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Lung transplantation provides a treatment option for many individuals with advanced lung disease due to cystic fibrosis (CF). Since the first transplants for CF in the 1980s, survival has improved and the opportunity for transplant has expanded to include individuals who previously were not considered candidates for transplant. Criteria to be a transplant candidate vary significantly among transplant programs, highlighting that the engagement in more than one transplant program may be necessary. Individuals with highly resistant CF pathogens, malnutrition, osteoporosis, CF liver disease, and other comorbidities may be suitable candidates for lung transplant, or if needed, multi-organ transplant. The transplant process involves several phases, from discussion of prognosis and referral to a transplant center, to transplant evaluation, to listing, transplant surgery, and care after transplant. While the availability of highly effective CF transmembrane conductance regulator (CFTR) modulators for many individuals with CF has improved lung function and slowed progression to respiratory failure, early discussion regarding transplant as a treatment option and referral to a transplant program are critical to maximizing opportunity and optimizing patient and family experience. The decision to be evaluated for transplant and to list for transplant are distinct, and early referral may provide a treatment option that can be urgently executed if needed. Survival after transplant for CF is improving, to a median survival of approximately 10 years, and most transplant survivors enjoy significant improvement in quality of life.

RATIONALE: Many lung transplant recipients with cystic fibrosis (CF) have low preoperative body mass index (BMI); however, post-transplant BMI recovery is not well understood. OBJECTIVES: To evaluate BMI recovery (⩾18.5 kg/m(2)) among CF lung transplant recipients with low preoperative BMI and to investigate the association of survival with BMI recovery. METHODS: The United Network for Organ Sharing and CF Foundation patient registries (June 2005–December 2016) were used to identify CF lung transplant recipients. Among recipients surviving ⩾1 year, Cox modeling compared post-transplant 1-year conditional survival between recipients with low (

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care. Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression. The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication. ispartof: J Cyst Fibros vol:22 issue:3 pages:374-380 ispartof: location:Netherlands status: published

The medical care of patients awaiting lung transplantation is complex and requires the treatment of active medical conditions, including lung disease, while at the same time maintaining candidacy for transplantation. Some medications that would otherwise be considered routine may create undesirable challenges or complications in the perioperative setting. Therefore, a comprehensive assessment of the risks and benefits of these medications must take into account both their potential utility in managing a patient's current disease state, as well as the risks of compromising postlung transplant outcomes. In this review, we summarize the available data regarding several medications that are commonly used to treat patients with a variety of lung diseases, but that may impact a patient's course on the waiting list or in the posttransplant period.

Systemic sclerosis (SSc) is a connective tissue disorder that results in fibrosis of the skin and visceral organs. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death amongst SSc patients. Racial disparity is noted in SSc as African Americans (AA) have a higher frequency and severity of disease than European Americans (EA). Using RNAseq, we determined differentially expressed genes (DEGs; q < 0.1, log2FC > |0.6|) in primary pulmonary fibroblasts from SSc lungs (SScL) and normal lungs (NL) of AA and EA patients to characterize the unique transcriptomic signatures of AA-NL and AA-SScL fibroblasts using systems-level analysis. We identified 69 DEGs in “AA-NL vs. EA-NL” and 384 DEGs in “AA-SScL vs. EA-SScL” analyses, and a comparison of disease mechanisms revealed that only 7.5% of DEGs were commonly deregulated in AA and EA patients. Surprisingly, we also identified an SSc-like signature in AA-NL fibroblasts. Our data highlight differences in disease mechanisms between AA and EA SScL fibroblasts and suggest that AA-NL fibroblasts are in a “pre-fibrosis” state, poised to respond to potential fibrotic triggers. The DEGs and pathways identified in our study provide a wealth of novel targets to better understand disease mechanisms leading to racial disparity in SSc-PF and develop more effective and personalized therapies.

Uncontrolled donation after cardiac death (uDCD) contributes little to ameliorating donor lung shortage due to rapidly progressive warm ischemia after circulatory arrest. Here, we demonstrated that nonhypoxia improves donor lung viability in a novel uDCD lung transplant model undergoing rapid ventilation after cardiac death and compared the evolution of ischemia-reperfusion injury to mice that underwent pulmonary artery ligation (PAL). The tolerable warm ischemia time at 37°C was initially determined in mice using a modified PAL model. The donor lung following PAL was also transplanted into syngeneic mice and compared with those that underwent rapid ventilation or no ventilation at 37°C before transplantation. Twenty-four hours following reperfusion, lung histology, [Formula: see text]/[Formula: see text] ratio, and inflammatory mediators were measured. Four hours of PAL had little impact on [Formula: see text]/[Formula: see text] ratio and acute lung injury score in contrast to significant injury induced by 5 h of PAL. Four-hour PAL lungs showed an early myeloid-dominant inflammatory signature when compared with naïve lungs and substantially injured 5 h PAL lungs. In the context of transplantation, unventilated donor lungs showed severe injury after reperfusion, whereas ventilated donor lungs showed minimal changes in [Formula: see text]/[Formula: see text] ratio, histologic score, and expression of inflammatory markers. Taken together, the tolerable warm ischemia time of murine lungs at 37°C can be extended by maintaining alveolar ventilation for up to 4 h. Nonhypoxic lung undergoing warm ischemia-reperfusion injury shows an early transcriptional signature of myeloid cell recruitment and extracellular matrix proteolysis before blood-gas barrier dysfunction and significant tissue damage.

Chronic lung allograft dysfunction is the major barrier to long-term survival in lung transplant recipients. Evidence supports type 1 alloimmunity as the predominant response in acute/chronic lung rejection, but the immunoregulatory mechanisms remain incompletely understood. We studied the combinatorial F-box E3 ligase system: F-box protein 3 (FBXO3; proinflammatory) and F-box and leucine-rich repeat protein 2 (FBXL2; anti-inflammatory and regulates TNFR-associated factor [TRAF] protein). Using the mouse orthotopic lung transplant model, we evaluated allografts from BALB/c → C57BL/6 (acute rejection; day 10) and found significant induction of FBXO3 and diminished FBXL2 protein along with elevated T-bet, IFN-γ, and TRAF proteins 1–5 compared with isografts. In the acute model, treatment with costimulation blockade (MR1/CTLA4-Ig) resulted in attenuated FBXO3, preserved FBXL2, and substantially reduced T-bet, IFN-γ, and TRAFs 1–5, consistent with a key role for type 1 alloimmunity. Immunohistochemistry revealed significant changes in the FBXO3/FBXL2 balance in airway epithelia and infiltrating mononuclear cells during rejection compared with isografts or costimulation blockade–treated allografts. In the chronic lung rejection model, DBA/2J/C57BL/6F1 > DBA/2J (day 28), we observed persistently elevated FBXO3/FBXL2 balance and T-bet/IFN-γ protein and similar findings from lung transplant recipient lungs with chronic lung allograft dysfunction versus controls. We hypothesized that FBXL2 regulated T-bet and found FBXL2 was sufficient to polyubiquitinate T-bet and coimmunoprecipitated with T-bet on pulldown experiments and vice versa in Jurkat cells. Transfection with FBXL2 diminished T-bet protein in a dose-dependent manner in mouse lung epithelial cells. In testing type 1 cytokines, TNF-α was found to negatively regulate FBXL2 protein and mRNA levels. Together, our findings show the combinatorial E3 ligase FBXO3/FBXL2 system plays a role in the regulation of T-bet through FBXL2, with negative cross-regulation of TNF-α on FBXL2 during lung allograft rejection.

Objectives Lung fibrosis is the leading cause of death in SSc, with no cure currently available. Antifibrotic Endostatin (ES) production does not reach therapeutic levels in SSc patients, suggesting a deficit in its release from Collagen XVIII by the main cleavage enzyme, Cathepsin L (CTSL). Thus, elucidating a potential deficit in CTSL expression and activity unravels an underlying molecular cause for SSc-driven lung fibrosis. Methods Fibrosis was induced experimentally using TGF-β in vitro, in primary human lung fibroblasts (pLFs), and ex vivo, in human lung tissues. ES and CTSL expression was quantified using ELISA, RT-qPCR, immunoblotting or immunofluorescence. Recombinant NC1-FLAG peptide was used to assess CTSL cleavage activity. CTSL expression was also compared between SSc vs normal (NL)-derived pLFs and lung tissues. Results ES levels were significantly reduced in media conditioned by TGF-β-induced pLFs. TGF-β-stimulated pLFs significantly reduced expression and secretion of CTSL into the extracellular matrix (ECM). CTSL was also sequestered in its inactive form into extracellular vesicles, further reducing its availability in the ECM. Media conditioned by TGF-β-induced pLFs showed reduced cleavage of NC1-Flag and reduced release of the antifibrotic ES fragment. SSc-derived pLFs and lung tissues expressed significantly lower levels of CTSL compared with NL. Conclusions Our findings identify CTSL as a protein protective against lung fibrosis via its activation of antifibrotic ES, and whose expression in SSc pLFs and lung tissues is suppressed. Identifying strategies to boost CTSL endogenous levels in SSc patients could serve as a viable therapeutic strategy.

Rationale: Tissue-resident memory T cells (TRM) play a critical role in the defense against inhaled pathogens. The isolation and study of human lung tissue–resident memory T cells and lung-resident...

The last decade has seen development of oral, small molecule therapies that address the basic cystic fibrosis transmembrane conductance regulator (CFTR) protein defect. Highly effective modulator treatment (HEMT) that is efficacious for a large majority of people living with cystic fibrosis (CF) promises to change the landscape of this chronic life-limiting disease. Some people living with CF have a CFTR genotype that renders them eligible for HEMT, but also have comorbidities that excluded them from the original Phase III clinical trials that led to US Food and Drug Administration approval. The purpose of this review is to address the use of HEMT in challenging situations, including initiation for those with advanced CF lung disease, and use after solid organ transplant, during pregnancy, and for individuals with CFTR-related disorders without a definitive diagnosis of CF.

Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes.We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA.DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ-specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ-specific DSAs (p = 0.03), and multiple DSAs (p = 0.02).Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ-specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.

Introduction Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) affect the quantity and/or function of CFTR protein reaching the cell surface. Ivacaftor, a CFTR potentiator that enhances chloride transport, increases the channel-open probability of normal and dysfunctional CFTR. Initially approved for people with CF (pwCF) with G551D-CFTR gating mutations, ivacaftor demonstrated clinical benefit in pwCF with other gating mutations and certain residual function mutations, including R117H-CFTR, in clinical studies. We evaluated the long-term safety and efficacy of ivacaftor in pwCF aged 6 years and older with non-G551D-CFTR ivacaftor-responsive mutations. Methods Efficacy and safety data from a phase 3, multicenter, open-label, extension study for participants from Study 110 (R117H-CFTR mutations), Study 111 (non–G551D-CFTR gating mutations), and Study 113 (n-of-1 pilot study in participants with residual CFTR function) were analyzed. Following washout from the randomized parent study, participants received oral ivacaftor 150 mg once every 12 h for 104 weeks. Results Forty-one of 121 participants completed treatment through 104 weeks; 59 participants who did not complete the extension study continued treatment with commercial ivacaftor. The most common adverse events were pulmonary exacerbation (46.3%) and cough (33.9%). Most treatment-emergent adverse events were mild/moderate in severity and consistent with manifestations of CF or the ivacaftor safety profile. Rapid, durable improvement occurred across all efficacy endpoints. Conclusions Ivacaftor was generally safe and well tolerated with no new safety concerns for up to 104 weeks in pwCF with ivacaftor-responsive mutations. The pattern of improvement across efficacy endpoints was durable and generally consistent with parent-study outcomes. Trial Registration NCT01707290

Background Reduced BMI is an absolute contraindication for lung transplantation (LTx) at most centers in the United States. The objective of this study was to quantify post-LTx survival of moderate to severely underweight patients with cystic fibrosis (CF) (BMI Methods Using United Network for Organ Sharing Registry data (undergoing transplant from June 2005-November 2015), Kaplan-Meier estimates of median posttransplant survival were calculated for all patients with CF, COPD, and idiopathic pulmonary fibrosis (IPF), as well as low and normal weight CF subgroups. Cox regression modeling stratified according to transplant center assessed risk of posttransplant mortality in recipients with CF and a BMI Results Median posttransplant survival (95% CI) for CF, COPD, and IPF was 7.9 (7.2-8.6), 5.9 (5.6-6.2), and 5.5 (5.2-5.8) years, respectively. Although an absolute decrease was noted in posttransplant survival for recipients with CF and a BMI Conclusions Transplant recipients with CF and a BMI

Deep vein thrombosis (DVT) remains a common complication following lung transplantation despite universal routine DVT screening. Moreover, many of the previously reported risk factors are incompletely defined. We sought to explore the influence of DVT screening and to more definitively assess predisposing risk factors.A single-institution, retrospective, cohort study of 1141 patients undergoing lung transplantation from January 1, 2005, to December 31, 2014, was performed evaluating for the rate of DVT. Patients were given prophylactic subcutaneous heparin postoperatively. DVT events were noted if they occurred before 90 days after transplant. We compared DVT rates before and after 2008 when universal screening was implemented. We also evaluated the timing of DVT event and location (above the knee vs below the knee). DVTs were treated with standard anticoagulation therapy or an inferior cava filter when patients were unable to tolerate anticoagulation treatment. Univariable and multivariable models were used to identify risk factors for occurrence. A propensity match was performed to match groups across the eras, and a Cox regression was performed to identify differences in 1-year survival trajectory between cohorts.The rates of DVT before and after routine screening were 8.8% (36 DVT out of 412 transplants) and 17.3% (126 out of 729 transplants), respectively. These 2 rates were significantly different (P .01); moreover, the observed DVT incidence per year was not significantly different across the 6 years after universal DVT screening was implemented (P .90 for all comparisons). Observed DVT incidence at day 0 and day 14 were 3.8% and 3.8%, respectively, for the cohort before DVT protocols were established. Observed DVT incidence for the cohort after protocols were established at the same time points was 8.7% and 3.7%, respectively. Univariable analysis revealed that significant factors associated with a DVT include hypercholesterolemia (odds ratio [OR], 6.90; 95% confidence interval [CI], 1.82-26.13; P .01), the number of days in the intensive care unit (OR, 1.03; 95% CI, 1.00-1.01; P .01), and the length of stay in the hospital (OR, 1.01; 95% CI, 1.01-1.02; P .01), whereas having quit smoking (vs never smoked) was associated with a decrease in DVT development (OR, 0.50; 95% CI, 0.33-0.75; P .01). Multivariable analysis revealed 2 significant variables: hypercholesterolemia (OR, 8.13; 95% CI, 1.22-54.37; P = .03) and length of stay (OR, 1.03; 95% CI, 1.01-1.05; P .01). There was a trend for better 1-year survival in the post-2008 era (Exp[β], 1.49; P = .09).The rate of DVT diagnosis significantly increased after universal DVT screening was implemented. Furthermore, those patients undergoing lung transplantation with extended length of stay and hypercholesterolemia were prone to increased rates of DVT. There was a trend toward better 1-year survival in DVT-screened patients, suggesting DVT screening may result in beneficial outcomes.

RATIONALE: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. OBJECTIVES: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. METHODS: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. MEASUREMENTS AND MAIN RESULTS: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4(+) lymphopenia predominated, with lower CD4(+)/CD8(+) ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4(+) T-cell responses to Spike-1 (S1) produced increased in vitro TNF-alpha (tumor necrosis factor-alpha) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4(+) TNF-alpha(+) T-cell responses inversely correlated with absolute CD4(+) counts from patients with severe COVID-19 (n = 76; R = - 0.797; P < 0.0001). In vitro TNF-alpha blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4 (+) T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFKB signaling in S1-stimulated CD4(+) cells with infliximab treatment. We also evaluated BAL and lung explant CD4(+) T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-alpha compared with peripheral blood mononuclear cells. CONCLUSIONS: Together, our findings show CD4(+) dysfunction in severe COVID-19 is TNF-alpha/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-alpha blockade may be beneficial in severe COVID-19.

Pseudomonas aeruginosais the most prevalent bacterial species that contribute to cystic fibrosis (CF) respiratory failure. The impaired function of CF transmembrane conductance regulator leads to abnormal epithelial Cl–/HCO3–transport and acidification of airway surface liquid. However, it remains unclear why the CF lung is most commonly infected byPseudomonas aeruginosaversus other pathogens. We carried out studies to investigate if lower pH helpsPseudomonas aeruginosaadapt and thrive in the CF-like acidic lung environment. Our results revealed thatPseudomonas aeruginosagenerally forms more biofilm, induces antibiotic resistance faster in acidic conditions, and can be reversed by returning the acidic environment to physiologically neutral conditions.Pseudomonas aeruginosaappears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronicPseudomonas aeruginosainfection and colonization.

Although the incidence of bronchial dehiscence following lung transplantation has decreased significantly due to improvements in perioperative managements and surgical techniques, it remains a devastating postoperative complication associated with high morbidity and mortality.We retrospectively reviewed 811 lung transplantation performed at our institution between January 2011 and December 2020. Bronchial dehiscence was confirmed with flexible bronchoscopy, computed tomography (CT) scan, or clinical findings grade using International Society for Heart and Lung Transplantation recommendations.Bronchial dehiscence was diagnosed in 38 patients (4.7%). The overall survival rates of the patients with bronchial dehiscence were significantly worse than those of the patients without bronchial dehiscence (p = .003). Multivariate analysis identified use of our basiliximab induction protocol (odds ratio = 3.03, p = .008) as an independent predictive factor of postoperative airway dehiscence in our multivariable model, along with total ventilator duration (odds ratio = 1.02, p = .002).Based on our analysis, patients that underwent our basiliximab induction protocol for lung transplantation experienced a higher rate of postoperative bronchial dehiscence when compared with patients who receive alemtuzumab induction. We believe this may be associated with a higher steroid exposure in this population. Additional studies are necessary to further characterize the relationship between different induction protocols and bronchial dehiscence following transplantation.

Acute cellular rejection is common after lung transplantation and is associated with an increased risk of early chronic rejection. We present combined single cell RNA and T cell receptor sequencing on recipient derived T cells obtained from the bronchoalveolar lavage of three lung transplant recipients with acute cellular rejection and compare them with T cells obtained from the same three patients after clinical treatment of rejection with high-dose, systemic glucocorticoids. At the time of acute cellular rejection, we find an oligoclonal expansion of cytotoxic CD8+T cells, that all persist as tissue resident memory T cells following successful treatment. Persisting CD8+allograft-resident T cells have reduced gene expression for cytotoxic mediators following therapy with glucocorticoids. This clonal expansion is discordant with circulating T cell clonal expansion at the time of rejection, suggesting in-situ expansion. These findings pose a potential biological mechanism linking acute cellular rejection to chronic allograft damage.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared to recovered, mild disease (p+ T cell responses to Spike-1(S1) produced increased in vitro TNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19.One Sentence SummaryAutocrine TNF-α/TNFRI regulates CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease.

Cardiopulmonary bypass and extracorporeal membrane oxygenation are commonly used adjuncts to lung transplantation. These techniques are not without associated morbidity and mortality, and the surgeon must be aware of the possibility of aberrant anatomy that could lead to vascular injury during cannulation. In this report, we describe a patient with congenital absence of the inferior vena cava undergoing lung transplantation who required perioperative cardiopulmonary support. A percutaneous dual lumen cannula, Protek Duo, was connected in an Oxy-RVAD configuration to provide right ventricular and oxygenation support both intraoperatively and postoperatively to this patient.

Ivacaftor is a drug that was recently approved by the U.S. Food and Drug Administration for the treatment of patients with cystic fibrosis (CF) and at least one copy of the G511D mutation in the CFTR (CF transmembrane conductance regulator) gene. The transcriptomic effect of ivacaftor in patients with CF remains unclear. Here, we sought to examine whether and how the transcriptome of patients is influenced by ivacaftor treatment, and to determine whether these data allow prediction of ivacaftor responsiveness. Our data originated from the G551D Observational Study (GOAL). We performed RNA sequencing (RNA-seq) on peripheral blood mononuclear cells (PBMCs) from 56 patients and compared the transcriptomic changes that occurred before and after ivacaftor treatment. We used consensus clustering to stratify patients into subgroups based on their clinical responses after treatment, and we determined differences between subgroups in baseline gene expression. A random forest model was built to predict ivacaftor responsiveness. We identified 239 genes (false discovery rate < 0.1) that were significantly influenced by ivacaftor in PBMCs. The functions of these genes relate to cell differentiation, microbial infection, inflammation, Toll-like receptor signaling, and metabolism. We classified patients into "good" and "moderate" responder groups based on their clinical response to ivacaftor. We identified a panel of signature genes and built a statistical model for predicting CFTR modulator responsiveness. Despite a limited sample size, adequate prediction performance was achieved with an accuracy of 0.92. In conclusion, for the first time, the present study demonstrates profound transcriptomic impacts of ivacaftor in PBMCs from patients with CF, and provides a pilot statistical model for predicting clinical responsiveness to ivacaftor before treatment.

Background Chronic rhinosinusitis (CRS) is a significant manifestation of cystic fibrosis (CF) with wide-ranging symptom and disease severity. The goal of the study was to determine clinical variables that correlate with outcome measures of disease severity. Methods A prospective, longitudinal, observational study of 33 adults with symptomatic CRS treated in a CF-focused otolaryngology clinic was performed. Symptom severity, the presence of rhinosinusitis exacerbations, and endoscopic appearance were assessed, and regression analysis was used to determine clinical predictors of disease outcome. Results Thirty-three adults with CF-CRS were included in the study and followed for a mean of 15 months. Rhinosinusitis exacerbations occurred in 61% of participants during the study, and female sex increased the odds of presenting with an exacerbation visit. Sinus disease exacerbations were associated with an odds ratio of 2.07 for presenting with a pulmonary exacerbation at the next visit. CF-related diabetes was found to be associated with worse symptoms and endoscopic appearance. Infection with Staphylococcus aureus predicted worsening of symptoms, whereas infections with Pseudomonas aeruginosa improved over time. Allergic rhinitis was associated with worse endoscopic appearance, and nasal steroid use was associated with improved endoscopic appearance. Conclusion Sex, CF-related diabetes, sinonasal infection status, allergic rhinitis, and nasal steroid use may all modulate severity of CF-CRS in adults. Sinusitis exacerbation may be a precursor to pulmonary exacerbation.

Idiopathic pulmonary fibrosis (IPF) pathogenesis has been postulated to involve a variety of mechanisms associated with the aging process, including loss of protein homeostasis (proteostasis). Heat shock proteins are cellular chaperones that serve a number of vital maintenance and repair functions, including the regulation of proteostasis. Previously published data have implicated heat shock protein 70 (Hsp70) in the development of pulmonary fibrosis in animal models. We sought to identify alterations in Hsp70 expression in IPF lung. Hsp70 mRNA and protein were decreased in primary fibroblasts cultured from IPF versus normal donor lung tissue. In addition to cultured fibroblasts, Hsp70 expression was decreased in intact IPF lung, a stressed environment in which upregulation of protective heat shock proteins would be anticipated. In support of a mechanistic association between decreased Hsp70 and fibrosis, cultured primary lung fibroblasts deficient in Hsp70 secreted increased extracellular matrix proteins. Treatment of primary normal human lung fibroblasts in vitro with either of the profibrotic molecules IGFBP5 (insulin-like growth factor-binding protein 5) or transforming growth factor-β1 downregulated Hsp70, suggesting Hsp70 is a downstream target in the fibrotic cascade. Hsp70-knockout mice subjected to an inhalational bleomycin model of pulmonary fibrosis demonstrated accelerated fibrosis versus wild-type control animals. We therefore conclude that reduced Hsp70 protein contributes to fibrosis and that interventions aimed at restoring normal expression of Hsp70 represent a novel therapeutic strategy for pulmonary fibrosis.

Objective Provide recommendations to the cystic fibrosis (CF) community to facilitate timely referral for lung transplantation for individuals with CF. Methods The CF Foundation organized a multidisciplinary committee to develop CF Lung Transplant Referral Consensus Guidelines. Three workgroups were formed: timing for transplant referral; modifiable barriers to transplant; and transition to transplant care. A focus group of lung transplant recipients with CF and spouses of CF recipients informed guideline development. Results The committee formulated 21 recommendation statements based on literature review, committee member practices, focus group insights, and in response to public comment. Critical approaches to optimizing access to lung transplant include early discussion of this treatment option, assessment for modifiable barriers to transplant, and open communication between the CF and lung transplant centers. Conclusions These guidelines will help CF providers counsel their patients and may reduce the number of individuals with CF who die without consideration for lung transplant.

Thrombocytopenia is associated with worse outcomes in patients with acute respiratory distress syndrome, which is most commonly caused by infection and marked by alveolar–capillary barrier disruption. However, the mechanisms by which platelets protect the lung alveolar–capillary barrier during infectious injury remain unclear. We found that natively thrombocytopenic Mpl−/− mice deficient in the thrombopoietin receptor sustain severe lung injury marked by alveolar barrier disruption and hemorrhagic pneumonia with early mortality following acute intrapulmonary Pseudomonas aeruginosa (PA) infection; barrier disruption was attenuated by platelet reconstitution. Although PA infection was associated with a brisk neutrophil influx, depletion of airspace neutrophils failed to substantially mitigate PA-triggered alveolar barrier disruption in Mpl−/− mice. Rather, PA cell-free supernatant was sufficient to induce lung epithelial cell apoptosis in vitro and in vivo and alveolar barrier disruption in both platelet-depleted mice and Mpl−/− mice in vivo. Cell-free supernatant from PA with genetic deletion of the type 2 secretion system, but not the type 3 secretion system, mitigated lung epithelial cell death in vitro and lung injury in Mpl−/− mice. Moreover, platelet releasates reduced poly (ADP ribose) polymerase cleavage and lung injury in Mpl−/− mice, and boiling of platelet releasates, but not apyrase treatment, abrogated PA supernatant–induced lung epithelial cell cytotoxicity in vitro. These findings indicate that while neutrophil airspace influx does not potentiate infectious lung injury in the thrombocytopenic host, platelets and their factors protect against severe pulmonary complications from pathogen-secreted virulence factors that promote host cell death even in the absence of overt infection.

The insulin‐like growth factor (IGF) system plays an important role in variety cellular biological functions; we previously reported levels of IGF binding proteins (IGFBP)‐3 and ‐5 are increased in dermal and pulmonary fibrosis associated with the prototypic fibrosing disease systemic sclerosis (SSc), induce extracellular matrix (ECM) production, and promote fibrosis. We sought to examine the effects of another member of the family, IGFBP‐4, on ECM production and fibrosis using cell‐based, ex vivo organ culture and in vivo mouse lung fibrosis models. IGFBP‐4 mRNA levels were significantly decreased in pulmonary fibroblasts of patients with SSc. ECM components were significantly reduced by endogenous and exogenous IGFBP‐4. IGFBP‐4 also blocked TGF‐β–induced ECM production, and inhibited ECM production ex vivo in human lung and skin in organ culture. In vivo, IGFBP‐4 reduced bleomycin‐induced collagen production and histologic evidence of fibrosis. Silencing IGFBP‐4 expression to mimic levels observed in SSc lung fibroblasts resulted in increased ECM production. IGFBP‐4 reduced mRNA and protein levels of the chemokine receptor CXCR4 and the profibrotic factor CTGF. Furthermore, CTGF silencing potentiated the antifibrotic effects of IGFBP‐4. Reduced IGFBP‐4 levels in SSc lung fibroblasts may contribute to the fibrotic phenotype via loss of IGFBP‐4 antifibrotic activity.

Background: Hypogammaglobulinemia (HGG), immunoglobulin G (IgG) Materials and Methods: This single-center retrospective cohort study of adult lung recipients evaluated 3 groups, no, untreated (u), or treated (t) HGG at first IgG administration or a matched time posttransplant. Primary outcome was freedom from allograft dysfunction. Secondary outcomes included development of advanced dysfunction, rejection, infection burden, and mortality. Results: Recipients included 484 (no HGG: 76, uHGG: 192, tHGG: 216). Freedom from chronic allograph dysfunction was highest in the non-HGG group 2 years post-enrollment (no HGG 77.9% vs uHGG 56.4% vs tHGG 52.5%; P = .002). Freedom from advanced dysfunction was significantly different 2 years post-enrollment (no HGG 90.5% vs uHGG 84.7% vs tHGG 75.4%; P = .017). Patients without HGG and those with uHGG had less mortality at 2 years post-enrollment (no HGG 84.2% vs uHGG 81.3% vs tHGG 64.8%; P < .001). Gram-negative pneumonias occurred more often in the tHGG group ( P = .02). Conclusions: Development of chronic lung allograft dysfunction, patient survival, rejection burden, and key infectious outcomes in lung transplant recipients were still problematic in the context of on-demand IgG therapy. Prospective studies are warranted.

CFTR function is required for normal mucociliary clearance (MCC) and cough-assisted clearance (CC). Lumacaftor-ivacaftor is approved for use in people with cystic fibrosis (CF) carrying two copies of F508del-CFTR. In this observational study performed at four study sites, we characterized the effect of lumacaftor-ivacaftor on mucociliary and cough clearance and related this to other clinical and research endpoints after one month of treatment. Twenty-five adolescents and adults were enrolled. No effect on whole lung MCC was observed, but CC was significantly increased. Sweat chloride improved by 18 mEq/L in this group, indicating a modest restoration of CFTR activity, but no demonstrable change in FEV1 or lung clearance index was observed. We speculate that the modest effect of lumacaftor-ivacaftor on CFTR function was insufficient to yield an improvement in MCC.

A role for hereditary influences in the susceptibility for chronic obstructive pulmonary disease (COPD) is widely recognized. Cytotoxic lymphocytes are implicated in COPD pathogenesis, and functions of these leukocytes are modulated by interactions between their killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA)-Class I molecules on target cells. We hypothesized HLA-Class I and KIR inheritance affect risks for COPD. HLA-Class I alleles and KIR genotypes were defined by candidate gene analyses in multiple cohorts of COPD patients (total n=392) and control smokers with normal spirometry (total n=342). Compared to controls, COPD patients had over-representations of HLA-C*07 and activating KIR2DS1, with under-representations of HLA-C*12. Particular HLA-KIR permutations were synergistic; e.g. the presence of HLA-C*07 + KIR2DS1 + HLA-C12null vs. HLAC*07null + KIR2DS1null + HLA-C12 was associated with COPD, especially among HLA-C1 allotype homozygotes (OR=18.5, 95%CI=3.7-90.9, p