Updates in Pediatric Pulmonary Symposium (1).pptx

Updates in diagnoses and management of cystic fibrosis and associated conditions.

1. Updates in Pediatric Pulmonary Symposium Updates in Cystic Fibrosis Dr. Hisham Hamdan Pediatric pulmonologist and Sleep Physician Amman 8 Aug 2024

2. Methods: Cystic Fibrosis Guidelines: 2023, 2024 ATS guidelines 2023-2024 BTS and NICE guidelines 2023-2024 National Library of Health Search “cystic Fibrosis” 2023-2024

3. Cystic Fibrosis Foundation Evidence-Based Guideline for the Management of CRMS/CFSPID. Pediatrics. 2024 May Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen-positive, inconclusive diagnosis (CRMS/CFSPID) Defined as people with CRMS/CFSPID as people with an abnormal CF NBS result and (1) a sweat Cl- of <30 mmol/l (normal) and 2 CFTR variants, at least 1 of which with unclear phenotypic consequences, or (2) sweat Cl- of 30 to 59 mmol/L (intermediate value) and 1 or no CF causing variants. Thorough evaluation with genetic sequencing, deletion/duplication analysis if <2 disease-causing variants were noted in newborn screening. Repeat sweat chloride testing at 6 months of life and annually at least until age 8 y but limiting further laboratory testing, including microbiology, radiology, and pulmonary function testing. The CFF recommends for people with CRMS/CFSPID that measurement of FE be provided at the initial assessment and selectively thereafter. Minimal use of medications, which when suggested, should lead to shared decision-making with families; and providing communication with emphasis on social determinants of health and shared decision-making to minimize barriers which may affect processing and understanding of this complex designation. Future research will be needed regarding medication use, antibiotic therapy, and the use of chest imaging for monitoring the development of lung disease

4. Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations. Hepatology 79(5):p 1220-1238, May 2024. The CFF recommends that annual labs (total bilirubin, AST, ALT, alkaline phosphatase, GGT, platelet count) should be performed, at a time of clinical stability, for identification of hepatobiliary involvement in all persons with CF starting at CF diagnosis The CFF recommends for persons with CF and hepatobiliary involvement an abdominal US be performed at least every 2 y to monitor for the progression of disease The CFF recommends against the routine use of ursodeoxycholic acid to prevent advanced liver disease in all persons with CF.

5. Bronchoscopy-guided antimicrobial therapy for cystic fibrosis. Cochrane Database Syst Rev. 2024 May Cochrane Database Syst Rev Objectives: To evaluate the use of bronchoscopy-guided (also known as bronchoscopy-directed) antimicrobial therapy in the management of lung infection in adults and children with cystic fibrosis. No evidence to support the routine use of BAL for the diagnosis and management of pulmonary infection in preschool children with CF compared to the standard practice of providing treatment based on results of oropharyngeal culture and clinical symptoms

6. A randomized trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment. Eur Respir J. 2024 Jun 6;63(6) This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

7. SALTI-CF Study Group. Saline at lower tonicity in cystic fibrosis (SALTI-CF) trial comparing 0.9% versus 3% versus 6% nebulized saline. Eur Respir J. 2023 Jul In people with cystic fibrosis (CF), regular nebulization of 6% or 7% saline improves lung function; however, these concentrations are not always tolerable. Clinically, some CF patients report using lower concentrations of saline to improve tolerability. Randomised , blinded, placebo-controlled, parallel-group, multicenter study where subjects inhaled 4 mL of 0.9%, 3% or 6% saline twice daily for 16 weeks. 140 subjects. The primary outcome was FEV1. The secondary outcomes were: FVC and FEF25-75%, quality of life; exercise capacity; acquisition or loss of bacterial organisms in expectorated sputum; tolerability of nebulised saline; pulmonary exacerbations; and adverse events. 3% saline significantly improved lung function and increased the time to first pulmonary exacerbation compared with 0.9% saline but did not improve quality of life. 6% saline had similar benefits to 3% saline but also significantly improved quality of life compared with 3% saline. Only 6% saline delayed the time to intravenous antibiotics for pulmonary exacerbation. Tolerability and adherence were similar.

8. The effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): a phase 3, randomised, double-blind, placebo-controlled clinical trial June 02, 2022 “We hypothesized that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans.” A phase three, randomised, double-blind, placebo-controlled trial was done at eight pediatric cystic fibrosis centers in Australia and New Zealand. Infants (aged 3–6 months) diagnosed with cystic fibrosis following newborn screening were eligible. Azithromycin treatment from diagnosis of cystic fibrosis did not reduce the extent of structural lung disease at 36 months of age; however, it did reduce airway inflammation, morbidity including pulmonary exacerbations in the first year of life and hospitalizations, and improved some clinical outcomes associated with cystic fibrosis lung disease. Therefore we suggest thrice-weekly azithromycin is a strategy that could be considered for the routine early management of pediatric patients with cystic fibrosis.

9. Lung function and secondhand smoke exposure among children with cystic fibrosis: A Bayesian meta-analysis. J Cyst Fibros . 2023 Jul A systematic review was performed using PRISMA guidelines. To estimate the association between secondhand smoke exposure and change in lung function (measured as FEV1% predicted). Quantitative synthesis of study estimates indicated that second-hand smoke exposure corresponded to a significant drop in FEV1 (estimated decrease: -5.11%) CONCLUSIONS: Our results quantify the impact at the pediatric population level and corroborate the assertion that secondhand smoke exposure negatively affects pulmonary function in children with CF.

10. Systematic review and meta-analysis: Associations of vitamin D with pulmonary function in children and young people with cystic fibrosis. Clin Nutr ESPEN. 2023 Apr The primary outcome was lung function [forced expiratory volume in 1 s (FEV1% predicted)] and secondary outcomes were rate of pulmonary exacerbations, 25OHD status and growth Conclusion: This systematic review suggests that 25OHD concentration is positively associated with lung function and a concentration of >75 nmol/L is associated with reduced frequency of pulmonary exacerbations, which may slow lung function decline in cypCF (children and young people diagnosed with Cystic Fibrosis)

11. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicenter, open-label, randomized, controlled, non-inferiority trials. Lancet Respir Med 2022; 11: 329–40 Published Online November 4, 2022 Two parallel, multicentre , open-label, randomised , controlled, non-inferiority trials at 80 participating clinics across the USA Included: pwCF aged 12–17 years with ppFEV1 >=70%, or those aged >=18 years with ppFEV1 of 60%, if they had been taking ETI and either (or both) mucoactive therapies (≥3% hypertonic saline or dornase alfa) for at least 90 days before screening. The primary objective for each trial was to determine whether discontinuing was non-inferior to continuing, measured by the 6-week change in ppFEV1 Results indicate that, among a study population of adolescents and adults with cystic fibrosis who have good lung function and are established on ETI, clinically meaningful reduction in pulmonary function did not occur with short-term discontinuation of daily use of inhaled medications that work on downstream manifestations of CFTR dysfunction in the airway, specifically hypertonic saline and dornase alfa.

12. SIMPLIFY MCC Study teams. The effect of discontinuing hypertonic saline or dornase alfa on mucociliary clearance in elexacaftor / tezacaftor /ivacaftor treated people with cystic fibrosis: The SIMPLIFY-MCC Study. J Cyst Fibros . 2024 May Many people with CF ( pwCF ) desire a reduction in inhaled treatment burden after initiation of elexacaftor / tezacaftor /ivacaftor. Randomized, open-label study The SIMPLIFY-MCC: used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. Discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period in patients with relatively well preserved pulmonary function. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA.

13. Impact of elexacaftor / tezacaftor /ivacaftor on lung function, nutritional status, pulmonary exacerbation frequency and sweat chloride in people with cystic fibrosis: real-world evidence from the German CF Registry The Lancet Regional Health - Europe 2023;32: 100690 Published Online 28 July 2023 Observational cohort study German CF Registry for pwCF who received ETI therapy All pwCF eligible for ETI (F508del/any other mutation) who were aged ≥12 years at the start of ETI, had an ETI therapy duration of ≥12 months, and no history of transplantation (any organ) were included Followed up for a period of 12 months. 2645 pwCF from 67 centres in Germany (mean age 28.0 ± 11.5 years). ppFEV1 increased by 11.3% BMI z-score increased by 0.3 Pulmonary exacerbations decreased by 75.9% Mean sweat chloride concentration decreased by 50.9 mmol/L

14. The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches Simon Y Graeber, Marcus A Mall; Lancet 2023; 402: 1185–98 Over 2000 variants have been identified in the CFTR gene and reported to the Cystic Fibrosis Mutation Database, and approximately 700 have been verified as disease-causing. Particular mutations can cause multiple molecular defects F508del, exhibits two distinct intramolecular defects that independently impair folding ( ie , instability of nucleotide-binding domain 1 and impaired interdomain assembly. F508del: not only affects protein folding and plasma membrane expression, but also leads to deficient channel gating and reduced stability at the plasma membrane. Similar to other common mutations.

15. The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches Simon Y Graeber, Marcus A Mall; Lancet 2023; 402: 1185–98 Two alternative chloride channels were identified at the molecular level that might compensate for CFTR dysfunction: transmembrane member 16A (TMEM16A) solute carrier family 26 member 9 (SLC26A9) was identified as a constitutively active chloride channel

16. The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches Simon Y Graeber, Marcus A Mall; Lancet 2023; 402: 1185–98 triple combination therapy with elexacaftor – tezacaftor –ivacaftor (ETI) restores CFTR function in the airways of patients with at least one F508del allele to approximately 50% of that measured in healthy people airway infection and inflammation persist to a lesser degree that is probably more similar to those observed in other chronic lung diseases such as non-cystic fibrosis bronchiectasis

17. The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches Simon Y Graeber, Marcus A Mall; Lancet 2023; 402: 1185–98 Restoration of CFTR function : CFTR modulator Vanzacaftor (corrector) – tezacaftor – deutivacaftor (potentiator) Phase 3 VERTEX once daily dosing with the potential to be modestly more efficacious than ETI Mucociliary clearance : inhaled lonodelestat (inhibitor of human neutrophil elastase) phase 1 ; small molecule potentiator of TMEM16A (ETX001) phase 1, mucin-reducing agents, P3001 and the thiol-saccharide preclinical mucolytic MUC-031 Genetic therapy : inhalation of stable CFTR mRNA, adeno-associated virus (AAV) gene therapy, Anti-inflammatory : Oral brensocatib phase 2 Anti-infective : systemic or inhaled administration of gallium phase 2

18. Behavioral and sleep issues after initiation of elexacaftor – tezacaftor –ivacaftor in preschool age children with cystic fibrosis. The LancetJune 28, 2024 197 preschool-age children ( ie , aged 2–5 years) were enrolled from 34 pediatric cystic fibrosis referral centers across France Evaluation at baseline and at follow-up visits at 1 month and 3 months. Parents or guardians were asked to complete a standardized questionnaire on adverse behavioral events and sleep difficulties At month 1, 93 (47%) of 197 children were reported to have sudden changes in behavior, reported to be abnormal for the child by parents, that was suspected to be related to ETI on the basis of the temporal relationship of receipt of the drug regimen and the occurrence of behavior, and absence of an alternative explanation.

19. Behavioral and sleep issues after initiation of elexacaftor – tezacaftor –ivacaftor in preschool age children with cystic fibrosis. The LancetJune 28, 2024 The amplified or new onset behavioral issues were attention deficit hyperactivity disorder (ADHD; 31 [33%] of 93), irritability (16 [17%]), and mood disorders (11 [12%]), such as abnormal sadness (ten [11%]) and suicidal ideation (one [1%]; The most frequent new onset issues were sleep difficulties, observed in 46 (49%) of 93 children, including difficulty falling asleep (22 [48%] of 46), frequent night awakening (16 [35%]), and abnormal nightmares (nine [20%]), with some children having more than one sleep-related difficulty difficulty concentrating (two [2%] of 93), exhibit opposition behaviour (six [6%]), and exhibit aggressive behavior (nine [10%]).

20. Behavioral and sleep issues after initiation of elexacaftor – tezacaftor –ivacaftor in preschool age children with cystic fibrosis. The LancetJune 28, 2024 Various studies have documented potential neuropsychiatric adverse effects associated with ETI in people with cystic fibrosis, such as low mood, anxiety, depression, sleep disturbances, cognitive difficulties, brain fog, and emergent suicidal thoughts, which were often observed in people with cystic fibrosis with pre-existing behavioral issues. 85% of the children in this study had no history of behavioral issues, according to pediatrician routine assessment. No association was identified between amplified or new onset behavioral issues and age, bodyweight, CFTR modulation response based on sweat chloride change, or ETI plasma concentrations.

21. Behavioral and sleep issues after initiation of elexacaftor – tezacaftor –ivacaftor in preschool age children with cystic fibrosis. The LancetJune 28, 2024 CFTR is widely expressed in the brain, including in the hypothalamus and hippocampus, which are two areas involved in sleep, emotion, memory, and learning. ETI crosses the blood–brain barrier, the sudden sleep difficulties and behavioural issues we observed are driven by ETI modulation of CFTR-dependent chloride transport within the brain. In 2023, the ETI label was updated by the European Medicines Agency to include depression as an adverse effect.

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