Cystic Fibrosis
ROLE OF SWEAT ION RATIOS IN DIAGNOSING CYSTIC FIBROSIS
Pediatr Pulmonol. 2021 Apr 6. doi: 10.1002/ppul.25395. Online ahead of print.
ABSTRACT
Sweat chloride (Cl- ) concentration is the gold standard for diagnosing cystic fibrosis (CF). This is however, challenging among patients with borderline values. Previous studies have reported that the sweat Cl- /Na+ ratio may be useful for diagnosing CF; however, little is known about Cl- /K+ and (Cl- +Na+ )/K+ ratios. This study aimed to retrospectively define the most appropriate outcome of the sweat test. Samples of sweat were collected using the Gibson and Cooke method. Cl- , Na+ , and K+ were further quantified in 2084 participants-1283 CF and 801 non-CF-based on clinical diagnosis. Among those with borderline sweat Cl- values (n=502), 34.8% had CF. In the receiver operating characteristic curve analysis, the area under the curve was calculated to evaluate the diagnostic value of the ion ratios. In the overall population, all the ratios significantly discriminated CF from non-CF, whereas in the borderline group, only Cl- /Na+ significantly discriminated CF and non-CF subjects, regardless of age. This article is protected by copyright. All rights reserved.
PMID:33822490 | DOI:10.1002/ppul.25395
Burkholderia cenocepacia BCAM2418-induced antibody inhibits bacterial adhesion, confers protection to infection and enables identification of host glycans as adhesin targets
Cell Microbiol. 2021 Apr 6. doi: 10.1111/cmi.13340. Online ahead of print.
ABSTRACT
Trimeric Autotransporter Adhesins (TAA) found in Gram-negative bacteria play a key role in virulence. This is the case of Burkholderia cepacia complex (Bcc), a group of related bacteria able to cause infections in patients with cystic fibrosis. These bacteria use TAAs, among other virulence factors, to bind to host protein receptors and their carbohydrate ligands. Blocking such contacts is an attractive approach to inhibit Bcc infections. In this study, using an antibody produced against the TAA BCAM2418 from the epidemic strain Burkholderia cenocepacia K56-2, we were able to uncover its roles as an adhesin and the type of host glycan structures that serve as recognition targets. The neutralization of BCAM2418 was found to cause a reduction in the adhesion of the bacteria to bronchial cells and mucins. Moreover, in vivo studies have shown that the anti-BCAM2418 antibody exerted an inhibitory effect during infection in Galleria mellonella. Finally, inferred by glycan arrays, we were able to predict for the first time, host glycan epitopes for a TAA. We show that BCAM2418 favoured binding to 3'sialyl-3-fucosyllactose, histo-blood group A, α-(1,2)-linked Fuc-containing structures, Lewis structures and GM1 gangliosides. Additionally, the glycan microarrays demonstrated similar specificities of Burkholderia species for their most intensely binding carbohydrates. This article is protected by copyright. All rights reserved.
PMID:33822465 | DOI:10.1111/cmi.13340
Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases
Cell Stress. 2021 Mar 8;5(4):40-51. doi: 10.15698/cst2021.04.246.
ABSTRACT
Phosphatidyl inositol 3 kinase gamma (PI3Kγ) is expressed in all the cell types that are involved in airway inflammation and disease, including not only leukocytes, but also structural cells, where it is expressed at very low levels under physiological conditions, while is significantly upregulated after stress. In the airways, PI3Kγ behaves as a trigger or a controller, depending on the pathological context. In this review, the contribution of PI3Kγ in a plethora of respiratory diseases, spanning from acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis and response to both bacterial and viral pathogens, will be commented.
PMID:33821232 | PMC:PMC8012884 | DOI:10.15698/cst2021.04.246
Integrative microbiomics in bronchiectasis exacerbations
Nat Med. 2021 Apr 5. doi: 10.1038/s41591-021-01289-7. Online ahead of print.
ABSTRACT
Bronchiectasis, a progressive chronic airway disease, is characterized by microbial colonization and infection. We present an approach to the multi-biome that integrates bacterial, viral and fungal communities in bronchiectasis through weighted similarity network fusion ( https://integrative-microbiomics.ntu.edu.sg ). Patients at greatest risk of exacerbation have less complex microbial co-occurrence networks, reduced diversity and a higher degree of antagonistic interactions in their airway microbiome. Furthermore, longitudinal interactome dynamics reveals microbial antagonism during exacerbation, which resolves following treatment in an otherwise stable multi-biome. Assessment of the Pseudomonas interactome shows that interaction networks, rather than abundance alone, are associated with exacerbation risk, and that incorporation of microbial interaction data improves clinical prediction models. Shotgun metagenomic sequencing of an independent cohort validated the multi-biome interactions detected in targeted analysis and confirmed the association with exacerbation. Integrative microbiomics captures microbial interactions to determine exacerbation risk, which cannot be appreciated by the study of a single microbial group. Antibiotic strategies probably target the interaction networks rather than individual microbes, providing a fresh approach to the understanding of respiratory infection.
PMID:33820995 | DOI:10.1038/s41591-021-01289-7
Trends of antimicrobial resistance and combination susceptibility testing of cystic fibrosis multidrug-resistant Pseudomonas aeruginosa: A ten-year update
Antimicrob Agents Chemother. 2021 Apr 5:AAC.02483-20. doi: 10.1128/AAC.02483-20. Online ahead of print.
ABSTRACT
Background: Antimicrobial combination therapy is a time/resource- intensive procedure commonly employed in the treatment of cystic fibrosis (CF) pulmonary exacerbations caused by P. aeruginosa Ten years ago the most promising antimicrobial combinations were proposed, but there has since been the introduction of new β-lactam+β-lactamase inhibitor antimicrobial combinations. The aims of this study were i) to compare in vitro activity of these new antimicrobials with other anti-pseudomonals agents and suggest their most synergistic antimicrobial combinations. ii) to determine antimicrobial resistance rates and study inherent trends of antimicrobials over ten years.Methods: A total of 721 multidrug-resistant P. aeruginosa isolates from 183 patients were collated over the study period. Antimicrobial susceptibility and combination testing were carried out using the Etest method. The results were further assessed using the fractional inhibitory concentration index (FICI) and the susceptible breakpoint index (SBPI).Results: Resistance to almost all antimicrobial agents maintained a similar level during the studied period. Colistin (p<0.001) and tobramycin (p=0.001) were the only antimicrobials with significant increasing isolate susceptibility while an increasing resistance trend was observed for levofloxacin. The most active antimicrobials were colistin, ceftolozane/tazobactam, ceftazidime/avibactam, and gentamicin. All combinations with β-lactam+β-lactamase inhibitors produced some synergistic results. Ciprofloxacin+ceftolozane/tazobactam (40%) and amikacin+ceftazidime (36.7%) were the most synergistic combinations while colistin combinations gave the best median SPBI (50.11).Conclusions: This study suggests that effective fluoroquinolone stewardship should be employed for CF patients. It also presents in vitro data to support the efficacy of novel combinations for use in the treatment of chronic P. aeruginosa infections.
PMID:33820772 | DOI:10.1128/AAC.02483-20
A complicated association between two different genetic rare disorders: Cystic Fibrosis and Spinal Muscular Atrophy
Minerva Pediatr (Torino). 2021 Apr 2. doi: 10.23736/S2724-5276.19.05614-7. Online ahead of print.
NO ABSTRACT
PMID:33820398 | DOI:10.23736/S2724-5276.19.05614-7
Severe obstructive biliopathy mimicking biliary atresia in an infant with cystic fibrosis
J Paediatr Child Health. 2021 Apr 5. doi: 10.1111/jpc.15475. Online ahead of print.
NO ABSTRACT
PMID:33818837 | DOI:10.1111/jpc.15475
Changes in the Cystic Fibrosis Airway Microbiome in Response to CFTR Modulator Therapy
Front Cell Infect Microbiol. 2021 Mar 17;11:548613. doi: 10.3389/fcimb.2021.548613. eCollection 2021.
ABSTRACT
The development of CFTR modulator therapies significantly changed the treatment scheme of people with cystic fibrosis. However, CFTR modulator therapy is still a life-long treatment, which is not able to correct the genetic defect and cure the disease. Therefore, it becomes crucial to understand the effects of such modulation of CFTR function on the airway physiology, especially on airway infections and inflammation that are currently the major life-limiting factors in people with cystic fibrosis. In this context, understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections. Whether and how the newly available therapies affect the airway microbiome is still at the beginning of being deciphered. We present here a brief review summarizing the latest information about microbiome alterations in light of modern cystic fibrosis modulator therapy.
PMID:33816324 | PMC:PMC8010178 | DOI:10.3389/fcimb.2021.548613
Involving patients' perspective in the development of an internet- and mobile-based CBT intervention for adolescents with chronic medical conditions: Findings from a qualitative study
Internet Interv. 2021 Mar 16;24:100383. doi: 10.1016/j.invent.2021.100383. eCollection 2021 Apr.
ABSTRACT
OBJECTIVE: A user-centered approach is critical for increasing the adherence to and effectiveness of an internet- and mobile-based intervention program. Therefore, potential future intervention users were involved in the development of an internet- and mobile-based cognitive behavioral therapy program (iCBT) for adolescents and young adults (AYA) with chronic medical conditions and comorbid symptoms of anxiety or depression. We aimed to identify challenges and coping strategies of the intended target group, as well as their needs and preferred intervention characteristics for an iCBT program.
METHODS: Twenty AYA (aged 14-20, 60% females) with either type 1 diabetes (55%), juvenile idiopathic arthritis (25%) or cystic fibrosis (20%) were interviewed in condition-specific focus groups (4-11 participants per group) either via videoconferencing or face-to-face. Transcript verbatim data was analyzed using content analysis.
RESULTS: Frequently reported disease-specific burdens were among others fear of disease progression, non-acceptance of disease and stressful incidents related to and aversions against medical therapy. Most frequently reported coping strategies included, seeking social support and accepting the disease. Recommendations for the content of an iCBT for comorbid symptoms of anxiety and depression comprised: dealing with disease-related fears and getting advice on health-promoting lifestyles. iCBT characteristics considered preferable by participants were: providing individual feedback by a real-person; implementation of a feature to monitor treatment progress; youthful and varied content presentation; time per session not exceeding 1 h; non-involvement of parents. A mobile-based reminder feature was considered useful, and individual tailoring and self-determination of iCBT content was considered desirable.
CONCLUSIONS: The findings highlight important patient perspectives and age-specific recommendations which can help design more optimal iCBT interventions for AYA with chronic medical conditions.
PMID:33816129 | PMC:PMC8008172 | DOI:10.1016/j.invent.2021.100383
Development and evaluation of an internet-based cognitive behavioral therapy intervention for anxiety and depression in adults with cystic fibrosis (eHealth CF-CBT): An international collaboration
Internet Interv. 2021 Feb 24;24:100372. doi: 10.1016/j.invent.2021.100372. eCollection 2021 Apr.
ABSTRACT
INTRODUCTION: Individuals with cystic fibrosis (CF) are at increased risk for anxiety and depression, with negative consequences for adherence, health, and quality of life. New approaches to prevent and treat anxiety and depression that are tailored to the concerns of this population are needed. A CF-specific internet-based cognitive-behavioral therapy (CBT) intervention was developed to increase access to evidence-based mental health care and decrease cost and burden of care for people with CF.
OBJECTIVE: To evaluate the usability and acceptability of "eHealth CF-CBT," an internet-based program integrating therapist-guided online self-management modules with in-person or virtual sessions.
METHODS: Dutch adults with CF (N = 16) and CF health care providers (N = 16) systematically tested all sessions of the eHealth CF-CBT program, provided qualitative feedback, and completed measures including eHealth Impact Questionnaire (eHIQ), and System Usability Scale (SUS).
RESULTS: Patient and provider ratings of their overall impression of the eHealth CF-CBT program were high, with scores (mean; SD) of 8.3; 0.6 and 8.2; 0.8 respectively on a 10-point scale. Mean ratings of usability by patients (77.0/100) and providers (73.4/100) surpassed the SUS cut point for good favorability. Ratings (pooled mean; SD) on the assessed eHIQ domains Motivation and Confidence to Act (71.3; 10.0), Information and Presentation (78.9; 9.6), and Identification (62.0; 15.1) were positive, as were assessments of specific elements of session content and format.
CONCLUSIONS: eHealth CF-CBT is the first therapist-guided internet-delivered CBT-based intervention for adults with CF. Initial evaluation with key stakeholders demonstrated high levels of acceptability and usability and provided input that was integrated to strengthen the program. Effectiveness testing in the Netherlands will be the next step, as well as future international adaptation and dissemination.
PMID:33816126 | PMC:PMC8010637 | DOI:10.1016/j.invent.2021.100372
Case Report of a Successful Pregnancy in a Cystic Fibrosis Patient with The c.1521_1523delCTT/c.3718-2477C>t Genotypes
Balkan J Med Genet. 2021 Mar 23;23(2):103-106. doi: 10.2478/bjmg-2020-0018. eCollection 2020 Nov.
ABSTRACT
The aim of this case report was to show the consequences of pregnancy in a cystic fibrosis (CF) patient with a rare mutation. We present a case of a patient with CF, pregnant for the second time, who gave birth to a healthy child. Her mutation status revealed the presence of relatively rare mutation c.3718-2477C>T that is associated with a milder phenotype of the disease. During pregnancy, her vital signs were within normal limits. She had no exacerbations after the third gestational month. Cystic fibrosis is the most common genetic disorder among Caucasians. Over the last few decades, the survival rate and the lifespan of patients with CF have increased progressively. This is why more affected women are choosing to become pregnant. Predictive factors for the pregnancy outcome are basal pulmonary function [measured by forced expiratory volume/1 second (FEV1)], nutritional status [measured by body mass index (BMI)], diabetes and bacterial colonization. The report of our case emphasizes the need for establishing the exact mutations in CF patients who plan to become pregnant in order to predict the possible outcomes of this specific period of life. Moreover, genetic counseling is strongly recommended for the right understanding of the pregnancy risks in such cases.
PMID:33816080 | PMC:PMC8009569 | DOI:10.2478/bjmg-2020-0018
Microbiota: A Missing Link in The Pathogenesis of Chronic Lung Inflammatory Diseases
Pol J Microbiol. 2021 Mar;70(1):25-32. doi: 10.33073/pjm-2021-013. Epub 2021 Feb 24.
ABSTRACT
Chronic respiratory diseases account for high morbidity and mortality, with asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) being the most prevalent globally. Even though the diseases increase in prevalence, the exact underlying mechanisms have still not been fully understood. Despite their differences in nature, pathophysiologies, and clinical phenotypes, a growing body of evidence indicates that the presence of lung microbiota can shape the pathogenic processes underlying chronic inflammation, typically observed in the course of the diseases. Therefore, the characterization of the lung microbiota may shed new light on the pathogenesis of these diseases. Specifically, in chronic respiratory tract diseases, the human microbiota may contribute to the disease's development and severity. The present review explores the role of the microbiota in the area of chronic pulmonary diseases, especially COPD, asthma, and CF.
PMID:33815524 | PMC:PMC8008760 | DOI:10.33073/pjm-2021-013
Ursodeoxycholic acid and liver disease associated with cystic fibrosis: A multicenter cohort study
J Cyst Fibros. 2021 Apr 1:S1569-1993(21)00090-4. doi: 10.1016/j.jcf.2021.03.014. Online ahead of print.
ABSTRACT
BACKGROUND: The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA.
METHODS: We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model.
RESULTS: Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12).
CONCLUSIONS: CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF.
PMID:33814323 | DOI:10.1016/j.jcf.2021.03.014
A mutational approach to dissect the functional role of the putative CFTR "PTM-CODE"
J Cyst Fibros. 2021 Apr 1:S1569-1993(21)00086-2. doi: 10.1016/j.jcf.2021.03.010. Online ahead of print.
ABSTRACT
Deletion of Phe at position 508 (F508del) in CFTR is the commonest cause of Cystic Fibrosis; this mutation affects the fate of the protein, since most of the F508del-CFTR is retained in the endoplasmic reticulum, ubiquitylated and degraded. CFTR is subjected to different post-translational modifications (PTMs) and the possibility to modulate these PTMs has been suggested as a potential therapeutic strategy for the functional recovery of F508del-CFTR. Recently, it has been suggested the presence of a PTM signature (phosphorylation, methylation and ubiquitylation) in the regulatory insertion element of the CFTR, named PTM-code, which is associated with CFTR maturation and F508del-CFTR recovery. However, the real contribution of these PTMs is still to be deciphered. Here, by using a mutational approach, we show that the PTM-code is dispensable for the functional recovery of F508del-CFTR and therefore its regulation would not be essential in the light of a therapeutical approach.
PMID:33814322 | DOI:10.1016/j.jcf.2021.03.010
Optical Measurements of Sweat for in Vivo Quantification of CFTR Function in Individual Sweat Glands
J Cyst Fibros. 2021 Apr 1:S1569-1993(21)00052-7. doi: 10.1016/j.jcf.2021.03.003. Online ahead of print.
ABSTRACT
Optical measurement of CFTR-dependent sweat secretion stimulated by a beta-adrenergic cocktail (C-phase) vs. CFTR-independent sweat secretion induced by methacholine (M-phase) can discriminate cystic fibrosis (CF) patientts from controls and healthy carriers by the ratio of sweat rate in the C-phase vs. the M-phase (C/M ratio). However, image analysis is experimentally demanding and time-consuming. Here, sweat droplet number (SDN) in the C-phase, corresponding to the number of sweat-secreting glands, was a statistically significant predictor for detecting the effects of CFTR-targeted therapy. We show that in 44 non-CF subjects and 110 CF patients, SDN in the C-phase provides a linear readout of CFTR function that is more sensitive than that using the C/M ratio. In CF patients, increased SDN in the C-phase during treatment with (LUMA/IVA) was associated with a trend toward improved lung function (FEV1). Our method is suitable for multicenter monitoring of the effects of CFTR modulators.
PMID:33814321 | DOI:10.1016/j.jcf.2021.03.003
Nasal high-flow therapy as an adjunct to exercise in patients with cystic fibrosis: A pilot feasibility trial
J Cyst Fibros. 2021 Apr 1:S1569-1993(21)00054-0. doi: 10.1016/j.jcf.2021.03.005. Online ahead of print.
ABSTRACT
BACKGROUND: Exercise tolerance in people with CF and advanced lung disease is often reduced. While supplemental oxygen can improve oxygenation, it does not affect dyspnoea, fatigue or comfort. Nasal high-flow therapy (NHFT), thanks to its pathophysiological mechanisms, could improve exercise tolerance, saturation and dyspnoea. This study explores the feasibility of conducting a clinical trial of using NHFT in patients with CF during exercise.
METHODS: A pilot, open-label, randomized crossover trial was performed, enroling 23 participants with CF and severe lung disease. Participants completed two treadmill walking test (TWT) with and without NHFT at 24-48 h interval. Primary outcome was trial feasibility, and exploratory outcomes were TWT distance (TWTD), SpO2, transcutaneous CO2, dyspnoea and comfort.
RESULTS: Recruitment rate was 2.4 subjects/month with 1.3:1 screening-to-randomization ratio. No adverse events caused by NHFT were observed. Tolerability was good and data completion rate was 100%. Twenty subjects (91%) were included in the exploratory study. Mean difference in TWTD on NHFT was 19 m (95% CI [4.8 - 33.1]). SpO2 was similar, but respiratory rate and mean tcCO2 were lower on NHFT (mean difference = -3.9 breaths/min 95% CI [-5.9 - -1.9] and -0.22 kPa 95% CI [-0.4 - 0.04]). NHFT reduced exercise-induced dyspnoea and discomfort.
CONCLUSION: Trials using NHFT in patients with CF during exercise are feasible. NHFT appears to improve walking distance, control respiratory rate, CO2, dyspnoea and improve comfort. A larger trial with a longer intervention is feasible and warranted to confirm the impact of NHFT in training programmes for patients with CF.
PMID:33814320 | DOI:10.1016/j.jcf.2021.03.005
CF Fungal Disease in the Age of CFTR Modulators
Mycopathologia. 2021 Apr 4. doi: 10.1007/s11046-021-00541-5. Online ahead of print.
ABSTRACT
Fungi are increasingly recognised to have a significant role in the progression of lung disease in Cystic fibrosis with Aspergillus fumigatus the most common fungus isolated during respiratory sampling. The emergence of novel CFTR modulators has, however, significantly changed the outlook of disease progression in CF. In this review we discuss what impact novel CFTR modulators will have on fungal lung disease and its management in CF. We discuss how CFTR modulators affect antifungal innate immunity and consider the impact of Ivacaftor on fungal disease in individuals with gating mutations. We further review the increasing complication of drug-drug interactions with concurrent use of azole antifungal medication and highlight key unknowns that require addressing to fully understand the impact of CFTR modulators on fungal disease.
PMID:33813719 | DOI:10.1007/s11046-021-00541-5
Antibody deficiencies are more common in adult versus pediatric recurrent acute rhinosinusitis
Am J Otolaryngol. 2021 Mar 29;42(5):103004. doi: 10.1016/j.amjoto.2021.103004. Online ahead of print.
ABSTRACT
PURPOSE: To evaluate the frequency and types of humoral immunodeficiencies (HID) in pediatric and adult patients with recurrent (RARS). Patients with HID commonly present with upper respiratory tract infections. Their pathophysiology in children is different than adult counterparts. It is unknown how HID affects those two age groups.
MATERIALS AND METHODS: We performed a retrospective chart review of pediatric (<18 years old) and adult (18 years and older) patients who were evaluated in our pediatric and adult rhinology clinic between July 2010 and December 2020 and had the diagnosis of recurrent (>3 times/year) rhinosinusitis. Patients with cystic fibrosis, Aspirin Exacerbated Respiratory Disease (AERD), and ciliary dyskinesia were excluded. Demographic data and associated conditions were reviewed. Immunologic evaluation included complete blood cell count (CBC) with differential, serum immunoglobulin G, A, and M levels, and baseline and post-vaccination pneumococcal antibody titers.
RESULTS: There were 135 patients who met the inclusion criteria. 86 patients (63.7%) were children, 49 patients (36.3%) were adults. 46.5% of the pediatric patients and 45% of the adult patients were female. 17.4% of children had abnormal immunologic findings: 8 had hypogammaglobulinemia (p < 0.0001), 2 had specific antibody deficiency (SAD), and 5 had selective IgA deficiency. 32.7% of adults (p < 0.0001) had abnormal immunologic findings: 4 had hypogammaglobulinemia, 11 had SAD (p < 0.0001), and 1 patient had both IgA deficiency and SAD.
CONCLUSION: Humoral immunodeficiency, specifically SAD, seems to be more common in adult versus pediatric RARS that is refractory to treatment.
PMID:33812207 | DOI:10.1016/j.amjoto.2021.103004
Simultaneous pancreas and kidney transplant after bilateral lung transplant for a recipient with Cystic Fibrosis
Am J Transplant. 2021 Apr 3. doi: 10.1111/ajt.16597. Online ahead of print.
ABSTRACT
Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. Lung transplantation is the only available therapy that deals definitively with the end-stage pulmonary disease and has become the treatment of choice for some of these patients. As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency and CF related diabetes (CFRD). Both of these can be managed through pancreas transplantation. We have previously reported our series of three simultaneous lung and pancreas transplants in patients with CF, which were complicated by surgical issues for both the thoracic and abdominal portions, rejection and resistant infections with disappointing long-term survival. Based on these results, a sequential approach was adopted: first, the thoracic transplant; and second, once the patient has recovered, the abdominal transplants. This is the first reported case of pancreas and kidney transplantation performed after a lung transplant in a patient with CF. It demonstrates a successful approach to treating CF with a lung transplant, and in an effort to improve the patient's long-term outcome, treating CFRD and pancreatic enzyme insufficiency, with a subsequent pancreas transplant.
PMID:33811791 | DOI:10.1111/ajt.16597
Real-world use of ivacaftor in Canada: A retrospective analysis using the Canadian Cystic Fibrosis Registry
J Cyst Fibros. 2021 Mar 30:S1569-1993(21)00057-6. doi: 10.1016/j.jcf.2021.03.008. Online ahead of print.
ABSTRACT
BACKGROUND: Ivacaftor is a CFTR potentiator with demonstrated efficacy in clinical trials and has been rapidly adopted within the CF community. Given the uptake of ivacaftor in eligible people, identifying a comparator group not on modulators to measure effectiveness is difficult. We evaluated health outcomes in individuals with G551D and non-G551D genotypes on ivacaftor using real-world longitudinal data.
METHODS: This population-based observational study compared clinical trajectories pre-post ivacaftor using the Canadian CF Registry from 2006 to 01-01 through 2018-12-31. Piece-wise linear mixed-effects models were used to compare lung function, nutritional status, pulmonary exacerbations, and Pseudomonas colonization pre- and post-ivacaftor. Multivariable models were used to adjust for confounding factors.
RESULTS: Forced expiratory volume in 1 second (FEV1) increased significantly by 5.7 percent predicted (95% confidence interval (CI) 3.9, 7.5; p<0.001) after initiation of ivacaftor. FEV1 decline rate was attenuated to -0.30% (95% CI -0.9, 0.29; p = 0.32) predicted/year post-ivacaftor, compared with -0.75% (95% CI -1.12, -0.37; p<0.001) predicted/year pre-ivacaftor, although this difference did not reach statistical significance. BMI percentiles also increased post-ivacaftor (6.57 percentiles, 95% CI 3.91, 9.24; p<0.001). Pulmonary exacerbations showed a nonsignificant reduction of 18% (RR 0.82, 95% CI 0.61, 1.11; p = 0.19) and the odds of a positive sputum culture for Pseudomonas aeruginosa decreased in the post-ivacaftor period (odds ratio 0.44, 95% CI 0.30, 0.63; p<0.001).
CONCLUSIONS: This real-world, observational study demonstrated improvement in health outcomes in a broad population of people with CF. Additional studies are needed to evaluate the impact of ivacaftor on quality of life and survival.
PMID:33810992 | DOI:10.1016/j.jcf.2021.03.008