture for IA was 80%, 60%, and 60%, respectively, and specificity was 74%, 71%, and 96%. CONCLUSIONS: In LTRs, a routine prospectively employed screening strategy in which all BAL samples were screened for Aspergillus PCR and GM, detected aspergillosis cases that were otherwise missed by a false-negative fungal culture, but resulted in more cases of colonization being detected. Clinical judgment is thus warranted to avoid unnecessary treatment of colonization.

Lung transplantation in cystic fibrosis patients in Israel: The importance of ethnicity and nutritional status.

OBJECTIVES: To assess the characteristics that correlate with better outcomes after lung transplantation for patients with cystic fibrosis (CF). METHODS: We retrospectively reviewed the charts of all patients with CF who underwent lung transplantation between 1996 and 2014 at Rabin Medical Center, Israel. RESULTS: Fifty patients with CF underwent 55 lung transplantations. Eighteen patients (36%) died during the study period. Actuarial survival was 83%, 68%, 62%, and 39% at 1, 3, 5, and 10 years, respectively. Better survival correlated with: BMI at 6 months and 1 year after transplantation (P = .002 and P = .003, respectively), ischemic time of less than 300 minutes (P = .023), absence of liver disease (P = .012), and Jewish compared to Arab ethnicity (P = .007). Freedom from bronchiolitis obliterans syndrome (BOS) was 87%, 75%, and 72% at 1, 3, and 5 years, respectively. BOS was more common and appeared earlier in the Arab than in the Jewish population (P = .012, P = .007). Additionally, prolonged time free of BOS correlated with male gender (P = .039), older age (P < .001), absence of liver disease (P = .012), and higher BMI 1 year after transplantation (P < .001). CONCLUSIONS: Clinically important determinants for survival include BMI pre- and 1-year post-transplantation and improved freedom from BOS. Arab ethnicity correlated with higher incidence and earlier onset of BOS compared to Jewish ethnicity in Israel.

Survival following lung transplantation for artificial stone silicosis relative to idiopathic pulmonary fibrosis.

BACKGROUND: Silicosis is a progressive lung disease resulting from the inhalation of respirable crystalline silica. Lung transplantation is the only treatment for end-stage silicosis. The aim of this study was to analyze the survival experience following lung transplantation among patients with silicosis. METHODS: We reviewed data for all patients who underwent lung transplantation for silicosis and a matched group undergoing lung transplantation for idiopathic pulmonary fibrosis (IPF) at a single medical center between March 2006 and the end of December 2013. Survival was followed through 2015. RESULTS: A total of 17 lung transplantations were performed for silicosis among 342 lung transplantations (4.9%) during the study period. We observed non-statistically significant survival advantage (hazard ratio 0.6; 95%CI 0.24-1.55) for those undergoing lung transplantation for silicosis relative to IPF patients undergoing lung transplantation during the same period. CONCLUSIONS: Within the limits of a small sample, survival in silicosis patients following lung transplantation was not reduced compared to IPF. Am. J. Ind. Med. 60:248-254, 2017. © 2017 Wiley Periodicals, Inc.

Radiation exposure and attributed cancer risk following lung transplantation.

BACKGROUND: Lung transplant recipients are exposed to radiation from various imaging procedures during surveillance; however, the cumulative radiation exposure and subsequent cancer risk after lung transplantation is not known. METHODS: We included all patients who underwent lung transplantation at our institute since January 2000 and survived at least four-yr follow-up continued until March 21, 2012 or until death. We identified all procedures with radiation exposure and all malignancies that developed during the study period. Estimation of the effective dose exposure and subsequent cancer risk was derived from previous reports. RESULTS: The study included 107 patients. Mean follow-up was 6.49 ± 1.74 yr. Radiation exposure during mean follow-up was 137.8 mSv, and the total cumulative exposure over 11 yr reached 205.25 mSv. This represents an additional cancer risk of 0.55% and 0.82%, respectively. Twenty-four cases of cancer in 21 patients (19.6%) were identified. The difference between the radiation exposure in the patients who developed cancer and in the cancer-free patients was not statistically significant. CONCLUSION: Lung transplant recipients are exposed to 7.8 times greater radiation dose from medical imaging compared to the general population. Nevertheless, the lifetime increase in cancer risk due to radiation is small.

Renal function preservation with the mTOR inhibitor, Everolimus, after lung transplant.

Chronic kidney disease (CKD) is a common complication of calcineurin inhibitors (CNIs) in solid organ transplantation. Previous data suggest that the use of everolimus as an immunosuppressant drug leads to improvement in renal function. The aim of our study was to establish the effect of everolimus in combination with lower doses of CNIs on renal function among lung transplant recipients. Data regarding renal function and pulmonary function were collected from 41 lung transplanted patients in whom treatment was converted to a combination of everolimus with lower doses of CNIs. Patients transferred to everolimus and low dose CNIs showed an improvement in renal function. Patients who continued treatment with everolimus showed improvement in renal function, as opposed to patients who discontinued the treatment. Subjects without proteinuria at baseline showed a better improvement compared with subjects with proteinuria. The incidence of graft rejection did not increase. We concluded that a protocol that includes everolimus and lower doses of CNIs is effective for preserving renal function in lung transplant recipients with CKD. We also believe that an early implementation of everolimus, before proteinuria occurs or creatinine clearance is reduced, could lead to better outcomes.

Pulmonary Langerhans cell histiocytosis and diabetes insipidus in pregnant women: our experience.

Pulmonary Langerhans cell histiocytosis (PLCH) occurs predominantly in young adult smokers. Diabetes insipidus occurs in up to 15 % patients with PLCH. Information on PLCH in pregnancy is sparse, especially associated with diabetes insipidus. We report three patients with these conditions and describe the disease history and pregnancy outcomes.

Comparison between diffuse and partial involvement of thoracic lymph nodes on the outcome of sarcoidosis patients.

BACKGROUND AND AIM: Sarcoidosis is a systemic disease of unknown etiology with diverse clinical manifestations. Disease may resolve spontaneously or require immunosuppression to control progression. Currently, there is no predictive model to direct treatment, and management is guided by symptoms and functional impairment. This study examines the association between biopsy features and prognosis. METHODS: This is a retrospective population-based cohort study. New cases of biopsy-proven sarcoidosis were divided into two groups: those with diffuse thoracic lymph nodes (TLN) involvement, versus partial TLN involvement (Defined as Non-necrotizing granuloma (NNG) found in some but not all sampled TLN). We compared outcomes one year after diagnosis. We assessed the need for immunosuppression, the number of hospitalizations, and lung function deterioration. RESULTS: 77 cases were included in the final analysis. 48.1% demonstrated extensive TLN involvement, and 51.9% demonstrated partial or non-involvement of sampled TLN. The partial positive group had a more aggressive disease, reflected by a significantly higher need for steroid therapy in the first year after diagnosis (45.0% vs. 18.9% p=0.015). The number of hospitalizations and lung functions were not significantly different between groups. CONCLUSIONS: Our findings demonstrate a significantly increased need for steroidal therapy among sarcoidosis patients with a partial positivity of TLN. These findings suggest that the degree of TLN involvement can help predict worse outcome and guide therapeutic decisions.

Personalizing non-small cell lung cancer treatment through patient-derived xenograft models: preclinical and clinical factors for consideration.

PURPOSE: In the pursuit of creating personalized and more effective treatment strategies for lung cancer patients, Patient-Derived Xenografts (PDXs) have been introduced as preclinical platforms that can recapitulate the specific patient's tumor in an in vivo model. We investigated how well PDX models can preserve the tumor's clinical and molecular characteristics across different generations. METHODS: A Non-Small Cell Lung Cancer (NSCLC) PDX model was established in NSG-SGM3 mice and clinical and preclinical factors were assessed throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to create 20 patient-specific PDX models in NSG-SGM3 mice. Histopathological staining and Whole Exome Sequencing (WES) analysis were preformed to understand tumor heterogeneity throughout serial passages. RESULTS: The main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to the long duration of chemotherapy treatment, which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of the histological type and grade; however, WES analysis revealed genomic instability in advanced passages, leading to the inconsistencies in clinically relevant alterations between the PDXs and biopsies. CONCLUSIONS: Our study highlights the impact of multiple clinical and preclinical factors on the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs, and underscores the importance of considering these factors when guiding and evaluating prolonged personalized treatment studies for NSCLC patients in these models, as well as signaling the imperative for additional investigations to determine the full clinical potential of this technique.

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.

Transbronchial cryo-biopsy in lung transplantation patients: first report.

BACKGROUND AND OBJECTIVE: Transbronchial lung biopsies remain the gold standard to establish the presence of allograft rejection or infection after lung transplantation. The aim of this study was to evaluate the efficacy and safety of cryo-transbronchial biopsies (cryo-TBB) in lung transplantation patients. METHODS: Forty lung transplantation patients (mean age 58.3 years) underwent cryo-TBB, either routine post lung transplantation surveillance bronchoscopy (n = 27), or clinically indicated bronchoscopy (n = 13). During the procedure, two to three biopsy samples were taken. Procedure characteristics, complications and the diagnostic yield were compared with 40 matched controls who underwent conventional forceps-TBB. RESULTS: No major complications occurred in the cryo-TBB group. The mean diameter of the specimen taken by cryo-TBB was 10 mm(2) compared with only 2 mm(2) using forceps-TBB (P < 0.05). The increased size and quality of biopsy samples in the study group translated to a significant increase in the percentage of alveolated tissue (65% vs 34% respectively, P < 0.05) that enabled a clear histological detection of acute rejection (n = 4), pneumonitis (n = 3), diffuse alveolar damage (n = 1) and confident exclusion of acute rejection, infection or pneumonitis (n = 32). Fluoroscopy time was significantly shorter in the cryo-biopsy patients compared with controls (25 s vs 90 s, respectively, P < 0.05). CONCLUSIONS: Cryo-TBB for both surveillance and clinically indicated bronchoscopy in lung transplantation patients provides larger and more diagnostic lung parenchyma specimens with low complication rate and shorter intervention time than traditional forceps biopsies.

The impact of fluoroquinolone resistance of Gram-negative bacteria in respiratory secretions on the outcome of lung transplant (non-cystic fibrosis) recipients.

Bacterial airway colonization is frequent among lung transplant recipients. These patients are often treated with antibiotics, which may lead to selection of resistant bacteria. The purpose of this study was to assess whether antibiotic treatment causes acquisition of quinolone-resistant Gram-negative bacteria (QR-GNB), and the effect of such colonization on mortality and on lung rejection. We retrospectively examined data from non-cystic fibrosis, non-bronchiectases lung transplant recipients for antibiotic treatment, GNB in respiratory secretions, bronchiolitis obliterans syndrome (BOS), and mortality. Of 126 patients included, 86 patients had QR-GNB, 22 had quinolone-sensitive bacteria (QS-GNB), and 17 had no growth. Median antibiotic exposure, defined as the fraction of days with antibiotic treatment, was 2.8% in patients without growth, 11.1% in patients with QS-GNB (p=0.012), and 26% in patients with QR-GNB (p<0.0001). Age-adjusted mortality hazard ratio was 9.2 (95% CI 1.272-78.9) for patients with QR-GNB compared with QS-GNB. Age-adjusted hazard ratios for BOS was 3.7 (95% CI 1.33-10.3) for QR-GNB compared with QS-GNB. We found a positive correlation between antibiotic treatment and emergence of QR-GNB. Airway colonization with QR-GNB was significantly associated with mortality and with BOS. Further research is needed to determine whether a change in antibiotic subscription policy is required.

Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes.

The main cause of late morbidity and mortality after lung transplantation is bronchiolitis obliterans syndrome (BOS). This study assesses the prevalence of gastroparesis among lung-transplant recipients and its association with BOS. The files of 139 patients who underwent nuclear gastric emptying studies before and/or three and 12 months after lung transplantation were reviewed, and the correlation of gastric emptying time (GET) at each time point with the occurrence of acute rejection or BOS (stage 0p or higher) was evaluated. Delayed gastric emptying (DGE; t(1/2) > 90 min) was documented in 50% of patients before transplantation - 74% at three months and 63% at 12 months. Median pre-transplant t(1/2) was 108 min in patients who acquired BOS and 77 min in BOS-free patients (p = 0.022). Among patients with pre-transplant DGE, 58% were BOS-free at 24 months post-operatively and 37% at 36 months; corresponding rates in patients with normal motility were 78% and 63% (p = 0.084). On multiple regression analysis adjusting for other measures of upper gastrointestinal dysfunction, GET before or three months after transplantation was significantly associated with BOS (OR 1.05 [95% CI 1.01-1.09] and OR 1.001 [1.001-1.005] per minute t(1/2)). Gastroparesis is common in lung-transplant recipients and associated with the development of BOS.

Multidrug-resistant Klebsiella pneumoniae acquisition in lung transplant recipients.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a pathogen that emerged in the late twentieth century and was associated with significant morbidity and mortality. We report for the first time the outcomes of lung transplant recipients infected with CRKP or extended spectrum-ß lactamases K. pneumoniae (ESBL-KP). METHODS: Retrospective review of 136 lung transplant recipients who underwent transplantation between 2004 and 2007 in Rabin Medical Center, Israel. MAIN RESULTS: There were 52 episodes of positive cultures for K. pneumoniae (KP) in 136 recipients - of them 11 (8.1%) with CRKP, 12 (8.8%) with ESBL-KP, and 29 (21.3%) with carbapenem-sensitive ESBL-negative KP. Isolation of CRKP/ESBL-KP was associated with death in the cohort (p < 0.0001) as well as recipients' age at transplantation (p < 0.005). Time-dependent age-adjusted CRKP or ESBL-KP acquisition was an independent factor for death in patients after lung transplant, compared to patients without KP isolation or carbapenem-sensitive ESBL-negative KP (p < 0.0001). CONCLUSION: CRKP and KP-ESBL acquisition was associated with reduced survival among lung transplant recipients.

First Presentation of Systemic Lupus Erythematosus in a 24-Year-Old Male following mRNA COVID-19 Vaccine.

The SARS-CoV-2 viral pandemic has had an immeasurable global impact, resulting in over 5 million deaths worldwide. Numerous vaccines were developed in an attempt to quell viral dissemination and reduce symptom severity among those infected. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antinuclear autoantibodies (ANAs) with heterogenic clinical manifestations, secondary to immune complex deposition in a multitude of organ systems. There are scarcely reported cases of SLE development following COVID-19 mRNA vaccination. We present a case of a 24-year-old male without preexisting conditions or family history of autoimmune disorders, presenting with SLE following the first dose of the SARS-CoV-2 Pfizer-BioNTech mRNA vaccine.

Ambulatory rehabilitation improves exercise capacity in patients with pulmonary hypertension.

BACKGROUND: Rehabilitation is a central treatment modality for patients with chronic cardiopulmonary disease. Physical exertion for patients with pulmonary arterial hypertension (PAH) has typically been discouraged. Inpatient pulmonary rehabilitation has been shown to improve exercise capacity in patients with PAH. The present study aimed to evaluate outpatient pulmonary rehabilitation for patients with PAH. METHODS AND RESULTS: Twenty-two patients with PAH or chronic pulmonary thromboembolic disease were allocated to ambulatory rehabilitation (n = 11) or to the control group (n = 11). All patients were stable on PAH-specific medication. The rehabilitation group underwent 24 1-hour sessions of exercise training/rehabilitation over 12 weeks. Primary end points were change in 6-minute walking distance (6MWD) and peak oxygen uptake (VO(2)) on cardiopulmonary exercise testing. All of the patients assigned to rehabilitation and 9 control subjects completed the study. In the rehabilitation group, 6MWD increased by 32 m, and in the control group 6MWD decreased by 26 meters (P = .003). Peak VO(2) increased in the rehabilitation group by 1.1 mL kg(-1) min(-1) and decreased by 0.5 mL kg(-1) min(-1) in the control group (P < .05). Peak work rate during cardiopulmonary exercise test also increased in the rehabilitation group, with borderline significance (P = .051). Echocardiography and blood N-terminal pro-brain natriuretic peptide levels were unchanged. No adverse events occurred due to the rehabilitation program. CONCLUSIONS: Ambulatory rehabilitation is a safe and efficacious treatment for patients with pulmonary hypertension already on medical therapy. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov ID: NCT00544726.