Introduction

​In people with cystic fibrosis (CF), CFTR modulator therapy has resulted in marked improvements in pulmonary exacerbations, lung function, body weight, and quality of life. However, it remains unclear how restoring CFTR function modifies existing airway infection and inflammation. Understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections.

Aims & Methods

Our aim was to conduct a systematic review and meta-analysis of all available studies.
We conducted a systematic search on the 26^th January, 2024 in MEDLINE, Embase, Web of Science, Scopus and CENTRAL. We performed a random-effects meta-analysis of any provided data pertaining to lower airway microbiota composition before versus after the initiation of CFTR modulator therapy. We calculated mean difference (MD) and standardized MD (SMD) with 95% confidence intervals (CI) and visualized the results on forest plots. Chi-squared tests were performed and I² values calculated to assess statistical heterogeneity.

Results

30 studies were eligible for inclusion, with most prospectively examining people with CF before and 4-12 months after the initiation of CFTR modulator therapy. The initiation of CFTR modulator therapy was associated with an increase in lower airway alpha-diversity (Shannon index; SMD: +0.39 (95% CI: +0.20 - +0.59), p<0.0001), evenness (Pielou index; SMD: +0.84 (95% CI: +0.55 - +1.12), p<0.00001) as well as a reduction in the relative abundance of classical CF lung pathogen species Pseudomonas (MD: -7.1% (95% CI: -1.2% - -13.1%), p=0.02) and Staphylococcus (MD: -4.3% (95% CI: -2.0% - -6.6%), p=0.0003).

Conclusion

Our results demonstrate a clear and statistically significant association between the initiation of CFTR modulator therapy and the stabilization of lower airway microbiota in terms of increased biodiversity, more balanced distribution of microbial species and reduction in the abundance of potentially pathogenic species, all of which contribute to a lower risk of respiratory tract infections.

Introduction

CFTR modulators represent a groundbreaking therapeutic approach in cystic fibrosis (CF) management, targeting the underlying cause of the disease. These therapies have the potential to directly influence pancreatic beta-cell function and pathways involved in insulin secretion, thereby improving the glycemic status of people with CF (pwCF).

Aims & Methods

We aimed to evaluate the effect of CFTR modulator therapy on endocrine pancreatic function in patients with CF. A systematic search of three databases (PubMed, Embase, and CENTRAL) was conducted up to March 6, 2024, to identify studies examining the impact of CFTR modulators on glucose metabolism in pwCF comparing variables before and after CFTR modulator therapy. Outcomes of interest included measures from oral glucose tolerance tests (OGTT), continuous glucose monitoring (CGM), and glycated hemoglobin (HbA1c). Meta-analysis was initiated using random-effects models to estimate pooled mean differences (MD) and 95% confidence intervals (CIs). Subgroup analyses were created based on CFTR modulators and length of therapy. Covariate regression analyses were made to assess the relationship between therapy length and pooled MD. A p-value less than 0.05 was considered to be statistically significant. The study protocol was registered in PROSPERO with registration number CRD42024516198.

Results

Conclusion

Our results revealed an improvement in the 120-minute OGTT plasma glucose level in the elexacaftor/tezacaftor/ivacaftor subgroup. The absence of significant changes in other analyses may indicate that these medications could potentially slow or halt the deterioration of glucose metabolism. Further prospective studies are required to overcome the limitation of a relatively small patient number and to validate our findings.

Introduction

Basic science results suggest that abnormalities of the endocrine pancreas in cystic fibrosis (CF) occur earlier than hitherto estimated (1). All stages of the abnormal glucose tolerance (AGT) spectrum are associated with declining pulmonary function and increased mortality which could be reduced by early recognition and treatment (2-4). Despite, screening for AGT is recommended only from 10 years of age (yoa) according to the current guidelines (5,6). Accurate knowledge of the prevalence of AGT and its subtypes is essential to develop a better screening strategy, therefore we conducted a systematic review and meta-analysis in the topic.

Aims & Methods

Our systematic review and meta-analysis (PROSPERO number: CRD42021282516) was conducted on studies that reported data on the prevalence of AGT or its subtypes in CF populations. Literature search was conducted in MEDLINE (via PubMed), Embase and Cochrane Register of Controlled Trials (CENTRAL). General and superselected populations (e.g.: pancreas exocrine insufficient, ΔF508 homozygous) were separately analyzed. Pooled proportions, risk and odds ratios with 95% confidence intervals (CI) were calculated in at least three age subgroups (pediatric, adult, mixed/unknown). One-stage dose-response random effect meta-analysis was used to assess the effect of age on CF- related diabetes (CFRD).

Results

The quantitative analysis included 457 studies and data from 520,544 patients. More than one third of children with CF (chwCF) were affected by AGT (0.31 [95% CI 0.25-0.37]), even under 10 yoa 0.33 [95% CI 0.23-0.44], and half of the adults with CF (awCF) had AGT (0.51 [95% CI 0.45-0.57]). The prevalence of prediabetes remained unchanged (impaired glucose tolerance in chwCF: 0.14 [95% CI 0.10-0.18]) vs. awCF: 0.19 [95% CI 0.14-0.25]), while the proportion of CFRD increased by age (<5 yoa: 0.005 [95% CI 0.0001-0.15]; 5-10 yoa: 0.05 [95% CI 0.01-0.27]; 10-18 yoa: 0.11 [95% CI 0.08-0.14]; >18 yoa: 0.27 [95% CI 0.24-0.30]).

Conclusion

CF-related AGT is common under 10 years of age. Reconsideration of the current guidelines and better awareness are needed for screening and treating AGT in CF, especially under 10 yoa, to delay the disease progression and maintain a better life quality.

References

1. Olivier AK, Yi Y, Sun X, Sui H, Liang B, Hu S, et al. Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest. 2012;122(10):3755-68.
2. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol. 2013;1(1):52-8.
3. Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D, Dunitz J, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200.
4. Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, et al. Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial. Diabetes Care. 2009;32(10):1783-8.
5. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33(12):2697-708.
6. Balfour-Lynn I. Clinical Guidelines: Care of Children with Cystic Fibrosis. UK: Royal Brompton and Harefield Hospital, NHS Trust Foundation; 2023.

Introduction

Gut micorbiota in patients with cystic fibrosis (pwCF) is severely disrupted and a potential source of further complications. We aim to provide quantitative evidence of the differences in gut microbiota between pwCF and non-CF controls to understand CF gut flora composition and identify potential sites for microbiota modulation with special focus on time-dependent changes.

Aims & Methods

We conducted a systematic review and meta-analysis of PubMed, EMBASE, CENTRAL, Web of Science, and Scopus up to November 13, 2023 (CRD42023482792). Included were case-control studies assessing gut microbial alpha diversity or relative abundance in pwCF and controls without gut-affecting conditions or drugs. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model for both outcomes. We performed subgroup analysis for alpha diversity for infants, children, and adults. We used the Joanna Briggs Institute risk of bias tool.

Results

Among 2550 studies, 11 met inclusion criteria (enrolling 1174 subjects). Alpha diversity analysis showed age-specific changes. Observed OTUs were non-significantly decreased in adult pwCF compared to controls (SMD=-1.57; 95%CI -4.21 to 1.08, across 3 studies, 80 pwCF and 100 controls). Children with CF displayed a significantly reduced Shannon index (SMD=-1.43; 95%CI -2.06 to -0.79, across 3 studies, 77 pwCF and 78 controls). However, in infants, no difference was detected in Shannon index between CF patients and controls (SMD=0.05; 95%CI -0.74 to 0.84, across 4 studies, 288 pwCF, 519 controls). Analysis of follow-up data in infants revealed a decreasing tendency of Shannon index in pwCF compared to controls during the first year of life (SMD=0.67; 95%CI -1.20 to 2.54 at 4 months vs. SMD=0.45; 95%CI -1.81 to 2.71 at 6 months vs. SMD=-0.61; 95%CI -1.98 to 0.75 at 12 months). A significant increase in the relative abundance of Veillonella and E.coli marked the CF group with a noticeable increase of Enterobacter and decrease of Bacteroides and Faecalibacterium compared to controls (see Table).

Conclusion

Gut microbial alpha diversity is reduced in adults and children with CF compared to controls, while infants with CF exhibit similar diversity, which continuously decreases during the first year of life. Perturbations in the intestinal microbial ecosystem are defined by a significant increase in E.coli and Veillonella abundances within individuals with CF compared to controls enabling specifically targeted microbiota modulation.

Introduction

With chronic inflammation, recurrent infections, and dysbiosis, people with CF (pwCF) are predisposed to autoimmunity. However, the role of autoimmune-mediated pancreatic beta-cell damage is yet unclear in the development of cystic fibrosis-related abnormal glucose tolerance (CF-AGT).

Aims & Methods

We aimed to assess the prevalence of various islet autoantibodies (AABs) according to glucose tolerance and age and the risk associated with islet AAB positivity for developing CF-AGT. A systematic search across four databases (CENTRAL, Embase, PubMed, Web of Science) identified studies reporting on AABs against glutamic acid decarboxylase (GADA), insulin (IAA), islet cell (ICA), insulinoma-associated protein 2 (IA-2A), and zinc transporter 8 (ZnT8A) in pwCF (CRD42020155846). Prevalence and odds ratios (OR) were calculated with 95% confidence intervals (CI) using a random effects model with subgroup analysis by glucose tolerance and age.

Results

Conclusion

Introduction

Inflammatory digestive diseases can have a major impact on the physical and mental wellbeing of affected patients. Psychosocial factors can alter the behaviour linked to disease and influence treatment outcomes.

Aims & Methods

The aim of this systematic review and meta-analysis was to assess the efficacy and safety of psychological interventions on depression, anxiety, and stress in patients with inflammatory digestive diseases. The study protocol was prospectively registered on PROSPERO (CRD42021282965). The systematic search was conducted on April 1st, 2023 in three medical databases (PubMed, CENTRAL, Embase). Randomized controlled trials (RCTs) that investigated the effects of various psychological interventions on mental and physical health in patients with all types of inflammatory digestive diseases were included. Outcomes were assessed at the end of therapy and at various timepoints during the follow-up period (short-, mid- and long-term follow-up). Owing to the differences in scales and questionnaires, the standardised mean difference (SMD) was used to pool effect sizes, with its corresponding 95% confidence interval (CI). Higgins and Thompson's I² statistics were used to assess heterogeneity.

Results

We included 24 RCTs that investigated the effect of psychological interventions on depressive symptoms, totalling 1572 participants. The pooled analysis found that psychological interventions resulted in a moderate reduction of depression compared to controls (SMD -0.46; 95% CI: -0.75; -0.18; I² 87%). Data from 19 RCTs with 1593 patients also demonstrated a moderate reduction in anxiety symptoms in subjects undergoing psychological interventions (SMD -0.58; 95% CI: -0.94; -0.22; I² 90%). The pooled analysis of 13 RCTs totalling 772 participants found that psychological therapy was associated with a moderate decrease in stress (SMD -0.53; 95% CI: -1.04; -0.03; I² 85%). Additional analysis of follow-up data showed that benefits resulting from treatment gradually decrease, showing no significant difference at the end of the long-term follow-up period.

Conclusion

Psychological interventions effectively improve mental health-related outcomes in patients with inflammatory digestive diseases. Since benefits from therapy seem to decrease during the follow-up period, repeated interventions may be necessary.

Introduction

To investigate the relationships between hand grip strength (HGS), physical activity levels, body composition and BMI in paediatric patients with cystic fibrosis (CF).

Aims & Methods

This single-centre prospective observational study measured hand grip strength (HGS) using a Jamar hydraulic dynamometer, body composition (using InBody 770) and lung function (FEV1) values. Physical activity was calculated using the Modified Godin Scale Score (GSS). Body weight, height and body mass index (BMI) were analysed as z-scores and HGS as percentiles standardised for age and sex. Linear regression was used to estimate relationships, with R² values indicating the strength of associations. Participants on CFTR modulators were compared with modulator-naïve individuals.

Results

The study included 82 children with CF (mean age: 12.4 ± 4.4 years). Out of these, 66 patients were receiving CFTR modulator therapy (39 LUM/IVA, 27 ETI). No significant differences were found in any of the investigated parameters between those on CFTR modulator therapy and those not receiving it (Table 1). However, the modulator groups showed a trend for higher height, weight and BMI z-scores. Based on their GSS, 95% of children were classified as active. Neither the HGS nor the GSS showed any correlation with BMI (R²=0.044; 0.034), fat mass percentile (R²< 0.001; 0.001) or skeletal muscle mass percentile (R²=0.001; 0.006). Similarly, the relationship between FEV1 and SMM was negligible (R²=0.002). Both HGS and GSS showed weak positive correlations with FEV1 (R²=0.121; 0.077) and with each other (R²=0.115).

Conclusion

GSS, HGS and FEV1 showed weak correlation and may be useful in assessing aspects of functional and physical performance in children with CF. In contrast, body composition and BMI showed no correlation with these performance measures.