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Single-center studies have suggested that up to 70% of adults with cystic fibrosis (CF) have lower than expected bone mineral density (BMD), substantially higher than the 25% prevalence reported from national registries. We determined the prevalence of low BMD in CF adults at our center and assessed risk factors for low BMD. This retrospective cohort study was conducted in all CF patients ≥18 years of age who had a dual-energy X-ray absorptiometry (DXA) scan performed at the Johns Hopkins Adult Cystic Fibrosis center between 2010 and 2018. Prevalence and incidence of low BMD during the study period were determined. Poisson regression based on generalized estimating equations and robust standard errors were used to evaluate selected risk factors and risk of disease progression. A total of 234 individuals underwent an initial DXA scan. At this scan, prevalence of low BMD was 52.6% (95% confidence interval [CI] 46.0-59.1). A total of 43.6% were at risk for CF-related low BMD (AR-CFLBMD) (95% CI 37.1-50.2) and 9.0% had CF-related low BMD (CFRLBMD) (95% CI 5.6-13.4). Of the 25 with normal BMD at initial scan and a subsequent follow-up scan, 8 (32.0%) progressed to AR-CFLBMD. Of the 53 with AR-CFLBMD on initial scan and a subsequent scan, 6 (11.3%) progressed to CFLBMD, 9 (17.0%) returned to normal BMD, and 38 (71.7%) remained AR-CFLBMD. Older age (relative risk [RR] = 1.01; 95% CI 1.00-1.01) and male sex (RR = 1.32; 95% CI 1.04-1.66) were associated with increased risk of low BMD, while higher forced expiratory volume over 1 second (FEV 1 %) predicted (RR = 0.99; 95% CI 0.99-1.00) and body mass index (BMI; RR = 0.97; 95% CI 0.94-1.00) were associated with lower risk for low BMD. The fact that more than half of all individuals were found to have lower than expected BMD suggests that the actual prevalence may be higher than currently reported in national registries. This supports the importance of universal bone health screening of all CF adults. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

Respiratory failure is a devastating complication of allogenic blood or marrow transplantation (BMT). Prior data suggest that respiratory failure occurs in 20% of BMT recipients and acute respiratory distress syndrome (ARDS) occurs in 15%. Nonmyeloablative (NMA) haploidentical BMT allows donor pool expansion and may decrease complications. Incidence, outcomes, and risk factors for respiratory failure after NMA haploidentical BMT are unknown. This study aimed to determine the incidence of respiratory failure after NMA haploidentical BMT and explore outcomes and risk factors for respiratory failure. In this single-center, retrospective study of all patients age >18 years undergoing NMA haploidentical BMT between 2004 and 2016, the primary outcome was respiratory failure, marked by the use of high-flow nasal cannula oxygen, noninvasive ventilation (NIV), or invasive mechanical ventilation (IMV) within 2 years after BMT. Respiratory failure incidence is reported as incidence rate ratio (IRR) with 95% confidence interval (CI). Unadjusted and multivariable Cox proportional hazards models with adjustment for a priori identified patient-level characteristics were used. Results are presented as hazard ratio (HR) with 95% CI. A total of 520 patients underwent NMA haploidentical BMT, of whom 82 (15.8%) developed respiratory failure (IRR, 0.114/person-year) at a median of 0.34 year (interquartile range, 0.06 to 0.75 year) after BMT. Older age (HR, 1.04; 95% CI, 1.02 to 1.07), transplantation for myelodysplastic syndrome (MDS) (HR, 1.99; 95% CI, 1.07 to 3.72), and parent donor (HR, 3.49; 95% CI, 1.32 to 9.26) were associated with an increased risk of respiratory failure, whereas higher pretransplantation lung diffusion capacity of carbon monoxide (DLCO; % of predicted) was associated with lower risk (HR, 0.98; 95% CI, 0.77 to 0.99). Sixty-one patients (11.7%) required IMV, and 30 were successfully extubated. Only 37 patients (7%) had ARDS. Of the 82 patients with respiratory failure, 43 (52.4%) died during index hospitalization and 61 (77.2%) died by 2 years post-transplantation. Only 40 (49%) had nonrelapse mortality. The incidence of respiratory failure and ARDS after NMA haploidentical BMT is modest at 15% by 2 years post-transplantation. Despite successful extubation in >50% of patients, respiratory failure, regardless of cause, is associated with a high rate of death by 2 years from both relapse and nonrelapse causes. Age, BMT for MDS, parental donor, and pretransplantation DLCO are risk factors for respiratory failure., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to assess the prognostic value of Neutrophil to Lymphocyte Ratio (NLR) on long-term outcomes and graft dysfunction after lung transplantation., Methods: We retrospectively reviewed all patients receiving a lung transplant at our institution from 2011 to 2014. The primary exposure was elevated NLR at the time of transplant, defined by NLR>4. The primary outcomes were graft failure and three-year all-cause mortality. Multivariate logistic regression and Kaplan-Meier survival analysis were used to analyze outcomes., Results: 95 patients were included. 40 patients (42%) had an elevated NLR. Elevated NLR was associated with graft failure (OR: 4.7 [1.2-18.8], p = 0.02), and three-year mortality (OR: 5.4 [1.3-23.2], p = 0.03) on multivariate logistic regression. Patients with elevated NLR demonstrated significantly lower survival on Kaplan-Meier analysis (50% versus 74%, p = 0.02). The c-statistic for our multivariate model was 0.91., Conclusion: Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation., Competing Interests: Declaration of competing interest All authors have contributed to the review and submission on this manuscript. None of the authors have personal conflict of interest nor have they received payments for the performance of this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history., Methods: We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period., Results: A total of 15 adult CF patients were identified with mean age of 44.1 years (SD ± 13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD ± 21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up., Conclusions: CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis., (Copyright © 2019. Published by Elsevier B.V.)

Rationale: In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor for use in patients with cystic fibrosis (CF). This drug targets the primary defect in the CFTR protein that is conferred by the F508del CFTR mutation., Objective: As there is limited experience with this therapy outside of clinical trials, this study aims to examine the clinical experience of this new drug in a population with CF., Results: Retrospective cohort study of individuals followed at the Johns Hopkins CF Center who initiated treatment with lumacaftor/ivacaftor. Patients were followed from 1 year before drug initiation to up to 11 months postinitiation. Key exclusion criteria include previous exposure to lumacaftor/ivacaftor through participation in a clinical trial. Of 116 individuals identified who started lumacaftor/ivacaftor treatment, 46 (39.7%) reported adverse effects related to lumacaftor/ivacaftor, with the vast majority (82.2%) being pulmonary adverse effects, and 20 (17.2%) discontinued lumacaftor/ivacaftor because of adverse effects. The mean change in FEV 1 % predicted was 0.11% (range: -39% to +20%; P = 0.9). Nineteen individuals had an FEV 1 % predicted of 40% or less before treatment, and there was a higher percentage of patients in this subgroup who reported adverse effects (57.9%) and a higher percentage of patients who discontinued lumacaftor/ivacaftor (31.6%). Female sex was associated with a higher odds of drug discontinuation (adjusted odds ratio, 3.12, 95% confidence interval, 1.04-9.38)., Conclusions: This study highlights the prevalence of adverse effects in a CF population newly exposed to lumacaftor/ivacaftor and demonstrates a relatively high rate of drug intolerance.

Rationale and Objectives: Noninfectious pulmonary complications are common among HIV-infected individuals and may be detected early by quantitative computed tomography (CT) scanning. The association of HIV disease markers with CT lung density measurement remains poorly understood., Materials and Methods: One hundred twenty-five participants free of spirometry-defined lung disease were recruited from a longitudinal cohort study of HIV-infected and HIV-uninfected individuals to undergo standardized CT scan of the chest. Parenchymal density for the entire lung volume was calculated using computerized software. Qualitative assessment of CT scans was conducted by two radiologists masked to HIV status. Linear regression models were developed to determine the independent association of markers of HIV infection on inspiratory scan mean lung density (MLD)., Results: HIV-infected participants had a significantly higher MLD (denser lung) compared to HIV-uninfected participants (-815 Hounsfield unit [HU] vs -837 HU; P = 0.002). After adjusting for relevant covariates, HIV infection was independently associated with 19.9 HU higher MLD (95% CI 6.04 to 33.7 HU; P = 0.005). In qualitative assessment, only ground glass attenuation and cysts were noted more commonly among HIV-infected individuals compared to HIV-uninfected individuals (34% vs 17% [P = 0.045] and 27% vs 10% [P = 0.03], respectively). No qualitative radiographic abnormalities attenuated the association between HIV infection and increased MLD., Conclusions: HIV infection is independently associated with increased lung density. Although qualitative CT abnormalities were common in this cohort, only ground glass attenuation and cysts were noted more frequently in HIV-infected participants, suggesting that the increased lung density observed among HIV-infected individuals may be associated with subclinical inflammatory lung changes., Competing Interests: The authors declare that there are no conflicts of interest for any author as it pertains to this manuscript., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Importance: The effect of prolonged graft ischemia (≥6 hours) on outcomes following lung transplantation is controversial., Objective: To evaluate the effect of prolonged total graft ischemia times on long-term survival rates and the development of primary graft failure (PGF) following lung transplantation., Design, Setting, and Participants: In this retrospective study, the United Network for Organ Sharing database was queried for adult patients who underwent lung transplantation from May 1, 2005, through December 31, 2011. Primary stratification by the presence of prolonged graft ischemia was performed. Kaplan-Meier estimates at 1 and 5 years were used to compare survival in the 2 cohorts. A multivariable Cox proportional hazards regression model was constructed to identify predictors of 1- and 5-year mortality. A risk-adjusted predictive model for the development of PGF was formulated in a similar fashion., Main Outcomes and Measures: The primary outcome of interest was 1- and 5-year survival. Secondary outcomes included PGF and other postoperative events, such as renal failure, biopsy-proven rejection, and stroke., Results: Of the 10,225 patients who underwent lung transplantation, 3127 (30.6%) had allografts exposed to prolonged ischemia. There was no difference in survival at 1 (83.6% [95% CI, 82.3%-84.9%] vs 84.1% [95% CI, 83.3%-85.0%]; P = .41) or 5 (52.5% [95% CI, 51.0%-54.0%] vs 53.5% [95% CI, 51.3%-55.6%]; P = .82) years between patients who received grafts that were or were not exposed to ischemia that lasted 6 hours or more, respectively. Prolonged graft ischemia did not independently predict 1- or 5-year mortality or the development of PGF (odds ratio, 1.11; 95% CI, 0.88-1.39; P = .37). Furthermore, prolonged ischemia did not independently predict 1-year (hazard ratio, 1.09; 95% CI, 0.97-1.22; P =.15) or 5-year (hazard ratio, 1.05; 95% CI, 0.98-1.14; P =.18) mortality or the development of PGF (odds ratio, 1.11; 95% CI, 0.88-1.39; P =.37)., Conclusions and Relevance: No association was found between prolonged total graft ischemia times and primary graft failure or survival following lung transplantation. Given the scarcity of organs and the paucity of suitable recipients, prolonged ischemia time should not preclude transplantation. It is, therefore, reasonable to consider extending the accepted period of ischemia to more than 6 hours in certain patient populations to improve organ use.

Background: Exhaled nitric oxide (FeNO), a marker of airway inflammation, is often elevated in lung transplant recipients (LTxRs) with acute rejection or infection. Isolated measurements in the setting of bronchiolitis obliterans syndrome have been variable. We sought to assess the utility of serial FeNO in predicting chronic allograft dysfunction or the presence of acute rejection or infection., Methods: Eighty-six LTxRs underwent 325 serial FeNO measurements at an expiratory flow rate of 50 ml/s. The change in FeNO (ΔFeNO) between two measurements obtained during a stable state (ΔFeNO-SS) was compared with ΔFeNO, where the first measurement was taken during a stable state and the second during an unstable state (defined as a subsequent decline in FEV1 > 10% over 3 months [ΔFeNO-SU]) or an acute complication (acute rejection, lymphocytic bronchiolitis or acute infection [ΔFeNO-SAC]). The median follow-up time after the baseline FeNO was 10 (range 3 to 25) months., Results: ΔFeNO-SS in 117 FeNO pairs was similar to ΔFeNO-SU in 26 pairs (2.1 ± 3 ppb vs 2.3 ± 4 ppb; p = 0.2). ΔFeNO-SAC in 17 pairs was markedly increased (27 ± 20 ppb; p < 0.001 vs ΔFeNO-SS). The area under the receiver-operating characteristic curve for ΔFeNO in detecting an acute complication was 0.93 (p < 0.001). By applying a cut-off of >10 ppb, the sensitivity and specificity was 82% and 100%, respectively, with positive and negative predictive values of 100% and 97.5%., Conclusions: Changes in FeNO may serve as a useful adjunct in the detection of acute complications after lung transplantation. In this limited analysis, ΔFeNO was not predictive of a subsequent decline in allograft function., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Rationale: As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD)., Objectives: To determine whether individuals with HIV-associated COPD exhibit dysregulated lung mucosal T-cell immunity compared with control subjects., Methods: Using flow cytometry, we evaluated peripheral blood and lung mucosal T-cell immunity in 14 HIV(+)COPD(+), 13 HIV(+)COPD(-), and 7 HIV(-)COPD(+) individuals., Measurements and Main Results: HIV(+)COPD(+) individuals demonstrated profound CD4(+) T-cell depletion with reduced CD4/CD8 T-cell ratios in bronchoalveolar lavage-derived lung mononuclear cells, not observed in peripheral blood mononuclear cells, and diminished CD4(+) T cell absolute numbers, compared with control subjects. Furthermore, HIV(+)COPD(+) individuals demonstrated decreased pulmonary HIV-specific and staphylococcal enterotoxin B-reactive CD4(+) memory responses, including loss of multifunctionality, compared with HIV(+)COPD(-) control subjects. In contrast, lung mucosal HIV-specific CD8(+) T-cell responses were preserved. Lung CD4(+) T cells from HIV(+)COPD(+) individuals expressed increased surface Fas death receptor (CD95) and programmed death-1, but similar bronchoalveolar lavage viral loads as control subjects. However, programmed death-1 expression inversely correlated with HIV-specific lung CD4(+)IFN-γ(+) T-cell responses, suggesting functional exhaustion. Moreover, lung CD4(+) T cells from HIV(+)COPD(+) patients demonstrated increased basal and HIV antigen-induced expression of the early apoptosis marker annexin V compared with control subjects, which was significantly attenuated with anti-Fas blockade. Lastly, lung mucosal, but not blood, CD4(+)/CD8(+) ratios from HIV(+) patients significantly correlated with the FEV1, but not in HIV(-)COPD(+) patients., Conclusions: Together, our results provide evidence for profound lung mucosal CD4(+) T-cell depletion via a Fas-dependent activation-induced cell death mechanism, along with impaired HIV-specific CD4(+) immunity as immunologic features of HIV-associated COPD.

This review of lung malignancies in human immunodeficiency virus (HIV) briefly highlights key epidemiologic and clinical features in the pulmonary involvement of AIDS-defining malignancies of Kaposi sarcoma and non-Hodgkin lymphoma. Then, focusing on non-AIDS defining lung cancer, the epidemiology and mechanisms, clinical presentation, pathology, treatment and outcomes, and prevention of HIV-associated lung cancer are discussed. Finally, the important knowledge gaps and future directions for research related to HIV-associated lung malignancies are highlighted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Acute kidney injury requiring renal replacement therapy (RRT) is associated with increased mortality after cardiac surgery. Studies examining the impact of RRT after lung transplantation (LTx) are limited. We evaluated risk factors and outcomes associated with RRT after LTx., Methods: We retrospectively reviewed all LTx recipients in the United Network for Organ Sharing database. Preoperative renal function was stratified by glomerular filtration rate (GFR) as determined by the Modification of Diet in Renal Disease formula (strata: ≥90, 60 to 90, and <60 mL · min(-1) · 1.73 m(-2)). Primary outcomes were 30-day, 1-year, and 5-year survival and need for post-LTx RRT. Risk adjusted multivariable Cox proportional hazards regression examined mortality. A multivariable logistic regression model evaluated risk factors for RRT., Results: From 2001 to 2011, 12,108 patients underwent LTx. After LTx, 655 patients (5.51%) required RRT. Patients requiring post-LTx RRT had decreased survival at 30 days (96.7% versus 76.0%, p < 0.001), 1 year (85.5% versus 35.8%, p < 0.001), and 5 years (56.4% versus 20.0%, p < 0.001). These differences persisted on multivariable analysis at 30 days (hazard ratio [HR] 7.98 [6.16 to 10.33], p < 0.001), 1 year (HR 7.93 [6.84 to 9.19], p < 0.001), and 5 years (HR 5.39 [4.75 to 6.11], p < 0.001). Preoperative kidney function was an important predictor of post-LTx RRT for a GFR of 60 to 90 (odds ratio 1.42 [1.16 to 1.75], p = 0.001) and a GFR less than 60 (odds ratio 2.68 [2.07 to 3.46], p < 0.001]. High center volume was protective., Conclusions: In the largest study to evaluate acute kidney injury after LTx, the incidence of RRT is 5.51%. The need for post-LTx RRT dramatically increases both short- and long-term mortality. Several variables, including preoperative renal function, are predictors of post-LTx RRT and could be used to identify transplant candidates at risk for acute kidney injury., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Persons infected with HIV have an elevated risk of lung cancer, but whether the increase simply reflects a higher smoking prevalence continues to be debated. This review summarizes existing data on the association of HIV infection and lung cancer, with particular attention to study design and adjustment for cigarette smoking. Potential mechanisms by which HIV infection may lead to lung cancer are discussed. Finally, irrespective of causality and mechanisms, lung cancer represents an important and growing problem confronting HIV-infected patients and their providers. Substantial efforts are needed to promote smoking cessation and to control lung cancer among HIV-infected populations.