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The main limitation to long-term lung transplant (LT) survival is chronic lung allograft dysfunction (CLAD), which leads to irreversible lung damage and significant mortality. Individual factors can impact CLAD, but no large genetic investigation has been conducted to date. We established the multicentric Genetic COhort in Lung Transplantation (GenCOLT) biobank from a rich and homogeneous sub-part of COLT cohort. GenCOLT collected DNA, high-quality GWAS (genome-wide association study) genotyping and robust HLA data for donors and recipients to supplement COLT clinical data. GenCOLT closely mirrors the global COLT cohort without significant variations in variables like demographics, initial disease and survival rates (P > 0.05). The GenCOLT donors were 45 years-old on average, 44% women, and primarily died of stroke (54%). The recipients were 48 years-old at transplantation on average, 45% women, and the main underlying disease was chronic obstructive pulmonary disease (45%). The mean follow-up time was 67 months and survival at 5 years was 57.3% for the CLAD subgroup and 97.4% for the non-CLAD subgroup. After stringent quality controls, GenCOLT gathered more than 7.3 million SNP and HLA genotypes for 387 LT pairs, including 91% pairs composed of donor and recipient of European ancestry. Overall, GenCOLT is an accurate snapshot of LT clinical practice in France and Belgium between 2009 and 2018. It currently represents one of the largest genetic biobanks dedicated to LT with data available simultaneously for donors and recipients. This unique cohort will empower to run comprehensive GWAS investigations of CLAD and other LT outcomes.
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Lung transplant recipients (LTRs) are susceptible to severe Coronavirus Disease 2019 (COVID-19) and had lower immune responses to primary severe acute respiratory syndrome-related to coronavirus 2 (SARS-CoV-2) vaccination as compared to the general population and to other solid organ transplant recipients. As immunity induced by booster vaccination and natural infection has increased since the beginning of the pandemic in the general population, immunity acquired by LTRs is not well documented. Humoral and cellular immunity to SARS-CoV-2 was monitored in February and May 2023 in 30 LTRs and compared to that of health care workers (HCWs) and nursing home residents (NHRs). LTRs had significantly lower levels of SARS-CoV-2 binding and neutralizing antibodies and lower interferon-gamma responses to Wuhan, Delta, and XBB1.5 variants as compared to HCWs and NHRs. Humoral immunity decreased between the 2 visits, whereas cellular immunity remained more stable. The persistent defect in SARS-CoV-2 immunity in LTRs should encourage continued monitoring and preventive measures for this vulnerable population.
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OBJECTIVES: Staphylococcus aureus and Pseudomonas aeruginosa co-infections in patients with cystic fibrosis (CF) are associated with disease severity. Their treatment is complicated by biofilm formation in the sticky mucus obstructing the airways. We investigated the activity of phages-antibiotics combinations using a dual species biofilm (P. aeruginosa/S. aureus) formed in artificial sputum medium. METHODS: Biofilmswere incubated with broad-spectrum antibiotics (meropenem, ceftazidime, ciprofloxacin, tobramycin) combined with a cocktail of two (bacterio)phages (PSP3 and ISP) proven active via spot tests and double agar on P. aeruginosa PAO1 and S. aureus ATCC 25923. RESULTS: At the highest tested concentrations (100 x MIC), antibiotics alone caused a 20-50% reduction in biomass and reduced S. aureus and P. aeruginosa CFU of 2.3 to 2.8 and 2.1 to 3.6 log10, respectively. Phages alone reduced biofilm biomass by 23% and reduced P. aeruginosa CFU of 2.1 log10, but did not affect S. aureus viability. Phages enhanced antibiotic effects on biomass and exhibited additive effects with antibiotics against P. aeruginosa, but not against S. aureus. Following inhibition of bacterial respiration by phages in planktonic cultures rationalised these observations by demonstrating that PSP3 was effective at multiplicities of infection (MOI) as low as 10-4 plaque forming units (PFU)/CFU on P. aeruginosa, but ISP, at higher MOI (> 0.1) against S. aureus. CONCLUSION: Pre-screening inhibition of bacterial respiration by phages may assist in selecting those showing activity at sufficiently low titers to showcase anti-biofilm activity in this complex but clinically-relevant in vitro model of biofilm.
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INTRODUCTION: The occurrence of hyperkalemic renal tubular acidosis (RTA) in the post-transplantation period is likely underestimated, and its identification remains important to offer adequate medical management. Transplant recipients frequently present with clinical and biological characteristics that may be associated with the occurrence of this complication. METHODS: This was a single-center retrospective study that compared transplanted patients with hyperkalemic RTA and a control group to identify variables associated with the occurrence of this complication. Fisher's exact test and the Mann-Whitney test, followed by multivariate logistic regression, were applied to test whether there was a significant association between hyperkalemic RTA and different variables. RESULTS: Kidney and heart transplant recipients were at greater risk of developing RTA than lung transplant recipients (p = 0.016). There was also a significant association between the development of RTA and kalemia (p < 0.01), chloremia (p < 0.01), and bicarbonatemia (p < 0.01). The significant impact of these last three variables was confirmed by the results of the multivariate logistic regression. Residual serum tacrolimus levels (p = 0.13) and creatinine levels (p = 0.17) of renal transplant patients were not significantly associated with hyperkalemic RTA. CONCLUSION: The type of transplanted organ, kalemia, chloremia, and bicarbonatemia were significantly associated with the occurrence of hyperkalemic RTA. This study calls into question certain approaches to managing this complication proposed in a number of case reports, such as reducing the target serum residual of tacrolimus or discontinuing trimethoprim-sulfamethoxazole (TMP-SMX) in favor of another antibiotic prophylactic agent, potentially exposing patients to graft rejection and opportunistic infections.
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BACKGROUND: Long-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development. METHODS: Participants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after. RESULTS: MMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0-253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%. CONCLUSION: Plasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD.
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Trasplante de Pulmón , Metaloproteinasa 9 de la Matriz , Humanos , Pronóstico , Aloinjertos , Trasplante de Pulmón/efectos adversos , Pulmón , Biomarcadores , Estudios RetrospectivosRESUMEN
BACKGROUND: Biofilm-associated pulmonary infections pose therapeutic challenges in cystic fibrosis patients, especially when involving multiple bacterial species. Enzymatic degradation of the biofilm matrix may offer a potential solution to enhance antibiotic efficacy. This study investigated the repurposing of DNase I, commonly used for its mucolytic activity in cystic fibrosis, to target extracellular DNA within biofilms, as well as potential synergies with alginate lyase and broad-spectrum antibiotics in dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus. METHODS: Dual-species biofilms were grown in artificial sputum medium using S. aureus and P. aeruginosa isolated by pairs from the same patients and exposed to various combinations of enzymes, meropenem, or tobramycin. Activity was assessed by measuring biofilm biomass and viable counts. Matrix degradation and decrease in bacterial load were visualized using confocal microscopy. Biofilm viscoelasticity was estimated by rheology. RESULTS: Nearly complete destruction of the biofilms was achieved only if combining the enzymatic cocktail with the two antibiotics, and if using supratherapeutic levels of DNase I and high concentrations of alginate lyase. Biofilms containing non-pigmented mucoid P. aeruginosa required higher antibiotic concentrations, despite low viscoelasticity. In contrast, for biofilms with pigmented mucoid P. aeruginosa, a correlation was observed between the efficacy of different treatments and the reduction they caused in elasticity and viscosity of the biofilm. CONCLUSIONS: In this complex, highly drug-tolerant biofilm model, enzymes prove useful adjuvants to enhance antibiotic activity. However, the necessity for high enzyme concentrations emphasizes the need for thorough concentration-response evaluations and safety assessments before considering clinical applications.
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Regular physical activity (PA) is essential in cystic fibrosis (CF). This study assessed the impact of a motivational interviewing (MI)-based project titled "Just move it .â.â. move it," aimed at improving the PA of pediatric CF patients. At baseline and month 6, body mass index, spirometric values, and duration of extracurricular sport activities were collected. Concurrently, the maximum oxygen uptake (VO2max) was estimated. MI was performed during each visit. Overall, 19 CF children were included. Ten patients (52.7%) increased their regular PA (mean 1.9 hours/week) between both visits (PA+ group), while 9 did not (PA- group). No significant differences in functional and nutritional values were observed between the groups, while extracurricular sport time significantly increased in the PA+ group. "Just move it .â.â. move it" seems to be an efficient approach, as it was able to motivate several CF patients to initiate or increase their PA, yet without improving functional parameters.
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BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients. METHODS: In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set ([FAS]; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symptoms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function measured by spirometry. RESULTS: Sixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference [95% CI], 0.10 [-0.43, 0.63] log10 copies/ml; p = 0.72) or the shorter symptom-duration subgroup (-0.12 [-0.94, 0.69] log10 copies/ml; p = 0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated. CONCLUSIONS: Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.
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Trasplante de Pulmón , Neumonía Viral , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Adulto , Humanos , Resultado del Tratamiento , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Neumonía Viral/complicaciones , Antivirales/uso terapéuticoRESUMEN
BACKGROUND: To examine safety and efficacy of tezacaftor-ivacaftor (TEZ/IVA) in a real-life setting in adults living with cystic fibrosis. METHODS: A multicentre retrospective observational study, including adults living with cystic fibrosis (pwCF) eligible for TEZ/IVA, with assessments at baseline, 3 months (visit3mo) and 6 months (visit6mo) after start of treatment. Outcomes included change in FEV1, LCI, FeNO, CFQ-R, estimated number of annual acute exacerbations, BMI, dosage of pancreatic enzyme replacement therapy (PERT) and airway microbiology. We also assessed safety. RESULTS: Forty-eight adult pwCF (mean (±SD) age 33 (±12) years; mean FEV1 65 (±19) %P) were included. Three subgroups were identified: pwCF F/F CFTR modulator-naive (n = 28; 58%), pwCF F/F previously treated with lumacaftor-ivacaftor (n = 11; 23%) and pwCF F/RF (n = 9; 19%). Adverse events were described in 3 pwCF (6%) during the 6-month observation period (in one leading to treatment interruption). At visit3mo, FEV1 had improved in all subgroups. In the entire group, mean FEV1 had increased from 66 (±2.9) %P to 72 (±2.9) %P (p < 0.0001). Similarly, LCI improved by approximately one unit at visit3mo (p = 0.02). At visit6mo mean annual acute exacerbation rate decreased significantly (p = 0.02). Only in the CFQ-R social functioning domain score, a significant improvement was observed at visit6mo (p < 0.01). CONCLUSIONS: We showed that TEZ/IVA is safe, well tolerated and effective in terms of improvement of lung function, ventilation inhomogeneity, health-related social functioning, and reduction of estimated annual acute exacerbation rate, in adult pwCF F/F and F/RF. Results in this real-life study reflect those observed in RCTs.
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Fibrosis Quística , Adulto , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , MutaciónRESUMEN
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F) in two pivotal Phase 3 trials, significantly improving percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire-Revised, Respiratory Domain (CFQ-R RD) scores, and sweat chloride concentration. Here, we analyzed the 11 non-respiratory domains (non-RDs) of the CFQ-R, which assess general health-related quality of life (i.e., Physical Functioning, Role Functioning, Vitality, Health Perceptions, Emotional Functioning, and Social Functioning) and quality of life impacted by CF (i.e., Body Image, Eating Problems, Treatment Burden, Weight, and Digestive Symptoms), for participants in these two Phase 3 trials. ELX/TEZ/IVA treatment led to higher scores in all CFQ-R non-RDs, with improvements in most domains compared with control treatments. These findings demonstrate that ELX/TEZ/IVA improves a range of CF-specific symptoms and general functioning and well-being.
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Fibrosis Quística , Humanos , Aminofenoles , Benzodioxoles , Agonistas de los Canales de Cloruro , Fibrosis Quística/diagnóstico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Mutación , Calidad de VidaRESUMEN
In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, the median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM). In lung transplant recipients with idiopathic inflammatory myopathy, survival was similar to that in all-cause transplantation and was worse in patients with muscle involvement compared to those with the amyopathic disease.
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Enfermedades Pulmonares Intersticiales , Trasplante de Pulmón , Miositis , Humanos , Masculino , Persona de Mediana Edad , Femenino , Estudios de Cohortes , Estudios Retrospectivos , Miositis/cirugía , Miositis/complicaciones , Enfermedades Pulmonares Intersticiales/cirugía , Enfermedades Pulmonares Intersticiales/etiología , Trasplante de Pulmón/efectos adversosRESUMEN
BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear. METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) - 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified. CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.
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Antiinfecciosos , Tratamiento Farmacológico de COVID-19 , Complemento C5 , Inactivadores del Complemento/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos , SARS-CoV-2 , Resultado del TratamientoRESUMEN
Background: Chronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx). Methods: 10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis. Results: A total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk. Conclusion: Based on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions.
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Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6-32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.
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Bronquiolitis Obliterante , Trasplante de Pulmón , Administración por Inhalación , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/prevención & control , Ciclosporina/uso terapéutico , Humanos , Pulmón , Trasplante de Pulmón/efectos adversosRESUMEN
Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.
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Enfermedades del Tejido Conjuntivo/cirugía , Manejo de la Enfermedad , Trasplante de Pulmón/normas , Atención Perioperativa/normas , Consenso , HumanosRESUMEN
Background: Mycoplasma hominis and Ureaplasma spp. are responsible for opportunistic infections in transplant patients, sometimes causing a life-threatening hyperammonemia syndrome. Both pathogens are not identified with standard microbiology techniques, resulting in missed or delayed diagnosis. We present a clinical case that illustrates the added value that next-generation sequencing (NGS) may offer in the diagnosis of respiratory infections in immune-compromised patients. Results: A 55 years-old man with idiopathic pulmonary fibrosis underwent double lung transplantation. He received antibiotic prophylaxis with piperacillin-tazobactam and azythromycin. At day 4 post-transplantation (PTx), the patient presented an acute respiratory distress. A broncho-alveolar lavage (BAL) was performed. At day 5 PTx, the patient presented a status epilepticus due to diffuse cerebral oedema. Serum ammonia concentration was 661 µg/dL. BAL bacterial culture was negative. Because of the clinical presentation, special cultures were performed and identified 100.000 CFU/mL of M. hominis and Ureaplasma spp. and specific PCRs were positive for M. hominis and Ureaplasma parvum. Antibiotic therapy was shifted to therapeutic dose of azithromycin and doxycycline; within 48 h ammonia serum concentrations returned to normal but the coma persisted several weeks, followed by a persistent frontal lobe syndrome. A follow-up BAL was performed on day 11 Ptx. The Mycoplasma/Ureaplasma culture was negative, yet the specific PCRs remained positive. Bacterial culture found 100 CFU/mL of Staphylococcus aureus and viral culture was positive for Herpes Simplex Virus-1. These results were confirmed by metagenomic next-generation sequencing (mNGS). In the bacterial fraction, the majority of reads belonged to Corynebacterium propinquum (34.7%), S. aureus (24.1%) and Staphylococcus epidermidis (17.1%). Reads assigned to M. hominis, Ureaplasma urealyticum and parvum represented 0.71, 0.13, and 0.04% of the bacterial fraction and corresponded to 6.9 × 103, 9.7 × 102, and 3.7 × 102 genome equivalents per mL of BAL fluid, respectively. These results are in favor of a cure of the atypical infection. Conclusions: mNGS offered added diagnostic and quantitative values compared to PCR tests, which can remain positive after resolved infections. The initiation of appropriate antibiotic therapy would have occurred earlier on, possibly resulting in a better clinical outcome if mNGS had been performed in a routine fashion.
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Antibiotic underdosing in prophylactic antibiotic regimes after lung transplantation (LTx) can increase the risk of infection. We aimed to study whether ß-lactam concentrations achieved desirable pharmacodynamic targets in the early phase after LTx and the association between drug concentrations and the development of early infections or the acquisition of multidrug-resistant (MDR) strains. We reviewed patients in whom broad-spectrum ß-lactam levels were measured after LTx during antibiotic prophylaxis. ß-Lactam concentrations were considered "insufficient" if drug levels remained below four times the clinical breakpoint of the minimal inhibitory concentration for Pseudomonas aeruginosa. The primary outcome was the occurrence of an infection and/or acquisition of MDR pathogens in the first 14 days after transplantation. A total of 70 patients were included. "Insufficient" drug concentrations were found in 40% of patients. In 27% of patients, an early MDR pathogen was identified and 49% patients were diagnosed with an early posttransplant infection. Patients with "insufficient" drug concentrations acquired more frequently MDR bacteria and/or developed an infection than others (22/28, 79% vs. 20/42, 48% - p = .01). ß-Lactam levels were often found to be below the desired drug targets in the early phase after transplantation and may be associated with the occurrence of early infectious complications.
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Trasplante de Pulmón , beta-Lactamas , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Humanos , Trasplante de Pulmón/efectos adversos , Pruebas de Sensibilidad Microbiana , beta-Lactamas/farmacologíaRESUMEN
STUDY QUESTION: In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation. PATIENTS AND METHODS: We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres. RESULTS: Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46-59)â years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5â years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16-89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications. ANSWER TO THE STUDY QUESTION: Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis.
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Trasplante de Pulmón , Sarcoidosis Pulmonar , Sarcoidosis , Anciano , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Sarcoidosis/cirugía , Sarcoidosis Pulmonar/cirugíaRESUMEN
BACKGROUND: Bronchoalveolar lavage (BAL) is currently not recommended in noncritically ill patients for the diagnosis of SARS-CoV-2 infection. Indeed, the diagnosis is based on the RT-PCR test on a nasopharyngeal swab (NPS) and abnormal findings on the chest CT scan. However, the sensitivity of the NPS and the specificity of the chest CT scan are low. Results of BAL in case of negative NPS testing are underreported, especially in the subgroup of immunocompromised patients. OBJECTIVES: The added value of BAL in the management of unstable, but noncritically ill patients, suspected of having SARS-CoV-2 infection despite one previous negative NPS and the side effects of the procedure for the patients and the health-care providers, were assessed during the epidemic peak of the COVID-19 outbreak in Belgium. METHODS: This multicentric study included all consecutive noncritically ill patients hospitalized with a clinical and radiological suspicion of SARS-CoV-2 infection but with a negative NPS. BAL was performed according to a predefined decisional algorithm based on their state of immunocompetence, the chest CT scan features, and their respiratory status. RESULTS: Among the 55 patients included in the study, 14 patients were diagnosed with a SARS-CoV-2 infection. Interestingly, there was a relationship between the cycle threshold of the RT-PCR and the interval of time between the symptom onset and the BAL procedure (Pearson's correlation coefficient = 0.8, p = 0.0004). Therapeutic management was changed in 33 patients because another infectious agent was identified in 23 patients or because an alternative diagnosis was made in 10 patients. In immunocompromised patients, the impact of BAL was even more marked (change in therapy for 13/17 patients). No significant adverse event was noted for patients or health-care staff. All health-care workers remained negative for SARS-CoV-2 NPS and serology at the end of the study. CONCLUSIONS: In this real-life study, BAL can be performed safely in selected noncritically ill patients suspected of SARS-CoV-2 infection, providing significant clinical benefits that outweigh the risks.