J Cyst Fibros. 2021 Jun 5:S1569-1993(21)00168-5. doi: 10.1016/j.jcf.2021.05.015. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic methicillin resistant Staphylococcus aureus (MRSA) in CF is associated with worse outcomes compared to early or intermittent infection. This observation could be related to adaptive bacterial changes such as biofilm formation or anaerobic growth.

METHODS: MRSA isolates stored from incident and during chronic (>2 years) infection were included at two study sites. MRSA isolates were characterised by spa-typing, antimicrobial susceptibility testing, biofilm formation and haemolysis under aerobic and anaerobic culture conditions.

RESULTS: Paired MRSA isolates from 49 patients were included. Mean age at incident infection was 9.7±1.2 years with mild to moderate lung disease (FEV1 74±4% predicted). Twenty-five subjects showed progression of disease/symptoms after onset of MRSA with significantly increased use of antibiotics. Most isolates belonged to t002 (38%) and t008 (36%) spa-types and 8 patients had a change in spa-type over time. Antimicrobial susceptibility testing showed few differences between incident and late isolates but significantly lower MIC under anaerobic vs. aerobic conditions for vancomycin, fusidic acid, rifampin but higher MIC for trimethoprim-sulfamethoxazole. Biofilm formation and haemolysis did not differ by stage of infection or disease course but both were lower under anaerobic conditions (biofilm p=0.018; haemolysis p=0.002) in multi-variate analyses that included study site, growth condition and stage of infection.

CONCLUSIONS: Persistent MRSA infection is frequently associated with clinical decline. Anaerobic growth conditions, which occur in CF airways, affect the expression of virulence factors and antibiotic susceptibility of MRSA more than duration of infection.

PMID:34103251 | DOI:10.1016/j.jcf.2021.05.015

J Cyst Fibros. 2021 Jun 5:S1569-1993(21)00167-3. doi: 10.1016/j.jcf.2021.05.014. Online ahead of print.

ABSTRACT

BACKGROUND: W1282X-CFTR variant (c.3846G>A) is the second most common nonsense cystic fibrosis (CF)-causing mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Even though remarkable breakthroughs have been done towards CF treatment with the approval of four CFTR protein modulators, none of these are approved for patients with nonsense mutations. CRISPR gene editing tools can be of great value to permanently correct the genetic defects caused by these mutations.

METHODS: We compared the capacity of homology-directed repair (HDR) mediated by Cas9 or Cas12a to correct W1282X CFTR mutation in the CFF-16HBEge W1282X CFTR cell line (obtained from CFF), using Cas9/gRNA and Cas12a/gRNA ribonucleoproteins (RNPs) and single strand DNA (ssODN) oligonucleotide donors.

RESULTS: Cas9 shows higher levels of correction than Cas12a as, by electroporating cells with Cas9 RNPs and ssODN donor, nearly 18% of precise editing was achieved compared to just 8% for Cas12a. Such levels of correction increase the abundance of CFTR mRNA and protein, and partially restore CFTR function in the pool of edited cells to 18% of WT CFTR function. Moreover, homozygous corrected clones produced levels of mRNA, protein, and function comparable to those of cells expressing WT CFTR.

CONCLUSION: Altogether, this work demonstrates the potential of gene editing as a therapeutic strategy for CF directly correcting the root cause of the disease.

PMID:34103250 | DOI:10.1016/j.jcf.2021.05.014

J Cyst Fibros. 2021 Jun 5:S1569-1993(21)00127-2. doi: 10.1016/j.jcf.2021.04.017. Online ahead of print.

NO ABSTRACT

PMID:34103249 | DOI:10.1016/j.jcf.2021.04.017

J Heart Lung Transplant. 2021 Apr 22:S1053-2498(21)02283-X. doi: 10.1016/j.healun.2021.04.011. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is the indication for transplantation in approximately 15% of recipients worldwide, and Cystic Fibrosis Lung Transplant Recipients (CFLTRs) have excellent long-term outcomes. Yet, CFLTRs have unique comorbidities that require specialized care. The objective of this document is to provide recommendations to CF and lung transplant clinicians for the management of perioperative and underlying comorbidities of CFLTRs and the impact of transplantation on these comorbidities. The Cystic Fibrosis Foundation (CFF) organized a multidisciplinary committee to develop CF Lung Transplant Clinical Care Recommendations. Three workgroups were formed to develop focused questions. Following a literature search, consensus recommendations were developed by the committee members based on literature review, committee experience and iterative revisions, and in response to public comment. The committee formulated 32 recommendation statements in the topics related to infectious disease, endocrine, gastroenterology, pharmacology, mental health and family planning. Broadly, the committee recommends close coordination of care between the lung transplant team, the cystic fibrosis care center, and specialists in other disciplines with experience in the care of CF and lung transplant recipients. These consensus statements will help lung transplant providers care for CFLTRs in order to improve post-transplant outcomes in this population.

PMID:34103223 | DOI:10.1016/j.healun.2021.04.011

Am J Respir Cell Mol Biol. 2021 Jun 8. doi: 10.1165/rcmb.2021-0125OC. Online ahead of print.

ABSTRACT

Excessive lung inflammation and airway epithelium damage are hallmarks of human inflammatory lung diseases, such as cystic fibrosis (CF). Enhancement of innate immunity provides protection against pathogens while reducing lung-damaging inflammation. However, the mechanisms underlying innate immunity-mediated protection in the lung remain mysterious, in part because of the lack of appropriate animal models for these human diseases. Toll-like receptor 5 (TLR5) stimulation by its specific ligand, the bacterial protein flagellin, has been proposed to enhance protection against several respiratory infectious diseases, although other cellular events, such as calcium signaling, may also control the intensity of innate immune response. Here, we investigated the molecular events prompted by stimulation with flagellin and its role in regulating innate immunity in the lung of the pig, which is anatomically and genetically more similar to humans than rodent models. We found that flagellin treatment modulated NF-κB signaling and intracellular calcium homeostasis in airway epithelial cells. Flagellin pre-treatment reduced the NF-κB nuclear translocation and the expression of pro-inflammatory cytokines to a second flagellin stimulus as well as to Pseudomonas aeruginosa infection. Moreover, in vivo administration of flagellin decreased the severity of P. aeruginosa-induced pneumonia. Then, we confirmed these beneficial effects of flagellin in a pathological model of CF by using ex vivo precision-cut lung slices from a CF pig model. These results provide evidence that flagellin treatment contribute to a better regulation of the inflammatory response in inflammatory lung diseases such as CF.

PMID:34102087 | DOI:10.1165/rcmb.2021-0125OC

Med Lett Drugs Ther. 2021 May 31;63(1625):85-86.

NO ABSTRACT

PMID:34101719

Nutr Clin Pract. 2021 Jun 8. doi: 10.1002/ncp.10684. Online ahead of print.

NO ABSTRACT

PMID:34101253 | DOI:10.1002/ncp.10684

Pulm Ther. 2021 Jun 8. doi: 10.1007/s41030-021-00158-5. Online ahead of print.

ABSTRACT

INTRODUCTION: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has demonstrated clinical benefits in phase 3 trials. We report results from a real-world study (BRIO) to assess the effectiveness of ivacaftor in people with cystic fibrosis (pwCF) in France.

METHODS: BRIO was an observational study conducted at 35 centers in France. Both pwCF initiating ivacaftor treatment and those already taking ivacaftor were included and prospectively followed for 24 months. The primary objective was to evaluate the effect of ivacaftor on percent predicted forced expiratory volume in 1 s (ppFEV1); secondary objectives were evaluating the effect of ivacaftor on clinical effectiveness, healthcare resource utilization (HCRU), and safety.

RESULTS: A total of 129 pwCF were enrolled; 58.9% were aged < 18 years; 64.3% had a G551D-CFTR allele. Mean age at ivacaftor initiation was 19.1 years (range, 2-64 years); ppFEV1 increased by a least squares mean of 8.49 percentage points in the first 6 months and was sustained through 36 months of ivacaftor use. Growth metrics increased during the first 12 months post-ivacaftor and remained stable. The rate of pulmonary exacerbations (PEx) decreased during the 12 months post-fivacaftor compared with the 12 months pre-ivacaftor; estimated rate ratios (95% CI) were 0.57 (0.43-0.75) for PEx events and 0.25 (0.13-0.48) for PEx requiring hospitalization. No new safety concerns were identified; no deaths occurred.

CONCLUSIONS: The results from this real-world study of ivacaftor usage in France were consistent with prior clinical trial outcomes, confirming the clinical effectiveness of ivacaftor, as well as an associated reduction in HCRU.

PMID:34101145 | DOI:10.1007/s41030-021-00158-5

Clin Infect Dis. 2021 Jun 8:ciab525. doi: 10.1093/cid/ciab525. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) are associated with significant morbidity. While standard PEx treatment for PwCF with Pseudomonas aeruginosa infection includes two IV antipseudomonal antibiotics, little evidence exists to recommend this approach. This study aimed to compare clinical outcomes of single versus double antipseudomonal antibiotic use for PEx treatment.

METHODS: Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were included if hospitalized between 2007-2018 and 6-21 years of age. Regression modeling accounting for repeated measures was used to compare lung function outcomes between single versus double IV antipseudomonal antibiotic regimens using propensity-score weighting to adjust for relevant confounding factors.

RESULTS: Among 10,660 PwCF in the dataset, we analyzed 2,578 PEx from 1,080 PwCF, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. We identified no significant differences between PEx treated with 1 versus 2 IV antipseudomonal antibiotics either in change between pre- and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (-0.84%, [95% CI -2.25, 0.56]; p=0.24), odds of returning to ≥90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; p=0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; p=0.69).

CONCLUSION: Use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not associated with greater improvements in measured respiratory and clinical outcomes compared to treatment with 1 IV antipseudomonal antibiotic.

PMID:34100912 | DOI:10.1093/cid/ciab525

JCI Insight. 2021 Jun 8;6(11):147699. doi: 10.1172/jci.insight.147699.

ABSTRACT

SLC26A6 (also known as putative anion transporter 1 [PAT1]) is a Cl-/HCO3- exchanger expressed at the luminal membrane of enterocytes where it facilitates intestinal Cl- and fluid absorption. Here, high-throughput screening of 50,000 synthetic small molecules in cells expressing PAT1 and a halide-sensing fluorescent protein identified several classes of inhibitors. The most potent compound, the pyrazolo-pyrido-pyrimidinone PAT1inh-B01, fully inhibited PAT1-mediated anion exchange (IC50 ~350 nM), without inhibition of the related intestinal transporter SLC26A3 (also known as DRA). In closed midjejunal loops in mice, PAT1inh-B01 inhibited fluid absorption by 50%, which increased to >90% when coadministered with DRA inhibitor DRAinh-A270. In ileal loops, PAT1inh-B01 blocked fluid absorption by >80%, whereas DRAinh-A270 was without effect. In colonic loops, PAT1inh-B01 was without effect, whereas DRAinh-A270 completely blocked fluid absorption. In a loperamide constipation model, coadministration of PAT1inh-B01 with DRAinh-A270 increased stool output compared with DRAinh-A270 alone. These results provide functional evidence for complementary and region-specific roles of PAT1 and DRA in intestinal fluid absorption, with PAT1 as the predominant anion exchanger in mouse ileum. We believe that PAT1inh-B01 is a novel tool to study intestinal ion and fluid transport and perhaps a drug candidate for small intestinal hyposecretory disorders such as cystic fibrosis-related meconium ileus and distal intestinal obstruction syndrome.

PMID:34100381 | DOI:10.1172/jci.insight.147699

J Trop Pediatr. 2021 May 17;67(2):fmab030. doi: 10.1093/tropej/fmab030.

ABSTRACT

OBJECTIVE: The objective of this study is to find the organism profile and antimicrobial susceptibility patterns in children with cystic fibrosis (CF).

DESIGN: Prospective cohort study.

SETTING: Hospital-based study.

INTERVENTION: Sputum cultures/throat swabs were collected from the study population. Relevant details like anthropometry, systemic examination findings and investigations were entered in a pre-designed format. Sputum culture was subjected to microbiological analysis at the hospital microbiology laboratory.

MAIN OUTCOME MEASURE: Prevalence of positive sputum/cough swab culture in CF patients, their organism profile and antibiotic sensitivity.

RESULTS: A total of 63 patients were enrolled in the study. A total of 136 organisms were grown in our study population. Thirteen different organisms were isolated, which included five gram-positive bacteria, six gram-negative bacteria, eight Candida spp. and one filamentous. Antibiotic sensitivity profile of the Pseudomonas aeruginosa showed excellent sensitivity to all the aminoglycosides, piperacillin-tazobacteum and polymixin, similarly methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus and Enterococcus spp. were uniformly sensitive to vancomycin, linezolid and teicoplanin. Fungal isolates showed 100% sensitivity to all the antifungals tested including azoles and amphotericin B.

CONCLUSION: We observed 61% of culture positivity for different organisms in our study. Staphylococcus aureus and P. aeruginosa were the most frequently isolated organisms. Pseudomonas aeruginosa isolates were largely sensitive to aminoglycosides, carbapenems and polymixin. We found an unusually higher incidence of enterococcal infection in our study cohort with few vancomycin-resistant isolates.

PMID:34100087 | DOI:10.1093/tropej/fmab030

J Cyst Fibros. 2021 Jun 4:S1569-1993(21)00051-5. doi: 10.1016/j.jcf.2021.03.002. Online ahead of print.

ABSTRACT

BACKGROUND: Levofloxacin inhalation solution is the most recently approved inhaled antibiotic in Europe and Canada for adult cystic fibrosis patients. Its efficacy and safety have been assessed in randomized controlled trials. Our aim was to evaluate real life experience and outcomes in our treatment centre.

METHODS: We evaluated the efficacy of inhaled levofloxacin solution in 86 patients with cystic fibrosis in terms of the following outcome parameters: changes in %-predicted forced expiratory volume in one second (FEV1), body-mass index (BMI), and exacerbation rate. We conducted an intraindividual analysis of patients who received levofloxacin inhalation solution twice daily 240 mg for at least 4 weeks.

RESULTS: Change in FEV1% predicted for the treatment period was +2.27% (p=0.0027) after 4 weeks. There was no change in BMI for overall group, but exacerbation rate compared to one year before initiation of inhaled levofloxacin decreased significantly (p=0.0024) after 1 year of treatment (3.23 ± 1.39 versus 2.71 ± 1.58).

CONCLUSIONS: In patients with cystic fibrosis, inhaled levofloxacin solution has the potential to improve FEV1 and to reduce the number of bronchopulmonary exacerbations.

PMID:34099405 | DOI:10.1016/j.jcf.2021.03.002

Chest. 2021 Jun;159(6):2507-2508. doi: 10.1016/j.chest.2021.01.021.

NO ABSTRACT

PMID:34099136 | DOI:10.1016/j.chest.2021.01.021

J Vis Exp. 2021 May 21;(171). doi: 10.3791/62193.

ABSTRACT

Proteases are regulators of countless physiological processes and the precise investigation of their activities remains an intriguing biomedical challenge. Among the ~600 proteases encoded by the human genome, neutrophil serine proteases (NSPs) are thoroughly investigated for their involvement in the onset and progression of inflammatory conditions including respiratory diseases. Uniquely, secreted NSPs not only diffuse within extracellular fluids but also localize to plasma membranes. During neutrophil extracellular trap (NETs) formation, NSPs become an integral part of the secreted chromatin. Such complex behavior renders the understanding of NSPs pathophysiology a challenging task. Here, detailed protocols are shown to visualize, quantify and discriminate free and membrane-bound neutrophil elastase (NE) and cathepsin G (CG) activities in sputum samples. NE and CG are NSPs whose activities have pleiotropic roles in the pathogenesis of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD): they promote tissue remodeling, regulate downstream immune responses and correlate with lung disease severity. The protocols show how to separate fluid and cellular fraction, as well as the isolation of neutrophils from human sputum for enzymatic activity quantification via small-molecule Förster resonance energy transfer-based (FRET) reporters. To gather specific insights into the relative role of NE and CG activities, a FRET readout can be measured by different technologies: i) in vitro plate reader measurements allow for high-throughput and bulk detection of protease activity; ii) confocal microscopy spatiotemporally resolves membrane-bound activity at the cell surface; iii) small-molecule FRET flow cytometry enables for the rapid evaluation of anti-inflammatory treatments via single-cell protease activity quantification and phenotyping. The implementation of such methods opens the doors to explore NSPs pathobiology and their potential as biomarkers of disease severity for CF and COPD. Given their standardization potential, their robust readout and simplicity of transfer, the described techniques are immediately shareable for implementation across research and diagnostic laboratories.

PMID:34096915 | DOI:10.3791/62193

Endocrinol Diabetes Metab Case Rep. 2021 Jun 1;2021:EDM210026. doi: 10.1530/EDM-21-0026. Online ahead of print.

ABSTRACT

SUMMARY: Phaeochromocytoma is a rare catecholamine-producing tumour. We present the case of phaeochromocytoma in a young man with a background history of a double-lung transplant for cystic fibrosis (CF). Clinical case: A 25-year-old man, with a background history of CF, CF-related diabetes (CFRD) and a double-lung transplant in 2012 was presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with distal intestinal obstructions syndrome (DIOS). Contrast-enhanced CT imaging of the abdomen and pelvis showed a 3.4 cm right adrenal lesion. This was confirmed by a subsequent MRI of adrenal glands that demonstrated moderate FDG uptake, suggestive of a diagnosis of phaeochromocytoma. The patient was noted to be hypertensive with a blood pressure averaging 170/90 mm/Hg despite treatment with three different anti-hypertensive medications - amlodipine, telmisartan and doxazosin. He had hypertension for the last 3 years and had noted increasingly frequent sweating episodes recently, without palpitations or headache. Laboratory analysis showed elevated plasma normetanephrines (NMN) of 3167 pmol/L (182-867) as well as elevated metanephrines (MN) of 793 pmol/L (61-377) and a high 3-MT of 257 pmol/L (<185). Once cathecholamine excess was identified biochemically, we proceeded to functional imaging to further investigate. MIBG scan showed a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary (MDT) meeting at which the diagnosis of phaeochromocytoma was made. Following a challenging period of 4 weeks to control the patient's blood pressure with an alpha-blocker and beta-blocker, the patient had an elective right adrenalectomy, with normalisation of his blood pressure post-surgery. The histopathology of the excised adrenal gland was consistent with a 3 cm phaeochromocytoma with no adverse features associated with malignant potential.

LEARNING POINTS: Five to ten per cent of patients have a secondary cause for hypertension. Phaeochromocytomas are rare tumours, originating in chromaffin cells and they represent 0.1-1.0% of all secondary hypertension cases. Secondary causes should be investigated in cases where: Patient is presenting <20 years of age or >50 years of age, There is refractory hypertension, or There is serious end-organ damage present. Patients may present with the triad of headache, sweating and palpitations or more vague, non-specific symptoms. Patients with suspected phaeochromocytoma should have 24-h urinary catecholamines measured and if available, plasma metanephrines measured. Those with abnormal biochemical tests should be further investigated with imaging to locate the tumour. Medical treatment involves alpha- and beta-blockade for at least 2 to 3 weeks before surgery as well as rehydration. There is a possibility of relapse so high-risk patients require life-long follow-up.

PMID:34096506 | DOI:10.1530/EDM-21-0026

Biochem Biophys Rep. 2021 May 26;26:101028. doi: 10.1016/j.bbrep.2021.101028. eCollection 2021 Jul.

ABSTRACT

Chronic mucoid Pseudomonas aeruginosa infections are a major scourge in cystic fibrosis patients. Mucoid P. aeruginosa displays structured alginate-rich biofilms that are resistant to antibiotics. Here, we have assessed the efficacy of a panel of alginate lyases in combating mucoid P. aeruginosa biofilms in cystic fibrosis. Albeit we could not demonstrate alginate degradation by alginate lyases in sputum, we demonstrate that the endotypic alginate lyases, CaAly (from Cellulophaga algicola) and VspAlyVI (from Vibrio sp. QY101) and the exotypic alginate lyases, FspAlyFRB (from Falsirhodobacterium sp. alg1), and SA1-IV (from Sphingomonas sp. A1), indeed inhibit biofilm formation by a mucoid P. aeruginosa strain isolated from the sputum of a cystic fibrosis patient with comparative effect to that of the glycoside hydrolase PslG, a promising candidate for biofilm treatment. We believe that these enzymes should be explored for in vivo efficacy in future studies.

PMID:34095554 | PMC:PMC8165544 | DOI:10.1016/j.bbrep.2021.101028

J Healthc Eng. 2021 May 10;2021:6671833. doi: 10.1155/2021/6671833. eCollection 2021.

ABSTRACT

Identifying disease progression through enhanced decision support tools is key to chronic management in cystic fibrosis at both the patient and care center level. Rapid decline in lung function relative to patient level and center norms is an important predictor of outcomes. Our objectives were to construct and utilize center-level classification of rapid decliners to develop an animated dashboard for comparisons within patients over time, multiple patients within centers, or between centers. A functional data analysis technique known as functional principal components analysis was applied to lung function trajectories from 18,387 patients across 247 accredited centers followed through the United States Cystic Fibrosis Foundation Patient Registry, in order to cluster patients into rapid decline phenotypes. Smaller centers (<30 patients) had older patients with lower baseline lung function and less severe rates of decline and had maximal decline later, compared to medium (30-150 patients) or large (>150 patients) centers. Small centers also had the lowest prevalence of early rapid decliners (17.7%, versus 24% and 25.7% for medium and large centers, resp.). The animated functional data analysis dashboard illustrated clustering and center-specific summaries of the rapid decline phenotypes. Clinical scenarios and utility of the center-level functional principal components analysis (FPCA) approach are considered and discussed.

PMID:34094041 | PMC:PMC8140832 | DOI:10.1155/2021/6671833

Int J Mol Epidemiol Genet. 2021 Apr 15;12(2):24-34. eCollection 2021.

ABSTRACT

Asthma is a complex genetic disease. Vitamin D and vitamin D receptor (VDR) gene polymorphisms are involved in asthma pathogenesis. However, accurate inflammatory mechanisms and their role in VDR gene polymorphisms are unclear. The objective of this study was to investigate the association of VDR gene polymorphisms, ApaI, FokI, TaqI, and BsmI with asthma as compared to controls. Children (age 5-15 years) with a history of respiratory symptoms (wheeze, shortness of breath and chest tightness) were recruited as cases. Age matched children admitted with central nervous system disorders (encephalitis/seizures) without any respiratory complaints were recruited as controls after parental consent. Children with a clinical diagnosis of cystic fibrosis, congenital heart disease and whose parents did not consent for participation in the study were excluded. VDR gene polymorphisms were genotyped using PCR-RFLP method. One hundred and sixty asthmatics and one hundred controls were enrolled in this study. Mean age of the cases was 103.29±32.7 months and controls 94.24±30.52 months. Children with heterozygous (AC) genotype [OR=1.83, 95% CI=1.01-3.32, p=0.046] of ApaI polymorphism were found to be associated with the risk of asthma. Our findings suggest that ApaI polymorphism of VDR gene may contribute to asthma susceptibility among children.

PMID:34093968 | PMC:PMC8166730

Pulmonology. 2021 Jun 3:S2531-0437(21)00093-3. doi: 10.1016/j.pulmoe.2021.04.004. Online ahead of print.

NO ABSTRACT

PMID:34092546 | DOI:10.1016/j.pulmoe.2021.04.004

J Pediatr Gastroenterol Nutr. 2021 Jun 1. doi: 10.1097/MPG.0000000000003194. Online ahead of print.

ABSTRACT

OBJECTIVES AND STUDY: Cystic fibrosis related liver disease (CFLD) with consecutive cirrhosis is the third most common cause of death in CF patients (3). The aim of this study is to identify the potential long-term benefits of liver transplantation (LTx) in a match-control comparison.

METHODS: Retrospective single-center data analysis of all pediatric LTx for CFLD between 1998 and 2014. A control group was selected from the local CF patient registry. Data were collected from case report forms and included clinical and laboratory data, lung function tests, the indication for LTx and details of surgical procedures.

RESULTS: At our institution 23 patients with severe CFLD median age 13.8 years (range 8.7-17.4; 16 boys) underwent LTx between 1998 and 2014. In all patients, normalization of hepatic CF manifestations were achieved after LTx. But obviously there was no significant positive influence on nutritional status. Signs of post-transplant liver steatosis were documented by ultrasound in 17 patients. Liver biopsies after LTx were performed in 19 patients, in 42% (n = 8) of these biopsies a fatty degeneration was observed. 5 patients died after LTx, none because of primary hepatic dysfunction (1 due to post-transplant proliferative disorder, 4 due to infection).Analysis of matched control pairs revealed that liver function, anthropometry, pulmonary function and life expectancy of CFLD patients with LTx are comparable to matched CF peers without CFLD.

CONCLUSION: Isolated LTx normalizes the hepatic manifestation of CF disease. LTx enables children and adolescents with severe CFLD to have a comparable prognosis in terms of growth, life expectancy and lung function as CF patients without advanced liver involvement. Our data clarifies the long-term perspectives of affected patients.

PMID:34091543 | DOI:10.1097/MPG.0000000000003194