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Background Aberrations in the coagulation system have been implicated in the pathogenesis of interstitial lung disease (ILD). Anticoagulants have been proposed as a potential therapy in ILD; however, a randomized controlled trial examining warfarin as a treatment for IPF was terminated early due to increased death rates. This has led some to speculate that warfarin specifically may be harmful in ILD, and use of direct oral anticoagulants (DOACs) could result in superior outcomes. Research Question The goal of this study was to delineate the relationship between anticoagulation and outcomes in patients with ILD through an analysis of the Pulmonary Fibrosis Foundation Patient Registry. Study Design and Methods An analysis of all patients in the Pulmonary Fibrosis Foundation Patient Registry was performed. Patients were stratified into three groups: no anticoagulation, DOAC use, or warfarin use. Survival was analyzed by using both Kaplan-Meier curves and Cox proportional hazards models. Results Of 1,911 patients included in the analysis, 174 (9.1%) were given anticoagulants; 93 (4.9%) received DOACs, and 81 (4.2%) received warfarin. There was a twofold increased risk of death or transplant for patients receiving DOACS; for warfarin, the risk was over two and half times greater. DOACs were not associated with an increased risk of mortality following adjustment for confounding variables. However, even after adjustment, patients given the anticoagulant warfarin remained at increased risk of mortality. In patients with IPF, warfarin was associated with reduced transplant-free survival, but DOACs were not. There was no statistically significant difference in survival between those receiving warfarin and those receiving a DOAC. Interpretation The need for anticoagulation is associated with an increased risk for death or transplant in patients with ILD, in both the IPF and non-IPF population. Further research is required to determine if warfarin and DOACs present varying safety profiles in patients with ILD.

Background: In the absence of legal provision for emergency use authorization, Nepal government approved convalescent plasma therapy (CPT) and remdesivir for investigational use to treat COVID-19. Methods: This prospective, multicentered, observational study describes the safety and outcomes of hospitalized CPT and remdesivir treated COVID-19 patients. The study enrolled 1315 patients from 31 hospitals across Nepal. Patients over 18 years age received remdesivir, CPT, or both. Clinical findings, lab results, adverse events, and outcomes were recorded. Findings: Patients were classified as having moderate (24.2%), severe (64%) or life-threatening (11.7%) COVID-19. Of 1083 patients with reported outcomes, 78.4% were discharged (74% in good condition, 4.4% with disability) and 21.6% died. Discharge rates were 84% for remdesivir only recipients (N=910), 39% for CPT only recipients (N=59), and 54.4% for CPT+REM (N=114) recipients. The vast majority of CPT and CPT+REM recipients had severe to life-threatening infections (CPT 98.3%; CPT+REM 92.1%) and were admitted to the ICU (CPT 91.8%; CPT+REM 94.6%) compared to REM alone recipients (73.3% and 57.5%, respectively). In a logistic model comparing death vs discharge and adjusted for age, gender, steroid use, and severity, the predicted margin for discharge was higher for remdesivir alone recipients (0.82; 95%CI 0.79-0.84) compared to CPT (0.58; 95%CI 0.47-0.70) or CPT+REM (0.67; 95%CI 0.60-0.74) recipients. Adverse events of Remdesivir and CPT were reported in

Purpose Prior studies have demonstrated that percentage donor-derived cell-free DNA (%dd-cfDNA) in lung transplant patients may serve as a noninvasive marker of allograft injury and aid in the detection of acute allograft rejection, infection and chronic lung allograft dysfunction (CLAD). Clinical interpretation of %dd-cfDNA values require an understanding of its normal biological variation in stable lung transplant patients in order to identify abnormal results that may indicate the presence of allograft dysfunction. This study establishes the biological variation and reference change values (RCV) of %dd-cfDNA in lung transplant patients using an analytically validated assay with an established analytic coefficient of variation (CVA) of 6.8%. Methods Levels of plasma %dd-cfDNA (Allosure®) were analyzed from a cohort of patients at 4 lung transplant centers using %ddcfDNA as a method to monitor for allograft rejection in place of surveillance transbronchial biopsy. Patients with stable allograft function and ≥ 3 %dd-cfDNA samples were included. Stable patients were defined as having no evidence of infection, rejection, symptoms or documented decline in forced expiratory volume in 1 second (FEV1) > 10% from baseline. The AlloSure assay, a next-generation sequencing-based approach, was used to measure %dd-cfDNA in the plasma. Intraindividual coefficient of variation (CVI), interindividual CV (CVG), the index of individuality (II) and the RCV were calculated. Results 35 patients with a combined 124 %dd-cfDNA samples were included in the final analysis. 57% were men, the mean age was 59 years and 77% had bilateral lung transplants. The median %dd-cfDNA was 0.31% (interquartile range 0.18% - 0.68%), the 97.5th percentile and 95th percentile were 1.3% and 1.0% respectively. In 30 patients with an average of 3.7 tests, the CVI was 25%, the CVG was 19%, the II was 1.3 and the RCV was 72%. Conclusion In stable lung transplant patients, fluctuations in %dd-cfDNA levels of up 72% or levels less than 1% are within normal biological variation. With further validation, these thresholds may be incorporated into surveillance monitoring algorithms to identify potentially abnormal results indicating allograft dysfunction.

Introduction L’interpretation des donnees radiologiques en association avec les donnees cliniques pourrait ameliorer la precision diagnostique dans la fibrose pulmonaire idiopathique (FPI). Dans cette hypothese, nous avons souhaite mettre en place un score base sur des parametres cliniques permettant d’evaluer la probabilite de FPI chez des patients se presentant pour le bilan d’une pneumopathie interstitielle diffuse (PID). Methodes Le modele de score clinique etait etabli par analyse des dossiers de patients s’etant presentes entre 2012 et 2019 au Inova Advanced Lung Disease Program (Fairfax, Virginie, USA) pour une PID. Seuls les patients avec un diagnostic etabli avec un haut degre de confiance et en accord avec les recommandations internationales sur la FPI ou les autres PID etaient inclus. 8 parametres cliniques etaient retenus pour la mise en place du modele. Le modele multivarie etait etabli par analyse des caracteristiques de la courbe ROC puis ensuite teste dans trois cohortes de validations internationales differentes. Resultats 844 patients atteints de PID et qui presentaient un diagnostic classable entre FPI (347, 41 %) ou PID non-FPI (497, 59 %) ont ete evalues pendant cette periode. Sur la base de rapports de cote calcules pour 8 parametres cliniques suivants, un index chiffre etait assigne a chaque variable: âge ( 80: +4), sujet masculin (+3), antecedent de tabagisme (+2), Caucasien (+2), antecedent familial de PID (+5), exposition respiratoire (−1), signe de connectivite (−3), crepitants velcro (+4). Le score final etait obtenu par addition des points et variait de −5 a 20. Ce score clinique presentait une precision diagnostique evaluee par l’aire sous la courbe (ASC) de 0,88. Un score de 5 points ou moins etait associe a une probabilite de FPI de 4 %, un score de 6–10: 29 %, 11–15: 75 % et > 15: 97 %. Les caracteristiques de la courbe ROC etaient comparable dans les cohortes internationales de validation (n = 694 patients, ASC: 0,87). Conclusion Ce modele de score clinique apparait comme un outil precis et simple pour estimer la probabilite pretest de FPI parmi les patients avec une PID. Son impact utilise en conjonction avec l’imagerie reste a determiner. Ce modele pourrait in fine etre utile pour augmenter le degre de confiance dans le diagnostic final, homogeneiser les DMD, diminuer le nombre de cas « inclassable » ou eviter le recours a une biopsie pulmonaire si la probabilite pretest de FPI etait elevee.

Purpose Prior observational data suggest that donor-derived cell-free DNA (dd-cfDNA) increases in lung transplant acute rejection and infection. The performance of dd-cfDNA in routine clinical care remains undefined. In response to the COVID-19 pandemic, to mitigate the risk of exposing patients to infection, four centers used dd-cfDNA for surveillance instead of surveillance bronchoscopy, providing a unique opportunity to assess the performance of dd-cfDNA in routine clinical care. Methods As part of routine care during the COVID-19 pandemic, four lung transplant centers implemented a home-based surveillance program using plasma dd-cfDNA (Allosure®) in preference to surveillance bronchoscopy. Based on prior data, dd-cfDNA > 1% triggered further work-up including bronchoscopy. dd-cfDNA testing was also performed in response to a decline in forced expiratory volume in 1 second (FEV1), symptoms or treatment follow up. Data was retrospectively analyzed from 4/1/2020 - 9/1/2020 to assess the performance of dd-cfDNA in diagnosing a composite of ACR, AMR and/or infection. Results 169 patients underwent 380 dd-cfDNA measurements over the study period. The mean age was 58.5 years, 54% of patients were male and 82% bilateral lung transplants. 99 (58%) patients were 1%. Of these, 19/31 (61%) had evidence of ACR, AMR or infection. 115 patients had surveillance levels that remained 1%). For diagnosis of ACR, AMR or infection in these patients, dd-cfDNA > 1% yielded a sensitivity of 84%, specificity of 77%, positive predictive value of 73% and negative predictive value of 87%. Conclusion In this study, dd-cfDNA identified ACR, AMR and/or infection in asymptomatic lung transplant patients that may not have been identified by clinically indicated biopsy alone. Low levels of dd-cfDNA may also be useful in ruling out AMR, ACR and/or infection, supporting its use as a potential non-invasive marker for surveillance monitoring.

Purpose The incidence of acute cellular rejection (ACR) in lung transplant recipients (LTRs) remains about 33% in the first-year post-transplant, the highest for any organ transplant. Although acute rejection frequently responds to treatment, at the present time there is no reliable biomarker to non-invasively monitor response to therapy after ACR treatment . We hypothesized %ddcfDNA levels following acute rejection treatment can predict response to therapy. Methods We retrospectively collected clinical and histopathology data on lung transplant recipients treated for ACR who underwent %ddcfDNA testing as part of clinical care between March 2020 and August 2020. Results We identified a total of 14 LTRs that were treated for ACR and had a %ddcfDNA value available. One patient had only one %ddcfDNA and was excluded from the analysis. 11/13 patients also had available %ddcfDNA values after treatment. 10/11 of these patients demonstrated a decline in %ddcfDNA level following treatment of rejection(figure 1) The mean reduction in %ddcfDNA after treatment was 55% (Log10 Ratio -0.35; 95% CI, 9% to 78%; p = 0.03). One patient had a significant increase in follow up %ddcfDNA level attributed to persistent ACR and antibody mediated rejection(AMR) requiring Anti-Thymocyte Globuline(ATG) treatment. Subsequent values for this patient also demonstrate that %ddcfDNA levels decrease following aggressive treatment of rejection. One patient(patient 6) had concurrent infection and rejection. Conclusion %ddcfDNA may to be a useful biomarker in evaluating allograft post rejection treatment. Persistent high levels are suggestive of ongoing ACR or AMR

Introduction Il n’existe pas d’echelle consensuelle pour evaluer la gravite de la maladie dans la fibrose pulmonaire idiopathique (FPI) bien qu’a ce titre, l’alteration fonctionnelle basee sur les epreuves fonctionnelles respiratoires (EFR) soit frequemment utilisee. Le but de cette etude etait de decrire les caracteristiques cliniques, fonctionnelles et evolutives des patients FPI presentant une alteration severe de leur fonction respiratoire. Methodes Tous patients presentant une FPI avec un deficit severe de sa fonction respiratoire, defini par un CVF ≤ 50 % et/ou une DLco ≤ 30 % de la theorique, evalue et pris en charge au Inova Advanced Lung Disease Program (Fairfax, Virginie, USA) entre 2011 et 2019 etaient inclus dans cette etude. Leurs caracteristiques demographiques, fonctionnelles ainsi que leur evolution et traitements etaient recueillis. Resultats 531 patients avec une FPI ont ete evalues durant cette periode parmi lesquels 185 (35 %) presentaient une alteration severe de leur fonction respiratoire a leur premiere visite (CVF ≤ 50 % et/ou DLco ≤ 30 %), tandis que 58 autres (11 %) franchissaient cette limite durant le suivi. L’âge moyen etait de 72 ± 8 ans ; la CVF initiale etait de 53 ± 17 % et la DL CO de 28 ± 9 % de la theorique. La distance moyenne au test de marche de 6 minutes (T6 M) etait de 304 ± 121 metres. 59 % des patients necessitaient une oxygenotherapie (groupe T6 M O2). On observait une faible correlation entre la distance parcourue au T6 M et la CVF % ou la DLco %. Les patients du groupe T6 M AA avaient une meilleure survie sans transplantation que ceux du groupe T6 M O2 (p = 0,002). Les patients pris en charge avant la disponibilite des antifibrosants (et non traites par ces molecules) presentaient un moins bon pronostic (diminution de la survie sans transplantation) que ceux traites par l’une des deux molecules antifibrosantes (n = 113) (log rank p Conclusion Les patients atteints de FPI evoluent frequemment vers une alteration severe de leur fonction respiratoire et celle-ci est faiblement correlee avec leur performance au T6 M. L’evaluation de la severite au cours de la FPI ne devrait pas uniquement se baser sur les capacites fonctionnelles, mais devrait egalement tenir compte du T6 M ainsi que de la necessite d’une oxygenotherapie additionnelle. L’utilisation des traitements antifibrosants dans cette population est associee a une amelioration du pronostic.

Purpose CMV infection is common among transplant recipients and may result in increased morbidity and mortality. Valganciclovir and ganciclovir are frequently used for viral prophylaxis or treatment. However, these agents can be difficult to tolerate due to myelosuppression. Letermovir, an anti-viral drug which inhibits CMV-terminase complex, has been demonstrated to reduce the risk of CMV infection in hematopoetic-cell transplantation. We sought to assess the utility of letermovir in thoracic organ recipients in whom valganciclovir and ganciclovir were not well tolerated or were ineffective due to resistance. Methods We examined our institutional experience with the use of letermovir for either CMV prophylaxis or treatment in heart and lung transplant recipients from February to September 2018. Results Nine total patients received letermovir during the study period (8 lung, 1 heart). Letermovir was administered for CMV prophylaxis in 8 instances and for treatment of CMV viremia in 2 instances (see Table). One patient received letermovir for both prophylaxis and treatment on temporally separate occasions. 3 of 8 (37.5%) of patients receiving letermovir for CMV prophylaxis developed viremia while on treatment. One patient treated for ganciclovir resistant CMV disease with letermovir had overt clinical failure with a sharp rise in serum CMV PCR. The other patient treated for low grade CMV viremia initially cleared but then relapsed with low grade viremia (CMV PCR 214). No major side effects were reported. 2 patients experienced minor side effects (1 edema, 1 fatigue). Conclusion Letermovir was well tolerated with only minor side effects reported in a population intolerant or resistant to conventional CMV prophylaxis and treatment. However, efficacy was poor, with a high rate of CMV viremia on therapy (50%). Further study of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients is nonetheless warranted to better characterize its potential role in this high risk population.

Purpose Immunosuppression after organ transplantation is typically protocol-driven and does not account for individual patient differences. Tacrolimus, the most common calcineurin inhibitor and the backbone of immunosuppression, is dosed based on trough levels but there is significant heterogeneity in dosing. Lung transplant recipients with pharmacogenomic variants impacting tacrolimus metabolism may require different dosing of the drug to achieve the same target level. Methods Blood samples collected from lung transplant recipients were analyzed using a comprehensive pharmacogenomic profile, MediMap™, developed by the Inova Genomics Laboratory. Baseline characteristics as well as data on tacrolimus levels and dosing were collected. Comparisons between those with and without identifiable genotypes that impact tacrolimus metabolism were performed. Results There were 59 lung transplant recipients with blood samples analyzed using MediMap™ testing. 16.9% patients were identified to have a genotype that predicted an altered response to tacrolimus, 25.4% to voriconazole, and 6.8% to both. Age, gender, and underlying lung disease were not different between the groups, however, there were more Caucasians among standard metabolizers compared to altered metabolizers (91.7% vs. 36.4%, p=0.0002). Those with altered tacrolimus metabolism required a higher daily dose at three months to achieve a therapeutic drug level compared to those without (5.5mg vs. 2.8mg, p=0.038) despite equal azole use between the groups. Time to initial therapeutic level after transplant surgery was 3.7 days vs. 2.8 days (p=0.11). All patients experienced a supratherapeutic tacrolimus level (>20ng/mL) in the first few months post-transplant, however the altered metabolizers had slightly more acute kidney injury than standard metabolizers (18% vs. 8.6%, p=0.24). Conclusion Knowledge of pharmacogenomic profile prior to transplant could inform initial dosing and potentially result in less subtherapeutic and supratherapeutic levels of tacrolimus. Indeed, better understanding of individual pharmacogenomic differences in tacrolimus and other commonly used medications post-transplant may prove invaluable in our quest to avoid unnecessary drug toxicity while optimizing long-term allograft and patient survival.

Chronic obstructive lung disease (COPD) is one of the most prevalent health conditions, and a major cause of morbidity and mortality around the globe. Once thought of primarily as a disease of men, COPD is now known to be increasingly prevalent among women. Although increasing tobacco consumption among women during the past several decades might explain some of this increase, the relationship may be more complex, including factors such as differential susceptibility to tobacco, anatomic and hormonal differences, behavioral differences, and differences in response to available therapeutic modalities. Moreover, women with COPD may present differently, may have a different pattern of comorbidities, and may have a better survival after acute exacerbations. Care providers continue to have a gender bias that may affect both diagnosis and treatment. Future work should focus on factors that lead to gender differences in COPD as well as gender-specific treatment strategies.

Chronic obstructive pulmonary disease represents a major cause of morbidity and mortality in industrialized and nonindustrialized countries. Although tobacco use remains the main factor associated with development of the disease, occupational risk factors represent an important and preventable cause. The most common occupationally related factors include exposure to organic dusts, metallic fumes, and a variety of other mineral gases and/or vapors. This article summarizes the literature on the subject and provides an update of the most recent advances in the field.

An 83-year-old man was transferred to our medical center with bilateral pneumothoraces. A biopsy of a nonhealing scalp lesion was done 4 weeks previously, and the specimen showed high-grade angiosarcoma. During the subsequent staging evaluation a week later, he was found to have asymptomatic bilateral pneumothoraces and multiple pulmonary cysts that were not metabolically active on 18 F-fluorodeoxyglucose (FDG)-PET scan. These findings were initially believed to be secondary to emphysema, and because of his absence of symptoms, the patient was sent home without intervention. However, several days later he developed a nonproductive cough with pleuritic chest pain and went to an outside ED. A chest radiograph again showed bilateral pneumothoraces, which resulted in placement of bilateral chest tubes with the subsequent transfer. His medical history was otherwise only remarkable for benign prostatic hypertrophy and cataracts. He admitted to smoking cigarettes remotely but denied fever, chills, leg swelling, palpitations, and syncope. He denied relevant occupational exposures, including asbestos.