Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Integrating anatomo-physiological changes and pharmacogenomics in anti-infective therapy management: is it a major concern?

Success of anti-infective therapy is a major challenge in some patients given anatomo-physiological changes and genetic variations. In this case anecdote, we report the management strategy of a patient suffering from chronic pulmonary aspergillosis in a context of anorexia nervosa and genetic polymorphism.

EG-VEGF, BV8, and their receptor expression in human bronchi and their modification in cystic fibrosis: Impact of CFTR mutation (delF508).

Enhanced lung angiogenesis has been reported in cystic fibrosis (CF). Recently, two highly homologous ligands, endocrine gland vascular endothelial growth factor (EG-VEGF) and mammalian Bv8, have been described as new angiogenic factors. Both ligands bind and activate two closely related G protein-coupled receptors, the prokineticin receptor (PROKR) 1 and 2. Yet, the expression, regulation, and potential role of EG-VEGF, BV8, and their receptors in normal and CF lung are still unknown. The expression of the receptors and their ligands was examined using molecular, biochemical, and immunocytochemistry analyses in lungs obtained from CF patients vs. control and in normal and CF bronchial epithelial cells. Cystic fibrosis transmembrane conductance regulator (CFTR) activity was evaluated in relation to both ligands, and concentrations of EG-VEGF were measured by ELISA. At the mRNA level, EG-VEGF, BV8, and PROKR2 gene expression was, respectively, approximately five, four, and two times higher in CF lungs compared with the controls. At the cellular level, both the ligands and their receptors showed elevated expressions in the CF condition. Similar results were observed at the protein level. The EG-VEGF secretion was apical and was approximately two times higher in CF compared with the normal epithelial cells. This secretion was increased following the inhibition of CFTR chloride channel activity. More importantly, EG-VEGF and BV8 increased the intracellular concentration of Ca(2+) and cAMP and stimulated CFTR-chloride channel activity. Altogether, these data suggest local roles for epithelial BV8 and EG-VEGF in the CF airway peribronchial vascular remodeling and highlighted the role of CFTR activity in both ligand biosynthesis and secretion.

Incidence of Avoidable 30-Day Readmissions Following Hospitalization for Community-Acquired Pneumonia in France.

Importance: Rates of 30-day readmissions following hospitalization for pneumonia are used to publicly report on hospital performance and to set financial penalties for the worst-performing hospitals. However, the rate of avoidable readmission following hospitalization for pneumonia is undefined. Objective: To assess how often 30-day readmissions following hospitalization for community-acquired pneumonia (CAP) are avoidable. Design, Setting, and Participants: This cohort study analyzed the results of an independent review of readmissions following hospitalization for CAP within 30 days among patients discharged from 2 large hospitals in France in 2014. Structured clinical records including clinical information (ie, baseline characteristics, physical examination, laboratory findings, x-ray or computed tomography scan findings, discharge plan, and treatments) for both index and readmission stays were independently reviewed by 4 certified board physicians. All consecutive adult patients hospitalized in 2014 with a diagnosis of CAP in our 2 eligible hospitals were eligible. All analyses presented were performed in March 2021. Main Outcomes and Measures: Avoidable readmission within 30 days of discharge from index hospitalization. The likelihood that a readmission was avoidable was quantified using latent class analysis based on the independent reviews. A readmission was considered avoidable if Bayes posterior probability exceeded 50%. Results: The total analytical sample consisted of 1150 index hospital stays with a diagnosis of CAP, which included 651 (56.6%) male patients. The median (IQR) age for all patients was 77.8 (IQR, 62.7-86.4) years. Out of the 1150 index hospital stays, 98 patients (8.5%) died in hospital, and 108 (9.4%) unplanned readmissions were found. Overall, 15 readmissions had a posterior probability of avoidability exceeding 0.50 (13.9% of the 108 unplanned readmissions; 95% CI, 8.0%-21.9%). The median (IQR) delay between the hospital discharge index and readmission was considerably shorter when readmission was deemed avoidable (4 [6-21] days vs 12 [2-18] days; P = .02). Conclusions and Relevance: Only a small number of readmissions following hospitalization for CAP were deemed avoidable, comprising less than 10% of all readmissions. Shorter time interval between hospitalization discharge and readmission was associated with avoidability.

Metabotypes of Pseudomonas aeruginosa Correlate with Antibiotic Resistance, Virulence and Clinical Outcome in Cystic Fibrosis Chronic Infections.

Pseudomonas aeruginosa (P.a) is one of the most critical antibiotic resistant bacteria in the world and is the most prevalent pathogen in cystic fibrosis (CF), causing chronic lung infections that are considered one of the major causes of mortality in CF patients. Although several studies have contributed to understanding P.a within-host adaptive evolution at a genomic level, it is still difficult to establish direct relationships between the observed mutations, expression of clinically relevant phenotypes, and clinical outcomes. Here, we performed a comparative untargeted LC/HRMS-based metabolomics analysis of sequential isolates from chronically infected CF patients to obtain a functional view of P.a adaptation. Metabolic profiles were integrated with expression of bacterial phenotypes and clinical measurements following multiscale analysis methods. Our results highlighted significant associations between P.a "metabotypes", expression of antibiotic resistance and virulence phenotypes, and frequency of clinical exacerbations, thus identifying promising biomarkers and therapeutic targets for difficult-to-treat P.a infections.

Hemodynamic Response to Treatment and Outcomes in Pulmonary Hypertension Associated With Interstitial Lung Disease Versus Pulmonary Arterial Hypertension in Systemic Sclerosis: Data From a Study Identifying Prognostic Factors in Pulmonary Hypertension Associated With Interstitial Lung Disease.

OBJECTIVE: Patients with systemic sclerosis and both pulmonary hypertension and interstitial lung disease (SSc-PH-ILD) generally carry a worse prognosis than patients with SSc and pulmonary arterial hypertension (SSc-PAH) without ILD. There is no evidence of the efficacy of PAH therapies in SSc-PH-ILD. We undertook this study to compare survival of and response to treatment in patients with SSc-PH-ILD and those with SSc-PAH. METHODS: We analyzed 128 patients (66 with SSc-PH-ILD and 62 with SSc-PAH) from 15 centers, in whom PH was diagnosed by right-sided heart catheterization; they were prospectively included in the PH registry. All patients received PAH-specific therapy. Computed tomography of the chest was used to confirm or exclude ILD. RESULTS: At baseline, patients with SSc-PH-ILD had less severe hemodynamic impairment than those with SSc-PAH (pulmonary vascular resistance 5.7 Wood units versus 8.7 Wood units; P = 0.0005) and lower diffusing capacity for carbon monoxide (median 25% [interquartile range (IQR) 18%, 35%] versus 40% [IQR 31%, 51%]; P = 0.0005). Additionally, patients with SSc-PH-ILD had increased mortality (8.1% at 1 year, 21.2% at 2 years, and 41.5% at 3 years) compared to those with SSc-PAH (4.1%, 8.7%, and 21.4%, respectively; P = 0.04). Upon treatment with PAH-targeted therapy, no improvement in the 6-minute walk distance was observed in either group. Improvement in the World Health Organization functional class was observed less frequently in patients with SSc-ILD-PH compared to those with SSc-PAH (13.6% versus 33.3%; P = 0.02). Hemodynamics improved similarly in both groups. CONCLUSION: ILD confers a worse prognosis to SSc-PH. Response to PAH-specific therapy is clinically poor in SSc-PH-ILD but was not found to be hemodynamically different from the response observed in SSc-PAH.

Clinical manifestations of anti-synthetase syndrome positive for anti-alanyl-tRNA synthetase (anti-PL12) antibodies: a retrospective study of 17 cases.

OBJECTIVE: To describe the clinical manifestations of the anti-synthetase syndrome (ASS) specifically associated with anti-alanyl-tRNA (anti-PL12) synthetase antibodies. METHODS: In a retrospective study, 17 patients (eight males, nine females, mean age = 60.3 years) with ASS symptoms confirmed by two consecutive tests (cyto-dot and/or immunoblot, or both), with positive results for anti-PL12 antibodies, were included. RESULTS: All patients presented with interstitial lung disease (ILD), which was associated with mild myositis in 41% of the cases. RP and general impairment were common, whereas rheumatic and dermatological symptoms were uncommon. Four patients suffered from SS, and four others had an atypical oesophageal involvement. The long-term course was assessable for 10 patients (follow-up of 41.1 months). Five patients required immunosuppressive drugs. Two patients are waiting for a lung transplant because of disproportionate and refractory pulmonary hypertension. CONCLUSION: The severity of anti-PL12 ASS varied because of the constant pulmonary involvement. ILD was the predominant prognosis factor, which was notable in cases associated with pulmonary hypertension.

Rheological analysis of sputum from patients with chronic bronchial diseases.

Bronchial diseases are characterised by the weak efficiency of mucus transport through the lower airways, leading in some cases to the muco-obstruction of bronchi. It has been hypothesised that this loss of clearance results from alterations in the mucus rheology, which are reflected in sputum samples collected from patients, making sputum rheology a possible biophysical marker of these diseases and their evolution. However, previous rheological studies have focused on quasi-static viscoelastic (linear storage and loss moduli) properties only, which are not representative of the mucus mobilisation within the respiratory tract. In this paper, we extend this approach further, by analysing both quasi-static and some dynamic (flow point) properties, to assess their usability and relative performance in characterising several chronic bronchial diseases (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) and distinguishing them from healthy subjects. We demonstrate that pathologies influence substantially the linear and flow properties. Linear moduli are weakly condition-specific and even though the corresponding ranges overlap, distinct levels can be identified. This directly relates to the specific mucus structure in each case. In contrast, the flow point is found to strongly increase in muco-obstructive diseases, which may reflect the complete failure of mucociliary clearance causing episodic obstructions. These results suggest that the analysis of quasi-static and dynamic regimes in sputum rheology is in fact useful as these regimes provide complementary markers of chronic bronchial diseases.

Development of a risk prediction model of potentially avoidable readmission for patients hospitalised with community-acquired pneumonia: study protocol and population.

INTRODUCTION: 30-day readmission rate is considered an adverse outcome reflecting suboptimal quality of care during index hospitalisation for community-acquired pneumonia (CAP). However, potentially avoidable readmission would be a more relevant metric than all-cause readmission for tracking quality of hospital care for CAP. The objectives of this study are (1) to estimate potentially avoidable 30-day readmission rate and (2) to develop a risk prediction model intended to identify potentially avoidable readmissions for CAP. METHODS AND ANALYSIS: The study population consists of consecutive patients admitted in two hospitals from the community or nursing home setting with pneumonia. To qualify for inclusion, patients must have a primary or secondary discharge diagnosis code of pneumonia. Data sources include routinely collected administrative claims data as part of diagnosis-related group prospective payment system and structured chart reviews. The main outcome measure is potentially avoidable readmission within 30 days of discharge from index hospitalisation. The likelihood that a readmission is potentially avoidable will be quantified using latent class analysis based on independent structured reviews performed by four panellists. We will use a two-stage approach to develop a claims data-based model intended to identify potentially avoidable readmissions. The first stage implies deriving a clinical model based on data collected through retrospective chart review only. In the second stage, the predictors comprising the medical record model will be translated into International Classification of Diseases, 10th revision discharge diagnosis codes in order to obtain a claim data-based risk model.The study sample consists of 1150 hospital stays with a diagnosis of CAP. 30-day index hospital readmission rate is 17.5%. ETHICS AND DISSEMINATION: The protocol was reviewed by the Comité de Protection des Personnes Sud Est V (IRB#6705). Efforts will be made to release the primary study results within 6 months of data collection completion. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02833259).

Clinical evaluation of pharmacists' interventions on multidisciplinary lung transplant outpatients' management: results of a 7-year observational study.

OBJECTIVES: Lung transplant (LT) recipients require multidisciplinary care because of the complexity of therapeutic management. Pharmacists are able to detect drug-related problems and provide recommendations to physicians through pharmacists' interventions (PIs). We aimed at assessing the clinical impact of PIs on therapeutic management in LT outpatients. DESIGN: Data were collected prospectively from an LT recipients cohort during 7 years. A multidisciplinary committee assessed retrospectively the clinical impact of accepted PIs. SETTING: French University Hospital. PARTICIPANTS: LT outpatients followed from 2009 to 2015. PRIMARY OUTCOME MEASURES: Clinical impact of PIs performed by pharmacists using the CLEO tool and the Pareto chart. RESULTS: 1449 PIs led to a change in patient therapeutic management and were mainly related to wrong dosage (39.6%) and untreated indication (19.6%). The clinical impact of PIs was 'avoids fatality', 'major' and 'moderate', in 0.1%, 7.0% and 57.9%, respectively. Immunosuppressants, antimycotics for systemic use and antithrombotic agents had the greatest clinical impact according to the Pareto chart. PIs related to drug-drug interactions (10%) mainly had a moderate and major clinical impact (82.3%, p<0.0001). CONCLUSION: Clinical pharmacists play a key role for detecting drug-related problems mostly leading to a change in therapeutic management among LT outpatients. Our study provides a new insight to analyse the clinical impact of PIs in order to target PIs which have most value and contribute to patient care through interdisciplinary approach.

An Atypical Case of Shiga Toxin Producing-Escherichia Coli Hemolytic and Uremic Syndrome (STEC-HUS) in a Lung Transplant Recipient.

We herein describe the first case of thrombotic microangiopathy (TMA) which was related to Shiga toxin producing-Escherichia Coli Hemolytic and Uremic Syndrome (STEC-HUS) after lung transplantation. His maintenance immunosuppression relied on tacrolimus plus mycophenolic acid. TMA was treated with plasma exchanges (PE) (fresh frozen plasma substitution). After five days of PE, platelets count and lactate dehydrogenase level normalized, whereas hemoglobin continued to gradually decrease and no improvement in kidney function was observed. After seven PE sessions, all TMA biological signs resolved. However, kidney function did not improve, and the patient still required chronic dialysis.

A successful antibiotic treatment by a new administration route: a case report of a subcutaneous administration of ceftazidime and tobramycin.

When intramuscular or intravenous administrations of parenteral drugs are not possible, the use of other routes (e.g., subcutaneous route) should be considered. We report a patient with Duchenne muscular dystrophy, who was hospitalized for acute pneumonia due to antibiotic-resistant strains of bacteria. Our patient was successfully recovered with antimicrobial therapy by subcutaneous administration of ceftazidime and tobramycin, for which no safety and efficacy data are available in humans. To the best of our knowledge, this case is the first supporting the subcutaneous administration safety and potential efficacy of both ceftazidime and tobramycin in humans.

Adherence to long-term therapies in cystic fibrosis: a French cross-sectional study linking prescribing, dispensing, and hospitalization data.

BACKGROUND: Cystic fibrosis (CF) is a life-shortening genetic condition that usually affects several organs and involves significant treatment burden. Adherence to medication is important for successful CF management. OBJECTIVE: To describe medication adherence according to age, therapeutic class, and pharmaceutical form in adults and children followed in four regional CF centers in France. METHODS: We conducted a cross-sectional study with non-transplanted patients followed in two adult and two pediatric centers during 2015 who were covered by the French National Health Insurance (NHI). Sociodemographic, clinical, hospitalization, and prescription data were collected from patient medical records. Medication dispensations were extracted from the regional French NHI database. Adherence was calculated over 12 months using continuous medication availability (CMA) accounting for dose adjustments and hospitalizations. Drug-specific CMA was computed in R with the AdhereR package for each medication prescribed more than 3 months, which was averaged to obtain a composite CMA score (cCMA) for all treatments and per therapeutic class as well as pharmaceutical form for each patient. RESULTS: A total of 228 patients were included. The number of chronic medications increased with age (r=0.50, p<0.001): a median of 7 medications per patient were prescribed. The mean±SD cCMA was significantly different between age groups (p=0.0098): it was 0.71±0.20 for the 0-5 years age group, 0.73±0.16 for 6-11 years, 0.64±0.17 for 12-17 years, 0.57±0.23 for 18-25 years, and 0.65±0.20 for the over 25 years age group. cCMA varied significantly according to pharmaceutical forms: the mean±SD cCMA was 0.70±0.21 for oral medications and 0.54±0.28 for inhaled medications (p<0.001). CONCLUSION: This study suggests that adherence to medication regimens in CF patients remains suboptimal and varies substantially between age groups and pharmaceutical forms. These variations in adherence should be considered when developing effective strategies to improve adherence.

Favorable Evolution of Cryptococcal Meningitis in the Context of Flucytosine Resistance.

Cryptococcal meningitis is a critical illness affecting 0.2% to 5% solid-organ transplant recipients with a 40% to 50% mortality. We report the case of a 48-year-old lung transplant recipient, who, 15 months after a right lung graft, kept parakeets and developed meningitis due to Cryptococcus neoformans. Immunosuppressive treatment was based on a quadruple sequential immunosuppressive therapy that included induction therapy with thymoglobulin, followed by corticosteroids, calcineurin inhibitors, and mycophenolate mofetil. Antifungal susceptibility testing of Cryptococcus neoformans showed resistance to flucytosine and intermediate sensitivity to fluconazole. Initial treatment adhered to international guidelines; however, the patient could not tolerate an effective double-antifungal therapy during the first 2 months of treatment. Despite this delayed treatment for an aggressive infection in an immunocompromised patient, the patient survived without relapse and received maintenance treatment with fluconazole during the course of 3 years. Administration of calcineurin inhibitors as immunosuppressive treatment may partly explain this outcome, as this therapeutic class is known to protect from severe forms of cryptococcal meningitis.

Killed but metabolically active Pseudomonas aeruginosa-based vaccine induces protective humoral- and cell-mediated immunity against Pseudomonas aeruginosa pulmonary infections.

Pseudomonas aeruginosa (Pa) is a significant cause of morbidity and mortality, especially in cystic fibrosis patients. Its eradication is difficult due to a wide phenotypic adaptability and an increase of its resistance to antibiotics. After the failure of several recombinant vaccines which mainly triggered humoral response, live-attenuated vaccines received attention thanks to their ability to elicit a broad immunity with both humoral- and cell-mediated responses, essential to fight this pathogen. In this study, we developed an innovative and safer live-attenuated Pa vaccine based on a Killed But Metabolically Active (KBMA) attenuation method. KBMA Pa has been further rationally designed to overexpress beneficial effectors like the type 3 secretion system apparatus. We demonstrated that KBMA Pa elicits a high and broad humoral response in mice against several antigens of particular interest such as OprF and PcrV proteins. Moreover, we assessed cytokines in the serum of immunized mice and showed that KBMA Pa elicits Th1, Th2 and especially Th17 pathways of cell-mediated immune responses. Th17 pathway involvement was also confirmed after specific stimulation of helper T cells in immunized mice. Finally, we showed that this vaccine is safe and has a protective effect in a murine acute pulmonary infectious challenge. In conclusion, KBMA Pa is a new platform with high potential for the development of a vaccine against Pa.

Perihepatitis and perinephric abscess due to Mycoplasma hominis in a kidney transplant patient.

Mycoplasma hominis has been incriminated in several genital and extragenital infections. Here, we report the first case of perihepatitis associated with a perinephric abscess in a woman who had received a kidney transplant. Four months after the transplant, the patient was admitted for perirenal allograft pain, fever, and elevated inflammatory parameters and liver enzyme levels. A renal ultrasonography found a collection of fluid. Results of blood and urine analyses were within normal limits. Fluid aspiration of the peritoneal cavity was performed, and the results of cultures for bacteria and fungi were negative. The patient was treated by surgical lavage of the peritoneal cavity. Her fever resolved 5 days later. Two months after surgical lavage of the peritoneal cavity, her liver enzyme levels returned to the normal range. Three months after surgical lavage, cultures of the perinephric fluid showed Mycoplasma hominis. We conclude that in patients who present with perinephric fluid suspected of being infected, bacteriologic analysis of the fluid (from surgical lavage of the peritoneal cavity) should be performed. Antibiotics active against intracellular bacteria should be administered.

Syphilis-related hepatitis in a liver transplant patient.

We herein describe a case of secondary syphilis hepatitis in a liver transplant patient. This homosexual man presented 15 years after an orthotopic liver transplant with nonsquamous papillomacular rash, mild cytolysis, and anicteric cholestasis. Laboratory tests showed syphilis seroconversionwith a VDRL test titer of 1/256, a Treponema pallidum hemagglutination assay of 1/5120, and a positive immunoglobulin M fluorescent Treponemal antibody absorbance. A liver biopsy performed 13 months after the diagnosis showed low-grade hepatitis with a METAVIR score of A1F1; it also showed moderate, nonspecific portal inflammation consisting primarily of neutrophils, with no evidence of cholestasis. The patient was given benzathine-penicillin (2400000 IU) with a transient increase in prednisolone dosages. Cytolysis rapidly, and cholestasis progressively, disappeared. Results of an immunoglobulin M fluorescent Treponemal antibody absorbance test became negative, whereas the VDRL test and the Treponema pallidum hemagglutination assay titers decreased slightly over time.

Grouped Cases of Pulmonary Pneumocystosis After Solid Organ Transplantation: Advantages of Coordination by an Infectious Diseases Unit for Overall Management and Epidemiological Monitoring.

OBJECTIVE To determine the origin of grouped cases of Pneumocystis pneumonia in solid-organ transplant recipients at our institution. DESIGN A case series with clinical examinations, genotyping, and an epidemiological survey. SETTING A university hospital in France. PATIENTS We report 12 solid-organ transplant recipients with successive cases of Pneumocystis pneumonia that occurred over 3 years; 10 of these cases occurred in a single year. METHODS We used molecular typing of P. jirovecii strains by multilocus sequence typing and clinical epidemiological survey to determine potential dates and places of transmission. RESULTS Between May 2014 and March 2015, 10 solid-organ transplant recipients (5 kidney transplants, 4 heart transplants, and 1 lung transplant) presented with Pneumocystis pneumonia. Molecular genotyping revealed the same P. jirovecii strain in at least 6 patients. This Pneumocystis strain was not identified in control patients (ie, nontransplant patients presenting with pulmonary pneumocystosis) during this period. The epidemiological survey guided by sequencing results provided information on the probable or possible dates and places of contamination for 5 of these patients. The mobile infectious diseases unit played a coordination role in the clinical management (adaptation of the local guidelines) and epidemiological survey. CONCLUSION Our cardiac and kidney transplant units experienced grouped cases of pulmonary pneumocystosis. Genotyping and epidemiological surveying results suggested interhuman contamination, which was quickly eliminated thanks to multidisciplinary coordination. Infect Control Hosp Epidemiol 2017;38:179-185.

Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease.

OBJECTIVE: To investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting. METHODS: A multicentre observational study investigated adverse events, treatment discontinuation, FEV1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV1 below 40% predicted. RESULTS: Respiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment. The mean absolute change in FEV1 was +2.06% after one month of treatment (P=0.086) and +3.19% after 3 months (P=0.009). BMI was unchanged. CONCLUSIONS: Treatment with lumacaftor/ivacaftor in patients with CF and severe lung disease was discontinued more frequently than reported in clinical trials, due to respiratory AEs. Nevertheless, the patients who continued treatment had an increase in lung function comparable to what was observed in pivotal trials.