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Case Study: Cystic Fibrosis in the Newborn

• PMID: 29789057
• DOI: 10.1891/0730-0832.37.3.164

Cystic fibrosis (CF) is considered one of the most commonly occurring fatal genetic disorders. This disorder is associated with pancreatic insufficiency and pulmonary complications. However, at birth the initial complications are associated with bowel obstruction. Cystic fibrosis management warrants an interdisciplinary team because this disorder affects various organ systems. Effective management of the newborn with CF assists in improving the child's overall prognosis. Family support is critical throughout the prenatal and postnatal periods. The case presented reviews a child born with suspected CF and the clinical course within the NICU.

Publication types

• Case Reports
• Cystic Fibrosis / complications*
• Cystic Fibrosis / diagnosis
• Cystic Fibrosis / genetics
• Cystic Fibrosis / physiopathology
• Cystic Fibrosis Transmembrane Conductance Regulator / genetics
• Family Health
• Infant, Newborn
• Intensive Care, Neonatal / methods
• Intestinal Obstruction* / diagnosis
• Intestinal Obstruction* / etiology
• Intestinal Obstruction* / physiopathology
• Intestinal Obstruction* / therapy
• Neonatal Nursing / methods*
• Patient Care Management / methods*
• Patient Care Team / organization & administration
• Social Support
• Cystic Fibrosis Transmembrane Conductance Regulator

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Chapter 19:  Case Study: Cystic Fibrosis

Julie M. Skrzat; Carole A. Tucker

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Introduction.

• Examination: Age 2 Months
• Evaluation, Diagnosis, and Prognosis
• Intervention
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• Examination: Age 8 Years
• Examination: Age 16 Years
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C ystic fibrosis (CF) is an autosomal recessive condition affecting approximately 30,000 Americans and 70,000 people worldwide. According to the Cystic Fibrosis Foundation ( Cystic Fibrosis Foundation, 2019a ), approximately 1,000 new cases are diagnosed yearly in the United States, with a known incidence of 1 per 3,900 live births. The disease prevalence varies greatly by ethnicity, with the highest prevalence occurring in Western European descendants and within the Ashkenazi Jewish population.

The CF gene, located on chromosome 7, was first identified in 1989. The disease process is caused by a mutation to the gene that encodes for the CF transmembrane conductance regulator (CFTR) protein. This mutation alters the production, structure, and function of cyclic adenosine monophosphate (cAMP), a dependent transmembrane chloride channel carrier protein found in the exocrine mucus glands throughout the body. The mutated carrier protein is unable to transport chloride across the cell membrane, resulting in an electrolyte and charge imbalance. Diffusion of water across the cell membrane is thus impaired, resulting in the development of a viscous layer of mucus. The thick mucus obstructs the cell membranes, traps nearby bacteria, and incites a local inflammatory response. Subsequent bacterial colonization occurs at an early age and ultimately this repetitive infectious process leads to progressive inflammatory damage to the organs involved in individuals with CF.

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• Open access
• Published: 20 April 2024

The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience

• Jagdev Singh 1 , 2 ,
• Sharon Hunt 1 ,
• Sharon Simonds 1 ,
• Christie Boyton 1 ,
• Anna Middleton 1 ,
• Matthew Elias 2 ,
• Susan Towns 1 , 3 ,
• Chetan Pandit 1 , 3 ,
• Paul Robinson 1 , 3 ,
• Dominic A. Fitzgerald 1 , 3 &
• Hiran Selvadurai 1 , 3  

Scientific Reports volume  14 , Article number:  9056 ( 2024 ) Cite this article

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• Bacterial infection
• Cystic fibrosis

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [− 3.86% (95% CI − 5.28–2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [− 3.46% (95% CI − 4.95–1.96)] and Pseudomonas aeruginosa [− 2.80%95% CI (− 4.26–1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus ( p  < 0.001), P. aeruginosa ( p  < 0.001), H. influenza ( p  < 0.001), Serratia marcescens ( p  = 0.006) and Aspergillus fumigatus ( p  = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p  = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p  = 0.032) were increasingly prescribed, while tobramycin (− 8.46 ± 4.7 prescriptions/year, p  < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year ( p  < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.

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Introduction.

The management of pulmonary infections is critical in the care of individuals with cystic fibrosis (CF). Despite an increase in the median survival age over recent years, chronic pulmonary infection and concomitant airway inflammation leading to respiratory failure still account for 80–95% of deaths in individuals with CF 1 , 2 . This vicious cycle of infection and inflammation begins early in life, resulting in a decline in lung function, poorer nutrition, and structural lung abnormalities 3 .

Assessing long-term epidemiological trends in CF among children poses significant challenges, with studies often limited to registry reports, of a limited timeframe 4 , involve a small number of children and adolescents 5 , focus on specific organisms of interest 6 , 7 , or are derived from results obtained from bronchioalveolar sampling alone 8 , 9 . Furthermore, larger studies conducted before the year 2000 may not reflect recent advancements in CF treatment 10 , 11 , 12 , 13 , 14 , highlighting the need to evaluate any changes in the incidence and prevalence of CF bacterial pathogens to establish a reference point for future therapeutic interventions.

To this end, we conducted a study to investigate the trends in the incidence and prevalence of respiratory pathogens among children and adolescents with CF since the turn of the new millennium. By evaluating long-term longitudinal data within a clinical setting in the modern era of eradication therapy 15 , we would like to determine the changes that may have occurred in different age groups over time.

Methodology

Study population.

Children and adolescents with CF between birth to 18 years of age who were managed within a large CF centre in Australia between January 2002 and December 2019 were included in this study. Universal newborn screening of cystic fibrosis had been well-established before the study period 16 . Data collected from their existing electronic medical record included; the microbiological culture result (method of collection, date during which sample was collected with the corresponding age of the child or adolescent), and hospital pharmacy-based medication prescription data. This study was approved by the Ethics Committee of the Sydney Children’s Hospital Network (2020/ETH00815) and was conducted based on local guidelines and regulations. Exemption from consent was obtained from, and approved by the same committee.

Clinical routine during the study period

In our centre which encompasses a large region in New South Wales, outpatient (CF clinic) reviews occur four times a year, with infants or those who are clinically unwell reviewed on a more frequent basis. During these visits, airway samples are routinely collected regardless of the presence or absence of symptoms either through spontaneous expectoration (typically in older children), oropharyngeal suctioning performed by a trained CF nurse (typically in younger children), or via bronchoalveolar lavage (BAL). Airway samples microbiological cultures are ordered based on either BAL culture order label (samples obtained via BAL) or sputum CF culture order label (samples obtained through either spontaneously expectorated sputum or airway sample obtained from oropharyngeal suctioning).

All infants less than one year of age have been prescribed oral flucloxacillin or occasionally amoxicillin and clavulanic acid from diagnosis as part of our CF clinics’ routine Staphylococcus aureus prophylaxis approach for over 20 years.

In terms of the microbiological practices which has remained consistent during this study period, sputum specimens have been set up on (1) MacConkey agar for gram-negative bacteria e.g., coliforms, Pseudomonas aeruginosa, and Inquilinus limosus , (2) Anaerobically incubated chocolate agar with Bacitracin for Haemophilus influenzae . (3) Mannitol salt agar for S. aureus (4) Horse blood agar for e.g., Streptococcus pneumoniae and Moraxella catarrhalis . (5) Cepacia agar for Burkholderia cepacia and incubated for 7 days. (6) Non-tuberculous mycobacteria (NTM) testing is performed in an external Mycobacterium Reference Laboratory (MRL) using the automated blood culture system (BD BACTEC™) and testing occurs annually. Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS) has been used since 2015 for the rapid identification of organisms.

The microbiologist's report on the results of the collected airway samples is routinely reviewed by the CF team within 5–7 days after the samples are obtained. Treatment, where applicable following discussion with the primary CF physician is then prescribed. The treatment strategy includes; admission for parenteral antibiotics, a course of oral antibiotics, and/or nebulised antibiotic treatment.

Case definitions and stratification

Incidence was defined as the first time a respiratory pathogen of interest is isolated from the sputum of the child or adolescent with CF. Once the child or adolescent is an incident case for that particular pathogen, they were excluded from the denominator for the subsequent years.

Prevalence was defined as a child or adolescent with a respiratory pathogen isolated from their sputum in a specific year. Once the child or adolescent is a prevalent case for that particular pathogen, any further positive culture of the same pathogen isolated from the same child or adolescent was excluded for the remainder of that year.

Nine organisms of clinical interest in CF were selected for analysis. This includes; S. aureus, P. aeruginosa, H. influenza, Aspergillus fumigatus, Serratia marcescens, NTM, B. cepacia, Achromobacter xylosoxidans , and Stenotrophomonas maltophilia 17 .

The cohort was divided into four age groups: < 2 years, 2–5 years, 6–11 years, and > 12 years. The rationale behind this age group includes (1) biological variability in terms of differences in microbiome composition, immune system development and environmental exposure e.g. home or pre-school (2) management approaches such as methods of physiotherapy, lung function testing or the availability of medications such as dornase alfa (3) to align with existing clinical trials in CF transmembrane conductance regulator (CFTR) and CF registry reports.

In terms of medications prescribed and obtained from the hospital pharmacy, prescription of oral antimicrobials (including amoxicillin and clavulanic acid, ciprofloxacin, trimethoprim/sulfamethoxazole, flucloxacillin, and itraconazole), nebulised antimicrobials (including amikacin, colistin, and tobramycin), and other medications (including dornase-alfa, hypertonic saline nebules, and CFTR modulators and correctors) were reviewed.

Statistical analysis

We used descriptive statistics to summarise the data, reporting organism incidence and prevalence as n (%). To assess changes over time, we calculated the annual incidence and prevalence of each organism based on individual airway samples, and used regression analysis to evaluate these measures. Based on the coefficients obtained from the regression model, the average change in incidence and prevalence was presented. Prescription trends were also analysed on an individual basis. Results are reported as % change (with 95% confidence intervals) for incidence and prevalence, and as number of prescriptions/year ± standard deviation for medications prescribed. Changes in the mean age of first organism isolation were assessed using analysis of variance. All statistical calculations were performed using the SPSS Statistic Data Editor (IBM Version 28, New York, USA, 2021). Statistical significance was defined as p  < 0.05.

Study population and bacterial samples

During the study period, 419 children and adolescents with CF were followed up with 206 (49.2%) born on, or after 1st January 2002. A total of 18,339 airway samples were collected during the study period with 401 (2.2%) collected via bronchioalveolar lavage, with the remaining samples obtained from expectorated sputum or oropharyngeal suction.

Out of the total airway samples that were collected, 724 (3.9%) samples met the criteria for incidence and 15,332 (83.6%) samples met the criteria for prevalence as defined in the methodology of this study were included in the analysis.

Incidence and prevalence of respiratory pathogens

Throughout the entire study period, S. aureus (25.1%), P. aeruginosa (26.2%), and H. influenzae (17.9%) exhibited the highest incidence among respiratory pathogens. Together, these pathogens accounted for 70% of the overall incidence over 18 years. In contrast, B. cepacia (0.69%), A. xylosoxidans (2.1%), and NTM (3.7%) had the lowest incidence across the study period, collectively representing 6.5% of the overall incidence over 18 years (Table 1 ).

Throughout the entire study period, S. aureus (47.8%), P. aeruginosa (34.5%), and A. fumigatus (8.4%) exhibited the highest prevalence among respiratory pathogens. Together, these organisms constituted almost 95% of the overall prevalence over 18 years. In contrast, the least prevalent respiratory pathogens were NTM (0.72%), B. cepacia (0.69%), and A. xylosoxidans (0.48%) throughout the study period. Collectively, these organisms represented less than two percent of the overall prevalence over 18 years (Table 2 ).

Changes in age of first isolation of respiratory pathogens

The ages at which these pathogens were first isolated are as follows: S. aureus (3.35 ± 2.1 years), H. influenza (4.28 ± 2.7 years), S. marcescens (5.24 ± 4.09 years), P. aeruginosa (5.27 ± 2.9 years), A. fumigatus (7.31 ± 2.85 years). This is followed by S. maltophilia (8.95 ± 2.95 years), B. cepacia (9.055 ± 2.3 years), NTM (11.38 ± 2.06 years), A. xylosoxidans (11.71 ± 2.86 years).

Over time, respiratory pathogens have shown an increase in the mean age of the first isolation: S. aureus ( p  < 0.001), P. aeruginosa ( p  < 0.001), H. influenza ( p  < 0.001), S. marcescens ( p  = 0.006), A. Fumigatus ( p  = 0.02), B. cepacia ( p  = 0.58), NTM ( p  = 0.052), S. marcescens ( p  = 0.308), S. maltophilia ( p  = 0.47), A. xylosoxidans ( p  = 0.80). The changes over years of these respiratory pathogens are illustrated in Fig.  1 .

Mean age group of the first culture of CF organisms.

Changes of overall and age-specific incidence and prevalence of CF organisms from 2002 to 2019

Amongst the organisms with the highest incidence, S. aureus showed the largest decline in incidence over time, followed by H. influenza and P. aeruginosa . Meanwhile, NTM and B. cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed (Tables 1 , 2 ).

With respect to age groups, incidence of S. aureus, P. aeruginosa, H. influenza and A. fumigatus in children < 2 years of age have remained unchanged. A similar pattern of change in prevalence was observed. Meanwhile, NTM showed a significant increase in both incidence and prevalence in children 6–11 years of age.

Throughout this study, a total of 29,203 medications (oral antimicrobials n = 18,367, 62.9%) were prescribed. The antibiotics that were increasingly prescribed include amikacin (3.09 ± 2.24 prescription/year, p  = 0.003), amoxicillin/clavulanic acid (8.98 ± 2.17 prescriptions/year, p  < 0.001), colistin (1.95 ± 0.3 prescriptions/year, p  = 0.032), trimethoprim/sulfamethoxazole (18.1 ± 8.7, p  < 0.001). Flucloxacillin (− 4.48 ± 1.073, p  < 0.001), tobramycin (− 8.46 ± 4.7, p  < 0.001) showed a decrease in prescription. Ciprofloxacin (− 6.049 ± 5.1 prescriptions/year, p  = 0.068) and itraconazole (− 4.53 ± 1 prescriptions/year, p  = 0.07) did not show any significant change over time.

Dornase alfa prescription increased by 16.74 ± 4.1 prescriptions/year ( p  < 0.001). The prescription of hypertonic saline nebulisation increased by 24 ± 4.6 prescriptions/year ( p  < 0.001). There were 7 children or adolescents on CFTR corrector or modulator therapy.

This paediatric-focused study evaluates annual changes in the incidence and prevalence rates of respiratory pathogens across different age groups, while also comparing medication prescription trends over an 18-year period. This study provides valuable data from a real-world clinical setting where infants under the age of one receive universal antimicrobial prophylaxis and, standardised respiratory pathogen surveillance is conducted by qualified personals using consistent sampling and microbiological testing protocols. In particular, obtaining samples through sputum and oropharyngeal suctioning is considered to have the highest concordance with BAL samples, rendering them more representative of lower airway infections compared to other sampling methods like throat or cough swabs 18 . The findings contribute to our understanding of the long-term trends in respiratory pathogens and associated clinical management in the paediatric population, particularly in the modern era of eradication therapy 15 .

Our study showed that together, S. aureus and P. aeruginosa make up the majority of respiratory pathogens both in terms of incidence (51.3%) and prevalence (82.3%). Data preceding 2000, report prevalence of these two respiratory pathogens to be higher at 95% 14 .

Registry data taken from 2018 to 2020 showed a prevalence of P. aeruginosa of 20.9% 17 and S. aureus of 55.26% in children and adolescents under the age of 18. In comparison, our data shows a recent prevalence of P. aeruginosa of 17.6% and S. aureus of 45.3%. Of the less frequent respiratory pathogens, NTM prevalence was 4.3% from registry data vs 3.7% from our cohort and B .cepacia  was 3.2% vs. 1.3% respectively.

In a recent publication by VanDevanter et al., a trend of decline in P. aeruginosa prevalence was observed, as evidenced by the examination and presentation of registry data within a comparable time frame 19 . Following this, Fischer et al. raised a crucial question regarding whether the observed changes in P. aeruginosa over time were also apparent in other respiratory pathogens of interest in CF 20 . We have demonstrated that over the past 18 years, the incidence and prevalence of the most common respiratory pathogens in CF such as S. aureus , P. aeruginosa , H. influenzae and A. fumigatus have decreased steadily. This significant decline of between 2 and 4% of individual respiratory pathogens are observed both in the incidence and prevalence. Meanwhile, less common organisms such as NTM , B. cepacia and A. xylosoxidans, S. maltophilia showed no significant change in terms of incidence and prevalence.

We also found that the incidence and prevalence of respiratory pathogens remain unchanged for infants up to 2 years of age across all respiratory pathogens. Additionally, we have found that our cohort of children and adolescents with CF are found to have a positive airway sample culture for these respiratory pathogens significantly later that the earlier years of this study.

Our centre has adopted the universal use of S. aureus prophylactic antibiotics in infants diagnosed with CF preceding this study period. In a systematic analysis performed which reviewed four studies, there was a weak indication that P.aeruginosa was isolated less frequently in children under three years and more frequently in children between three to six years in the prophylactic group 21 . In contrast, despite our universal use of prophylactic antibiotics in infants, our study shows (1) a decline in the incidence and prevalence of P. aeruginosa , (2) no  significant increase in the incidence and prevalence of organisms such as NTM and B. cepacia (3) an increase in the mean age of first isolation of respiratory pathogens of interest, (4) no change of incidence and prevalence of respiratory pathogen < 2 years of age. A contributing factor in terms of improvements in infection control practices may have helped keep our incidence and prevalence lower than the national average. While being potentially circumstantial, these findings suggest that the use of prophylactic anti-staphylococcal antibiotics is not associated with an increase in P. aeruginosa or increase in prevalence of other less common respiratory pathogen. Prospective studies such as the CF-START study in evaluating outcomes of prophylactic treatments will hopefully provide conclusive proof of its benefits and safety 21 .

By examining prescription trends, we have found that there is a rise in the use of anti-pseudomonal nebulised antibiotics such as amikacin and colistin. This suggests that P.aeruginosa is being more aggressively treated over time as both this antibiotics are considered as second line after tobramycin 22 . However, the increase in use of amikacin could also be attributed to an increase in NTM incidence and prevalence. Encouragingly, we have found that the emphasis on respiratory clearance has increased over time with the significant increase in the prescription of dornase alpha and hypertonic saline in our cohort.

Our study comes with certain limitations that warrant consideration. Firstly, the sputum and prescription data lack representation from external laboratories or pharmacies, potentially limiting the comprehensiveness of our findings. Additionally, we did not culture anaerobic bacteria and did not routinely test for co-infection with respiratory viruses, leading to an omission in addressing potential co-infections among these organisms in our study. Moreover, the annual frequency of NTM testing, as opposed to routine CF airway sample cultures, may result in an underrepresentation of NTM within our study cohort.

Thirdly, our data originated from a single CF centre in Australia, raising concerns about the generalisability of our findings to a broader population. Fourthly, our incidence calculation may involve a small number of children or adolescents intermittently found to have these respiratory pathogens in their airway samples. Finally, the relatively limited sample size of children and adolescents on CFTR modulators or correctors is noteworthy, as our study predates the widespread adoption that followed the approval and government funding of these medications in Australia. Current evidence suggests that while it may more difficult to obtain sputum samples in children on CFTR therapy, its’ impact on the growth of specific bacterial pathogens needs to be closely examined 23 . The low number of children or adolescents on CFTR modulators or correctors is an important aspect of this study as it will enable future comparison in a post-modulator era in the management of CF.

Our study has several strengths. First, we analysed a large number of sputum samples, both overall and in different age groups, providing a longitudinal comparison of changes in CF treatment over the past 18 years. This is the first study of such magnitude in children and adolescents with CF, providing age-specific incidence and prevalence, as well as prescription trends. In particular, our review of incidences of these organisms and the age of first positive culture provides additional information towards our understanding of CF respiratory pathogens over the past two decades.

Second, our study includes a large cohort of children born on or after January 1st, 2002, when newborn screening has already been well-established, allowing us to assess the acquisition of respiratory pathogens from shortly after birth over the past 18 years. Third, the practice of using prophylactic anti-staphylococcus antibiotics universally has given us the opportunity to assess the outcomes of its’ use over a significantly long period of time. While strong conclusions cannot be made without a non-prophylactic control arm, it does provide insight into the long-term impact of its’ implementation on respiratory pathogens in our cohort.

In summary, our study shows a change in the epidemiology of CF pathogens in a single large paediatric clinic that practices universal prophylaxis in children. First, we observed a decline in the incidence and prevalence of the most commonly found CF pathogens such as S. aureus, P. aeruginosa, H. influenzae, and A. fumigatus , as well as a delay in the first acquisition of these pathogens. However, less common pathogens such as S. marcescens , NTM, B. cepacia, A. xylosoxidans , and S. maltophilia did not show significant changes. Second, we found no change in the incidence or prevalence of respiratory pathogens in infants under 2 years of age over time.

Data availability

Data is available from the corresponding author, upon reasonable request.

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We extend our gratitude to The Cure4CF Foundation and The Team Simon Foundation for Cystic Fibrosis for their generous financial support towards this study.

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H.S. and J.S. conceived the research question. J.S., H.S. and D.F. designed the study and analysis plan. J.S., S.H., S.S., C.B., A.M. and M.E. collected the data. J.S. performed the statistical analysis. H.S., D.F., P.R., S.T. and C.P. reviewed the data. J.S. drafted the initial and final versions of the manuscript. All authors critically reviewed early and final versions of the manuscript.

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Singh, J., Hunt, S., Simonds, S. et al. The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience. Sci Rep 14 , 9056 (2024). https://doi.org/10.1038/s41598-024-59658-4

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• Published: 27 April 2024

Predicting lung function decline in cystic fibrosis: the impact of initiating ivacaftor therapy

• Grace C. Zhou 1 , 2 ,
• Ziyun Wang 2 , 3 ,
• Anushka K. Palipana 2 , 4 ,
• Eleni-Rosalina Andrinopoulou 5 , 8 ,
• Pedro Miranda Afonso 5 , 8 ,
• Gary L. McPhail 6 , 7 ,
• Christopher M. Siracusa 6 , 7 ,
• Emrah Gecili 2 , 7 &
• Rhonda D. Szczesniak 2 , 6 , 7  

Respiratory Research volume  25 , Article number:  187 ( 2024 ) Cite this article

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Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake.

We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry ( N  = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level.

Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications.

Conclusions

The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care.

Cystic fibrosis (CF) is a progressive, genetic disease caused by CF transmembrane conductance regulator (CFTR) protein dysfunction, leading to cyclical lung infection and inflammation. As a result, lung function monitoring through longitudinal measurement of forced expiratory volume in 1 s of % predicted (FEV1pp) has been a key element of CF care. Highly effective CFTR modulator therapies, which are designed to correct malfunctioning protein made by the CFTR gene, have revolutionized the clinical landscape. The first of these therapies, ivacaftor, which has been in widespread use in the U.S. since January 2012 for select mutations (e.g., G551D), has been shown to improve FEV1pp markedly [ 1 ]. Analysis of trial participants with a G551D mutation on ivacaftor, matched with historical F508del homozygotes from the U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) as controls, found that ivacaftor treatment associated with 50% slower decline in FEV1pp over a 3-year period [ 2 ]. A more recent pre-post study of the Canadian CF Registry considered follow-up as long as 8 years before and 8 years after ivacaftor initiation and reported more variable benefits, demonstrating age-related reductions in FEV1pp slope of 60% and 71% for pediatric and adult ivacaftor patients, respectively (difference in the FEV1pp slope between the pre and post ivacaftor: 0.58 predicted/year and 0.72 predicted/year, respectively) [ 3 ]. Another study of CF patients who carry the G551D mutation included data from a two-year clinical trial and a 5-year observational cohort from West of Scotland suggested sustained lung function benefit from ivacaftor use among adults, but long-term improvement seemingly plateaued year over year in the pediatric population [ 4 ]. These findings corroborate a prior U.S. multi-center study, which showed that the rate of decline in FEV1pp over a 5.5-year period after ivacaftor initiation was worse for pediatric subjects than adults (1.68% predicted/year versus 0.63% predicted/year) [ 5 ].

While treatment heterogeneity is expected, the reported variability, both between patients and within an individual patient over time, demonstrates the need to reevaluate the suitability of both FEV1pp prediction models and the thresholds used to identify meaningful lung function decline after ivacaftor initiation. Prediction models of CF FEV1pp decline have historically been useful for early identification of pulmonary exacerbation events and other phenomena clinically known as “rapid decline,” which have been defined as a meaningful drop in FEV1pp relative to center- and/or patient-level norms [ 6 , 7 ]. Early detection and timely treatment of rapid decline improve lung function but can be difficult to achieve without prediction models [ 8 , 9 , 10 ]. One such model was developed specifically for real-time prediction of rapid decline in CF using target functions [ 10 ]. These functions were derived mathematically based on clinically relevant definitions of rapid decline. However, these definitions reflect pre-modulator thresholds (e.g., drops more than 1.5% predicted/year) [ 11 ]. More recent approaches have included the use of an alternative method to identify pulmonary exacerbations, known as the FEV1-indicated exacerbation signal (FIES) [ 12 ]. While pulmonary exacerbation has historically been defined heterogeneously through assessment primarily of lung function drops, there has been limited consensus on how to define such drops [ 13 ].

For these reasons, the aims of our study were to (i) evaluate the robustness of an existing prediction model framework that accurately detected rapid decline in the pre-modulator era and (ii) adapt this framework to examine a novel target function specific to FIES events.

Study design and cohort

We conducted a retrospective longitudinal cohort study using the CFFPR, which is a national patient registry that collects demographic and clinical data on individuals with CF who are patients at care centers across the U.S [ 14 ]. The study included data from 2003 to 2018. To construct the analysis cohort, we considered patients with a valid CF diagnosis (e.g., blood test, sweat test, genetic test) who carry the G551D mutation and received ivacaftor any time after January 1, 2012, which represents the era of widespread U.S. Food and Drug Administration (FDA) approval for this therapy. Data observed when patients were younger than 6 years old was excluded, given the potential for unreliable pulmonary function test (PFT) results in very young patients with CF. Data observed after lung transplantation were censored.

Determining ivacaftor initiation. We omitted PFTs observed during the first 30 days after the CFFPR-recorded ivacaftor start date (Fig.  1 ). Our rationale was (i) we wanted to avoid estimating the initial increase in FEV1pp related to ivacaftor that has been previously reported in other analyses [ 2 ], and (ii) we sought to reduce the potential bias between the ivacaftor prescription date and the actual start date recorded in the CFFPR. To ensure valid estimation before and after ivacaftor initiation, we restricted the cohort to patients who had at least one PFT before initiation and at least two PFTs after, and for whom the earliest and latest post-initiation PFTs were separated by at least 6 months in time.

Lung function trajectory and ivacaftor initiation shown for a male with cystic fibrosis in the analysis cohort. The outcome was measured as the percent predicted forced expiratory volume in 1 s (FEV1pp, y-axis) observed over time (x-axis). (A) before and (B) after ivacaftor initiation. His pre-ivacaftor FEV1 ranged from 68 to 118% predicted, while post-ivacaftor was 82 to 102% predicted. His overall FEV1pp increased, but he experienced FIES events (examples of events shown using red arrows in A and B) before and after ivacaftor initiation

FIES definition . We derived our criteria at each clinical encounter from the definition provided by the CF Learning Network [ 12 ], which was applied as follows:

For baseline FEV1pp  ≥  50, if the current FEV1pp represents a 10% or more relative decline in lung function, compared to the baseline.

For baseline FEV1pp < 50, if the current FEV1pp represents a 5% or more relative decline in lung function, compared to the baseline.

In this definition, baseline is the average of the two highest FEV1pp values in the past 12 months that were not recorded during intravenous antibiotic treatment. Expanded details on the FIES definition are provided as supplemental material (Part 1, Section I).

Statistical analysis

Outcome, covariates, and missing data. The study outcome was the FEV1pp value observed at each clinical encounter. Covariates included observed demographic and clinical characteristics that have been previously associated with accelerated FEV1pp decline: the time-varying variables were Medicaid insurance use, infection with methicillin-resistant Staphylococcus aureus (MRSA), infection with Pseudomonas aeruginosa (Pa), diagnosis of CF-related diabetes (CFRD), and numbers of acute pulmonary exacerbations and outpatient visits within the previous year; the non-time-varying variables were age and FEV1pp at study entry, birth cohort (defined based on year of birth), sex, and pancreatic insufficiency (defined as any reported use of pancreatic enzymes). All subsequently described prediction modeling assumed that outcome data were missing at random [ 15 ].

Prediction model setup. A previously described longitudinal model framework with nonstationary stochastic process to the prediction of FEV1pp and the use of clinically relevant target functions in CF was adapted for this study [ 10 ]. Particularly, the variance terms in the linear mixed effects model included a random intercept to account for between-patient variation, an integrated Brownian motion covariance function to account for within-patient variation over time and to allow us to create predictive probability distributions using a prior approach, and a residual measurement error [ 16 ]. We first set up a saturated model within this framework to examine various covariate effects. The time since study entry (in years) was used as the time variable. A change point term, which represented pre- and post-ivacaftor initiation periods, was included as a main effect, and its interaction with time was used to examine associations between ivacaftor response and absolute FEV1pp, as well as the difference in slopes between pre- and post-ivacaftor initiation periods. Covariates were considered as both main effects and interactions with the time variable in the saturated model. Results were scaled to the time since ivacaftor initiation (in years) for presentation purposes. Details of the model setup are presented as supplemental material (Part 2, Section I) and the residual diagnostics of the selected model are shown in the supplemental material (Part 1, Section II).

Covariate selection. Reduced forms of the previously described terms in the saturated model were examined with the Akaike and Bayesian information criteria (AIC and BIC, respectively) and the likelihood ratio test (LRT).

Predictive probabilities for FIES events. The target function derived from the above FIES definition was implemented as part of the model fitting in the R package “lmenssp” version 1.2 [ 17 ]. The formulas and code can be found from supplementary material Part 2, Sections II-III and Part I, Section V, respectively.

Validation. Two types of validation were performed that are relevant to clinical scenarios: (i) predictions for “new patients,” and (ii) forecasting for patients who were part of the model building but return for follow-up visits (i.e., updated predictions). To accomplish both types of predictions, the analysis cohort was randomly split into 80% for training and 20% for independent testing (Fig.  2 ). For type (i), we examined predictions within the testing cohort. For type (ii), we examined data that were held out for the last 6 months of follow-up in the training cohort. Both types of predictions were evaluated using 5-fold cross-validation.

Dataflow for model fitting and validation. The overarching analysis cohort (the first level) was segmented into training and testing cohorts (the second level). The training cohort was further split into a cohort for model fitting and a masked cohort for forecast validation (the third level)

Evaluation of predictive performance. Metrics to evaluate predictive accuracy included the root-mean-square error (RMSE), the mean absolute error (MAE), the Brier score, and the area under the receiver operating characteristic curve (AUC). Formulas for the metrics are provided as supplemental material (Part 1, Section III). Lower values of the RMSE, MAE, and Brier score imply higher predictive accuracy, while lower AUC values indicate lower predictive accuracy. The 95% confidence interval (CI) for each AUC estimate was obtained through nonparametric bootstrapping with 1,000 replicates via the R package “boot” version 1.3–28.1 [ 18 ].

Patient characteristics

The analysis cohort consisted of 867 ivacaftor-treated patients with CF who had a total of 45,540 PFTs over the study timeframe. Patients typically entered the study as adolescents with ivacaftor initiation in early adulthood (Table  1 ). There were slightly more males than females (53.1% versus 46.9%). Most patients had pancreatic insufficiency, reported Medicaid insurance use, and had lung infections with MRSA or Pa during the follow-up period. Slightly more than half of all patients developed CFRD. There was a total of 11,328 FIES events, which occurred in 27% and 25% of observations before and after ivacaftor initiation, respectively.

Prediction model

In the final model, ivacaftor initiation was associated with a change in absolute FEV1pp and a slower rate of decline in FEV1pp (Table  2 ). The estimated improvement in FEV1pp was 4.89% predicted (95% CI: 3.90 to 5.89). The rate of decline was reduced by 0.14% predicted/year (95% CI: 0.01 to 0.27). The overall rate of FEV1pp decline throughout the follow-up period was 0.61% predicted/year (95% CI: 0.84 to 0.37). Those who had more outpatient visits before entering the study and males tended to have higher absolute FEV1pp values. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations prior to the study, infection with MRSA or Pa, CFRD, and use of Medicaid insurance corresponded to lower absolute FEV1pp values. In model selection, these covariates were not associated with an accelerated rate of decline in FEV1pp. The final model also indicated high between-patient variability (quantified as the estimated standard deviation [SD] and 95% CI, which were 8.10 and 7.59 to 8.57, respectively). The changes in absolute FEV1pp corresponded to a meaningful increase and slower decline after ivacaftor initiation (Fig.  3 ). Carrying forward the projected rate of decline from the pre-ivacaftor initiation period (the light blue dashed line), there were differences between the pre- and post-ivacaftor initiation trajectories with non-overlapping 95% CIs (comparing the light blue dashed line with the darker blue solid line during the post-ivacaftor period).

Population-level estimate of lung function trajectories and 95% confidence bands for the pre-ivacaftor trend (lightly shaded curve, extended to show the projected rate of decline without ivacaftor initiation) versus the post-ivacaftor trend (darker shaded curve). The outcome was measured as the percent predicted forced expiratory volume in 1 s (FEV1pp, y-axis) observed over the follow-up time (in years, x-axis). The start of the darker blue curve (vertical dashed line) corresponds to ivacaftor initiation

Predictive accuracy

The selected model presented a reasonable predictive performance for both the FEV1pp outcome and FIES events (Table  3 ). It achieved similar predictive accuracy for FEV1pp across the different segments of the analysis cohort, which were formed to carry out the different types of validation, indicating the ability of the model to predict data in real time and to forecast data accurately. In the case of FIES events, the Brier Score consistently remained low across all cohorts, which are indicative of better-calibrated predictions. The AUC (over 80%) indicated high levels of predictive accuracy, with the highest accuracy in the masked cohort and similar levels of accuracy in the fitting and independent testing cohorts.

Dynamic predictions

To further illustrate the model’s predictive performance at an individual patient level, we evaluated the predictive probability of FIES events for two randomly selected patients from the training set (Fig.  4 ). The top row shows a female CF patient. Her trajectory was variable throughout both the pre- and post-ivacaftor initiation periods (represented by light blue and dark blue shaded trajectories, respectively). She experienced a series of FIES events over both periods. The gray area shows the 95% confidence band for projected estimates of FEV1pp and the trend during the 6-month held-out timeframe. Her predictive probability of FIES events also varied significantly during both the pre- and post-ivacaftor initiation periods. The model accurately projected an elevated risk of FIES events during periods in which they occurred, including in the yellow-shaded prediction intervals for the 6-month held-out timeframe. The male CF patient in the bottom row had a more stable FEV1pp trajectory that exhibited more gradual increases, with a FIES risk that increased over time.

Dynamic predictions from the training cohort shown for a female patient with baseline age 9.36 years (first row) and a male patient with baseline age 31.2 years (second row). Left panel: observed FEV1pp against time with estimated values, 95% CI, and six-month forecasted lung function; gray shaded area shows estimation for 6-month held-out data. Right panel: predictive probabilities of FIES, including observed FIES events, predicted probability, and bootstrapped 95% CI. Abbreviations: CI = confidence interval; IVA = ivacaftor

We similarly showed individual trajectories for patients who were in the independent testing cohort (Fig.  5 ). The female CF patient with data and predictions displayed in the top row experienced a more gradual FEV1pp decline over the follow-up period with relatively few FIES events. Although this patient did not contribute data to the model development, since she was in the testing cohort, her projected low risk of FIES was accurate (based on the cut point for predictive probabilities from the receiver operating characteristic analysis). The male CF patient in the bottom row appears to have benefited from ivacaftor initiation, as evidenced by the overall increase in FEV1pp and slower rate of FEV1pp decline.

Dynamic predictions from the independent test validation cohort for a female patient with baseline age 48.8 years (first row) and a male patient with baseline age 15.4 years (second row). Left panel: observed FEV1pp against time with estimated values, 95% CI, and six-month forecasted lung function. Right panel: predictive probabilities of FIES, including observed FIES events, predicted probability, and bootstrapped 95% CI. Abbreviations: CI = confidence interval; IVA = ivacaftor

Robustness of predictive performance across models

The individual predictive performance of the models tended to be invariant under different combinations of covariates. To evaluate the robustness of predictive performance across models, we performed simulation studies that support this conclusion (see supplemental Part 1, Section IV a, for further details). From the results, we found that to choose the “best” model, we should rely on model information criteria (AIC and BIC) rather than accuracy metrics because in some cases, both correctly and incorrectly specified models presented similar, small predictive errors, but their AIC and BIC values were distinct. In addition, in cases with extremely poor model performance (i.e., extremely large RMSE or AIC/BIC), we found that examining different variance-covariance structures improved performance. Across these alternative models, all those with the ivacaftor initiation period as a covariate had both higher AIC and BIC values (see Supplement Part 1, Section IV b).

This study found that dynamic prediction models from the pre-CFTR modulator era can be effectively adapted to characterize ivacaftor responsiveness in people with CF while providing accurate, individualized predictions of precipitous drops in lung function that may provide an early signal for the onset of a pulmonary exacerbation. We developed a novel target function to predict FIES events, which serve as data-driven surrogates intended to standardize pulmonary exacerbation definitions and enhance early detection. Moreover, the findings demonstrate that FIES events were equally prevalent before and after ivacaftor initiation, highlighting the need for lung function monitoring even after a modulator is initiated.

Parameter estimates from this model echoed the short-term ivacaftor benefits on FEV1pp that were observed in prior studies, along with the potential for dwindling effects. While we observed a 23% reduction in the rate of FEV1pp decline with ivacaftor initiation, this reduction was less substantial than in the Canadian CF registry study, which included a wider variety of mutation types [ 3 ]. However, the lack of consensus on a minimal clinically important difference for FEV1pp as a CF clinical trial endpoint makes it challenging to determine the clinical relevance of observed differences [ 19 ]. Another prospective multi-center study that included only G551D patients treated with ivacaftor found an average post-ivacaftor initiation decline of 1.22% predicted/year over the 5.5-year study period, which is steeper than our current study estimate. Despite these differences, which may be attributable to differences in cohort definitions, covariate information, or model structure, the dynamic prediction model developed in the current study was able to estimate lung function trajectory and FIES-defined drops accurately at the individual patient level. Perhaps more importantly, the current study sought to develop an accurate prediction model that allows projections after initiation rather than estimating ivacaftor effects; explaining and predicting are viewed in statistical modeling as requiring two different approaches [ 20 ]. For the purposes of real-time lung function monitoring and clinical surveillance, the dynamic prediction model and predictive probabilities of FIES can be embedded into existing prediction tools that have relied on frameworks established prior to the availability of CFTR modulators [ 21 ].

Although the current study focused only on ivacaftor use among individuals with a G551D mutation, highly effective modulator therapy is now available for many CF patients with other ivacaftor-responsive variants (10–15% of patients) and/or a copy of the most common CFTR variant, F508del corresponding to treatment with elexacaftor/tezacaftor/ivacaftor therapy (currently totaling 94% of the U.S. population, given latest FDA approvals) [ 22 , 23 , 24 ]. Available short-term clinical effectiveness studies of elexacaftor/tezacaftor/ivacaftor suggest substantial improvements over a 6-month period (increase in FEV 1 : 9.76 [8.76, 10.76]% predicted) [ 25 , 26 , 27 ]. These studies also indicated response heterogeneity within subgroups (the improvement ranged from 6.14 to 10.84% predicted depending on prior use of another modulator). Challenges to evaluating the robustness of prediction models for patients on elexacaftor/tezacaftor/ivacaftor include limited post-approval follow-up and less frequent PFTs during 2020 and part of 2021, which could be attributed to COVID-19 pandemic restrictions or the positive pulmonary impacts of the therapy itself [ 28 ].

While our retrospective analysis provides valuable insights, it is essential to acknowledge the absence of prospective validation. The broad uptake of the newest modulator, elexacaftor/tezacaftor/ivacaftor, which coincided with the COVID-19 pandemic era, brings about the need for assessing its effectiveness in new data and mitigating the risk of overfitting to historical data. Future work should prioritize prospective validation and adjust our approach based on its performance in practical settings to account for other modulator use and the pandemic. Our study uses an accurate prediction model to identify FIES events, which correspond to a universal definition of what constitutes a decline in FEV1pp. However, real-world diagnoses of pulmonary exacerbations may consider changes in symptoms or other clinical factors, such as weight. A symptom-indicated exacerbation score has also been considered, as well as standardizing home exacerbation detection [ 12 ]. The prediction model framework presented here could be extended to incorporate weight thresholds, e.g., changes in body mass index over time, as another element of the target function. More novel statistical methodology is required to implement bivariate target functions, but this represents an important research direction for clinical monitoring in the post-modulator era.

The methods and applications of dynamic prediction models developed using pre-CFTR modulator data have the potential to inform post-CFTR modulator projections of lung function and enhance clinical surveillance in the new era of CF.

Data availability

The data that support the findings of this study are available from the Cystic Fibrosis Foundation, but restrictions apply to the availability of these data, which were used under an information use agreement for the current study, and so are not publicly available. Requests for these data can be directed to the Cystic Fibrosis Foundation Patient Registry Team via email: [email protected].

Abbreviations

Area under the receiver operating characteristic curve

• Cystic fibrosis

Cystic Fibrosis Foundation Patient Registry

Cystic fibrosis-related diabetes

Percent predicted forced expiratory volume in 1 s

FEV1-indicated exacerbation signal

Mean absolute error

Methicillin-resistant Staphylococcus aureus

Pseudomonas aeruginosa

Root-mean-square error

Standard deviation

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Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809–19. https://doi.org/10.1056/NEJMoa1908639 .

Foundation CF. FDA approves Trikafta for Children ages 2 through 5 years with certain CF mutations. Cyst Fibros Foundation. ( https://www.cff.org/news/2023-04/trikafta-approval-ages-2-5-mutations ).

Foundation CF. FDA Approves Trikafta for Children Ages 6 Through 11 With Certain Mutations. ( https://www.cff.org/news/2021-06/fda-approves-trikafta-children-ages-6-through-11-certain-mutations ).

Nichols DP, Paynter AC, Heltshe SL, et al. Clinical effectiveness of Elexacaftor/Tezacftor/Ivacaftor in people with cystic fibrosis. Am J Respir Crit Care Med. 2021. https://doi.org/10.1164/rccm.202108-1986OC .

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Acknowledgements

The authors would like to thank the Cystic Fibrosis Foundation for the use of CF Foundation Patient Registry data to conduct this study. Additionally, we would like to thank the patients, care providers, and clinic coordinators at CF centers throughout the United States for their contributions to the CF Foundation Patient Registry.

National Heart, Lung and Blood Institute of the National Institutes of Health Grant R01HL141286; Cystic Fibrosis Foundation Grant SZCZES18AB0.

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Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

Grace C. Zhou

Division of Biostatistics & Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Grace C. Zhou, Ziyun Wang, Anushka K. Palipana, Emrah Gecili & Rhonda D. Szczesniak

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Duke University School of Nursing, Durham, NC, USA

Anushka K. Palipana

Departments of Biostatistics and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

Eleni-Rosalina Andrinopoulou & Pedro Miranda Afonso

Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Gary L. McPhail, Christopher M. Siracusa & Rhonda D. Szczesniak

Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA

Gary L. McPhail, Christopher M. Siracusa, Emrah Gecili & Rhonda D. Szczesniak

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Contributions

Conceptualization: GCZ, RDS. Data curation: AP, EG, GCZ, RDS, ZY. Formal analysis: GCZ, RDS, ZY. Methodology: AP, CS, EG, E-RA, GCZ, GLM, PA, RDS, ZY. Writing – original draft: GCZ, RDS. Writing – review, editing, and revising: AP, CS, EG, E-RA, GCZ, GLM, PM, RDS, ZY. All authors read and approved the final version of the manuscript and supplemental material.

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Correspondence to Rhonda D. Szczesniak .

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Ethical approval.

This study was approved by the Cincinnati Children’s Hospital Medical Center’s Institutional Review Board (Study ID: 2018–3912) and approved by the Cystic Fibrosis Foundation Patient Registry (CFFPR) Committee. The CFFPR collects information on the health status of people with cystic fibrosis who receive care in Cystic Fibrosis Foundation-accredited care centers and agree to participate in the CFFPR.

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To contribute data to the CFFPR, each Registry participant or their legal guardian completes an informed consent through their CF Foundation accredited care center. All experiments were performed in accordance with the CCHMC Human Research Program within the Office of Research Compliance and Regulatory Affairs and CF Foundation information use agreement terms.

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Zhou, G.C., Wang, Z., Palipana, A.K. et al. Predicting lung function decline in cystic fibrosis: the impact of initiating ivacaftor therapy. Respir Res 25 , 187 (2024). https://doi.org/10.1186/s12931-024-02794-2

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So effective is Vertex Pharmaceuticals’ blockbuster cystic fibrosis (CF) drug, Trikafta, that studies project it could extend the lives of some young patients by up to 45 years. As such, it is not cheap: in the US, it costs $300,000 per patient, per year. But given the transformative nature of the treatment for a disease with a poor prognosis, the high list price has not held back sales for the pharma group.

And, now, the same team of scientists at Vertex’s San Diego laboratory have a second decades-long research project coming to fruition that could unlock another potentially huge market: non-opioid painkillers.

If patients live longer, “it’s good for business”, says David Altshuler, Vertex’s chief scientific officer. The number of people living with CF worldwide is now 105,000, up from 70,000 in 2012, according to estimates from US non-profit the Cystic Fibrosis Foundation — a rise that experts attribute both to Vertex’s drugs and improved diagnostics.

“If you take a life-threatening disease that shortens life and you have a transformative medicine, you not only have the benefit in the short run, but then people live a long time and it’s a positive thing for everyone,” adds Altshuler. These positive effects are evident in Vertex’s revenues, which more than doubled between 2019 and 2022, from $4.2bn to $8.9bn, the period covered by the FT-Statista ranking of the Americas’ 500 fastest-growing companies. Revenues then rose again, to $9.9bn, in 2023.

Since its launch in 2019, Trikafta has generated $26bn in revenues and is expected to hit $10bn in annual sales next year. The Boston-based biotech is also poised to seek regulatory approval this year for its fifth CF treatment, known as the vanza triple, which is also projected to generate nearly $10bn in annual sales, according to investment bank William Blair.

Vertex “is probably going to be one of the fastest-growing top lines outside of the weight-loss drugmakers [Eli] Lilly and Novo [Nordisk],” predicts Debjit Chattopadhyay, a healthcare analyst at Guggenheim Securities. “I’d put Vertex in my pharma top three [to invest in].” This year, Vertex’s market capitalisation surpassed $100bn for the first time.

Daniel Lyons, a portfolio manager at Janus Henderson, a top-25 Vertex shareholder, says the biotech faces “no real competitive threats” to its dominance in CF, with patents extending until at least 2039.

“That gives the company an incredibly profitable base business and they’ve basically reinvested a significant amount of those profits in their pipeline.”

Altshuler says Vertex learnt the importance of continued investment in research from the troubled rollout of its hepatitis C treatment, Incivek. After becoming the fastest drug ever to hit $1bn in annual sales, it was rapidly supplanted by a superior treatment from rival Gilead. “It’s never the case that the first or second medicine is the best — but most companies think that no one’s going to keep with them so they stop,” he says. “We learnt from that: never assume you’re going to win; keep building better and better medicine.”

However, Vertex has come under fire for the hefty price tag of Trikafta, which has meant only 12 per cent of CF patients worldwide have been prescribed the treatment, according to research published in the Journal of Cystic Fibrosis in 2022.

The researchers concluded that “the medicines are so expensive they are essentially unavailable unless reimbursed by government or health system authorities”. Altshuler says the “vast majority” of CF patients worldwide who meet the prescription criteria for Trikafta have been prescribed the drug.

The challenge for Vertex is whether it can reproduce its success in CF in other diseases. The company received regulatory approval last year for the first ever treatment based on Crispr gene editing, which targets sickle cell disease and beta thalassaemia. It also paid $4.9bn this month for Alpine Immune Sciences, which is developing a treatment for an autoimmune kidney disease.

But it is a new generation of non-addictive painkillers that analysts say are the most promising drugs in Vertex’s pipeline.

Vertex hopes to receive US Food and Drug Administration approval for a non-opioid painkiller, known as VX-548, this year after a late-stage clinical study showed it lowered pain with a far lower incidence of side-effects such as nausea and vomiting — and without the risk of addiction.

“Each year, we’re layering on evidence that we’re going to crack another disease open,” says Stuart Arbuckle, Vertex’s chief operating officer. He says Vertex’s $4.8bn R&D budget is not about maximising “shots on goal”; it is instead focused on “a set number” of diseases where Vertex has “super-high conviction that they’re going to work”.

Vertex’s acute pain drug is projected to generate $2.3bn in annual sales by 2030, according to analysts’ consensus forecasts, but the much bigger opportunity is an approved non-opioid painkiller that can serve as an alternative to the prescription opioids that have led to the deaths of hundreds of thousands of Americans.

If you can go from acute to chronic pain, we could be talking about a $10bn-$20bn revenue potential Hartaj Singh, biotech analyst

“Wall Street is all over the place with how to handle chronic pain, because of the dirtiness of the opioid crisis and because people have gotten bullish on pain launches and the pain launches have failed,” says a person at a biotech fund with a shareholding in Vertex.

To overcome competition from cheap generic opioids, Vertex has hired a salesforce of several hundred people — much larger than its team focused on CF — to work on the product’s launch.

Some analysts say non-opioid pain medication could be the next blockbuster class of drugs, with an impact on the industry similar to the weight-loss medications. “Pain could be analogous to another GLP-1 scenario,” says Hartaj Singh, a biotech analyst at equity research company Oppen­heimer — referring to the hormone targeted by the weight-loss drugs. “If you can go from acute to chronic pain, we could be talking about a $10bn-$20bn revenue potential.”

Altshuler recalls how experts dismissed GLP-1s. “What they said . . . ten years ago, was that no medicines for diabetes and obesity are needed — they’re all generic, nothing really works, it’s not going to happen. That turned out to be untrue . . . I can’t promise but, to me, [the pain franchise] looks like [CF] in 2012.”

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Case Study: Cystic Fibrosis - CER

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Part I: A​ ​Case​ ​of​ ​Cystic​ ​Fibrosis

Dr. Weyland examined a six month old infant that had been admitted to University Hospital earlier in the day. The baby's parents had brought young Zoey to the emergency room because she had been suffering from a chronic cough. In addition, they said that Zoey sometimes would "wheeze" a lot more than they thought was normal for a child with a cold. Upon arriving at the emergency room, the attending pediatrician noted that salt crystals were present on Zoey's skin and called Dr. Weyland, a pediatric pulmonologist. Dr. Weyland suspects that baby Zoey may be suffering from cystic fibrosis.

CF affects more than 30,000 kids and young adults in the United States. It disrupts the normal function of epithelial cells — cells that make up the sweat glands in the skin and that also line passageways inside the lungs, pancreas, and digestive and reproductive systems.

The inherited CF gene directs the body's epithelial cells to produce a defective form of a protein called CFTR (or cystic fibrosis transmembrane conductance regulator) found in cells that line the lungs, digestive tract, sweat glands, and genitourinary system.

When the CFTR protein is defective, epithelial cells can't regulate the way that chloride ions pass across cell membranes. This disrupts the balance of salt and water needed to maintain a normal thin coating of mucus inside the lungs and other passageways. The mucus becomes thick, sticky, and hard to move, and can result in infections from bacterial colonization.

• "Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon will die" This is an old saying from the eighteenth century and describes one of the symptoms of CF (salty skin). Why do you think babies in the modern age have a better chance of survival than babies in the 18th century?
• What symptoms lead Dr. Weyland to his initial diagnosis?
• Consider the graph of infections, which organism stays relatively constant in numbers over a lifetime. What organism is most likely affecting baby Zoey?
• What do you think is the most dangerous time period for a patient with CF? Justify your answer.

Part​ ​II:​ ​ ​CF​ ​is​ ​a​ ​disorder​ ​of​ ​the​ ​cell​ ​membrane.

Imagine a door with key and combination locks on both sides, back and front. Now imagine trying to unlock that door blind-folded. This is the challenge faced by David Gadsby, Ph.D., who for years struggled to understand the highly intricate and unusual cystic fibrosis chloride channel – a cellular doorway for salt ions that is defective in people with cystic fibrosis.

His findings, reported in a series of three recent papers in the Journal of General Physiology, detail the type and order of molecular events required to open and close the gates of the cystic fibrosis chloride channel, or as scientists call it, the cystic fibrosis transmembrane conductance regulator (CFTR).

Ultimately, the research may have medical applications, though ironically not likely for most cystic fibrosis patients. Because two-thirds of cystic fibrosis patients fail to produce the cystic fibrosis channel altogether, a cure for most is expected to result from research focused on replacing the lost channel.

5. Suggest a molecular fix for a mutated CFTR channel. How would you correct it if you had the ability to tinker with it on a molecular level?

6. Why would treatment that targets the CFTR channel not be effective for 2⁄3 of those with cystic fibrosis?

7. Sweat glands cool the body by releasing perspiration (sweat) from the lower layers of the skin onto the surface. Sodium and chloride (salt) help carry water to the skin's surface and are then reabsorbed into the body. Why does a person with cystic fibrosis have salty tasting skin?

Part​ ​III:​ ​No​ ​cell​ ​is​ ​an​ ​island

Like people, cells need to communicate and interact with their environment to survive. One way they go about this is through pores in their outer membranes, called ion channels, which provide charged ions, such as chloride or potassium, with their own personalized cellular doorways. But, ion channels are not like open doors; instead, they are more like gateways with high-security locks that are opened and closed to carefully control the passage of their respective ions.

In the case of CFTR, chloride ions travel in and out of the cell through the channel’s guarded pore as a means to control the flow of water in and out of cells. In cystic fibrosis patients, this delicate salt/water balance is disturbed, most prominently in the lungs, resulting in thick coats of mucus that eventually spur life-threatening infections. Shown below are several mutations linked to CFTR:

8. Which mutation do you think would be easiest to correct. Justify your answer. 9. Consider what you know about proteins, why does the “folding” of the protein matter?

Part​ ​IV:​ ​Open​ ​sesame

Among the numerous ion channels in cell membranes, there are two principal types: voltage-gated and ligand-gated. Voltage-gated channels are triggered to open and shut their doors by changes in the electric potential difference across the membrane. Ligand-gated channels, in contrast, require a special “key” to unlock their doors, which usually comes in the form of a small molecule.

CFTR is a ligand-gated channel, but it’s an unusual one. Its “key” is ATP, a small molecule that plays a critical role in the storage and release of energy within cells in the body. In addition to binding the ATP, the CFTR channel must snip a phosphate group – one of three “P’s” – off the ATP molecule to function. But when, where and how often this crucial event takes place has remains obscure.

10. Compare the action of the ligand-gated channel to how an enzyme works.

11. Consider the model of the membrane channel, What could go wrong to prevent the channel from opening?

12. Where is ATP generated in the cell? How might ATP production affect the symptoms of cystic fibrosis?

13. Label the image below to show how the ligand-gated channel for CFTR works. Include a summary.

Part​ ​V:​ Can​ ​a​ ​Drug​ ​Treat​ ​Zoey’s​ ​Condition?

Dr. Weyland confirmed that Zoey does have cystic fibrosis and called the parents in to talk about potential treatments. “Good news, there are two experimental drugs that have shown promise in CF patients. These drugs can help Zoey clear the mucus from his lungs. Unfortunately, the drugs do not work in all cases.” The doctor gave the parents literature about the drugs and asked them to consider signing Zoey up for trials.

The​ ​Experimental​ ​Drugs

Ivacaftor TM is a potentiator that increases CFTR channel opening time. We know from the cell culture studies that this increases chloride transport by as much as 50% from baseline and restores it closer to what we would expect to observe in wild type CFTR. Basically, the drug increases CFTR activity by unlocking the gate that allows for the normal flow of salt and fluids.

In early trials, 144 patients all of whom were age over the age of 12 were treated with 150 mg of Ivacaftor twice daily. The total length of treatment was 48 weeks. Graph A shows changes in FEV (forced expiratory volume) with individuals using the drug versus a placebo. Graph B shows concentrations of chloride in patient’s sweat.

14. What is FEV? Describe a way that a doctor could take a measurement of FEV.

15. Why do you think it was important to have placebos in both of these studies?

16. Which graph do you think provides the most compelling evidence for the effectiveness of Ivacafor? Defend your choice.

17. Take a look at the mutations that can occur in the cell membrane proteins from Part III. For which mutation do you think Ivacaftor will be most effective? Justify your answer.

18. Would you sign Zoey up for clinical trials based on the evidence? What concerns would a parent have before considering an experimental drug?

Part​ ​VI:​ ​Zoey’s​ ​Mutation

Dr. Weyland calls a week later to inform the parents that genetic tests show that Zoey chromosomes show that she has two copies of the F508del mutation. This mutation, while the most common type of CF mutation, is also one that is difficult to treat with just Ivacaftor. There are still some options for treatment.

In people with the most common CF mutation, F508del, a series of problems prevents the CFTR protein from taking its correct shape and reaching its proper place on the cell surface. The cell recognizes the protein as not normal and targets it for degradation before it makes it to the cell surface. In order to treat this problem, we need to do two things: first, an agent to get the protein to the surface, and then ivacaftor (VX-770) to open up the channel and increase chloride transport. VX-809 has been identified as a way to help with the trafficking of the protein to the cell surface. When added VX-809 is added to ivacaftor (now called Lumacaftor,) the protein gets to the surface and also increases in chloride transport by increasing channel opening time.

In early trials, experiments were done in-vitro, where studies were done on cell cultures to see if the drugs would affect the proteins made by the cell. General observations can be made from the cells, but drugs may not work on an individual’s phenotype. A new type of research uses ex-vivo experiments, where rectal organoids (mini-guts) were grown from rectal biopsies of the patient that would be treated with the drug. Ex-vivo experiments are personalized medicine, each person may have different correctors and potentiators evaluated using their own rectal organoids. The graph below shows how each drug works for 8 different patients (#1-#8)

19. Compare ex-vivo trials to in-vitro trials.

20. One the graph, label the group that represents Ivacaftor and Lumacaftor. What is the difference between these two drugs?

21. Complete a CER Chart. If the profile labeled #7 is Zoey, rank the possible drug treatments in order of their effectiveness for her mutation. This is your CLAIM. Provide EVIDENCE​ to support your claim. Provide REASONING​ that explains why this treatment would be more effective than other treatments and why what works for Zoey may not work for other patients. This is where you tie the graph above to everything you have learned in this case. Attach a page.

• Gene Therapy

Gene Therapy Case Study: Cystic Fibrosis

Introduction

Materials and methods, statement of ethics, conflict of interest statement, funding sources, author contributions, data availability statement, improved nutritional outcomes and gastrointestinal symptoms in adult cystic fibrosis patients treated with elexacaftor/tezacaftor/ivacaftor.

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Nela Stastna , Lumir Kunovsky , Michal Svoboda , Eva Pokojova , Lukas Homola , Miriam Mala , Zaneta Gracova , Barbora Jerabkova , Jana Skrickova , Jan Trna; Improved Nutritional Outcomes and Gastrointestinal Symptoms in Adult Cystic Fibrosis Patients Treated with Elexacaftor/Tezacaftor/Ivacaftor. Dig Dis 2024; https://doi.org/10.1159/000538606

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Introduction: Cystic fibrosis transmembrane conductance regulator modulator therapy improves nutritional status and quality of life. Clinical trials have shown pancreatic insufficiency conversion, mostly in pediatric patients treated with ivacaftor. Studies with elexacaftor/tezacaftor/ivacaftor (ETI) in older patients have not suggested restoration of exocrine pancreas function, but quality data in adults are lacking. Our aim was to show the effect of ETI in adults with cystic fibrosis (CF) on nutritional status and digestive function. We hypothesized improvement of nutritional parameters and gastrointestinal symptoms, reduction of pancreatic enzyme replacement therapy, but uncertain improvement in exocrine pancreatic function. Methods: We prospectively enrolled adults with CF treated with ETI from August 2021 to June 2022. We measured anthropometric parameters, laboratory nutritional markers, change of fecal elastase, pancreatic enzymes replacement therapy needs, and gastrointestinal symptoms. Results: In the cohort of 29 patients (mean age 29.1 years), 82.8% suffered exocrine pancreatic insufficiency. After ETI, mean BMI increased by 1.20 kg/m 2 ( p < 0.001), mean body weight by 3.51 kg ( p < 0.001), albumin by 2.81 g/L, and prealbumin by 0.06 (both p < 0.001). Only 1 patient, initially pancreatic insufficient (4.5%, p < 0.001), developed pancreatic sufficiency, indicated by increased fecal elastase from 45 μg/g to 442.1 μg/g. Mean change in lipase substitution decreased by 1,969 units/kg/day ( p < 0.001) and stools frequency by 1.18 per day ( p < 0.001). Conclusion: Our data suggest increased nutritional parameters, lower pancreatic substitution requirements, and improved defecation in adult CF patients on ETI. Improvement in exocrine pancreatic function might be mutation-specific and needs further study.

Cystic fibrosis (CF) is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which regulates the Cl − channel [ 1 ]. Exocrine pancreatic insufficiency is a key characteristic of CF. Approximately 85% of newborns with CF have pancreatic exocrine insufficiency (EPI) [ 1 ]. Type and severity of pancreatic function depend on CFTR mutation status. Mild mutations (classes IV and V) are likely associated with pancreatic sufficiency (PS) with a higher prevalence of recurrent acute pancreatitis. Patients with severe mutations (classes I–III, VI) are likely EPI and with CF-related diabetes developing over time [ 1 ]. Measurement of fecal elastase (FE-1) is considered the gold standard for exocrine pancreatic function assessment. There is no exact consensus on cutoff limit for EPI [ 1, 2 ]. Usually, FE-1 ≤ 200 μg/g of stool is regarded as EPI. Values of ≤100 μg/g are regarded as severe EPI and 100–200 μg/g as moderate/mild EPI [ 2‒4 ]. Patients with CF-related EPI require, pancreatic enzyme replacement therapy (PERT), fat-soluble vitamin supplementation. Disruption of dietary nutrient digestion and absorption increase energy expenditure of the organism, thereby leading to malnutrition and underweight condition. Poor nutritional status is associated with poorer clinical outcome and increased mortality [ 1, 5 ].

The development of CFTR modulators was considered to be game-changing: potentiators (ivacaftor) and correctors (lumacaftor, tezacaftor, elexacaftor). This therapy improves pulmonary outcomes, but the effect on nutritional parameters and pancreatic function is not enough reported [ 6 ]. The most data are available about the effect of ivacaftor. The newest studies of elexacaftor/tezacaftor/ivacaftor (ETI) in the adult population have shown a quite wide range of absolute change (0.6–2.02 kg/m 2 ) in BMI [ 6‒10 ]. This enhancement is caused by multiple factors, and differences in effect might be mutation-specific.

Those studies demonstrating reduced prevalence of EPI conversion to PS with CFTR modulator use have mostly been just case series and case reports [ 11, 12 ]. These have reported 21.3–67% of patients converted to PS [ 11, 12 ]. Those who converted were younger than patients persistent on EPI (8.0 vs. 9.8 years, p = 0.032), and no differences in genotype, drug, or treatment duration are reported [ 11 ]. Studies demonstrating pancreatic conversion according to FE-1 levels have reported average age of 5.9 versus 8.4 years ( p = 0.003) [ 11 ]. Most of these data relate to ivacaftor monotherapy.

Impact of CFTR Modulator Therapy on Nutritional Markers

The STRIVE study evaluating ivacaftor in CF patients >12 years of age reported mean weight gain of 2.7 kg [ 13 ]. In the same aged population, trials with lumacaftor/ivacaftor reported BMI increase by 0.2 kg/m 2 , while treatment with tezacaftor/ivacaftor was not associated with BMI improvement [ 14, 15 ]. Trials of ETI have demonstrated absolute change in BMI in the range 0.6–2.02 kg/m 2 and mean body weight increase by 1.6–3.4 kg [ 6‒10 ]. A study evaluating albumin in a cohort with ivacaftor (mean age 20) found no significant change [ 5 ].

Impact of CFTR Modulator Therapy on Exocrine Pancreatic Function

There are many case reports demonstrating improved pancreatic function after ivacaftor initiation. Clinical trials have reported overall increased FE-1 by 99.8–299 μg/g, which is consistent with conversion to PS [ 12 , 16‒18 ]. These data relate mainly to children 1–14 years of age. A study of 23 patients (ages 5–61 years) reported no change in FE-1 [ 19 ]. All these participants had mild gating mutations. To date, only 1 adult patient has been described in a case report as pancreatic insufficiency conversion after ivacaftor treatment [ 20 ].

Individual cases of improved pancreatic function in patients treated with lumacaftor/ivacaftor have been presented, mostly in case reports [ 21‒23 ]. A clinical trial in patients 2–5 years of age showed a mean absolute change in FE-1 by 52.6 μg/g [ 24 ]. Gould et al. [ 25 ] published a case series of increasing risk of acute pancreatitis in EPI patients (8–16 years of age), while 3 of 5 of these patients also developed PS (indicated by FE-1 >100 μg/g). All these patients had two severe mutations.

A study evaluating the efficacy of tezacaftor/ivacaftor in patients 6–11 years of age observed no significant improvement from EPI to PS [ 26 ]. Data from the PROMISE study recently published by Schwarzenberg et al. [ 27 ] showed no change in FE-1 in patients >12 years of age at 24 weeks of treatment with ETI (mean change by 7.08 μg/g).

Impact of CFTR Modulator Therapy on PERT Dose and Defecation Symptoms

PERT dosing is reported only in a few studies, in which cases the patients were treated with ivacaftor. Mean PERT doses were decreased by 1,202–4,655 units of lipase/kg/day [ 12, 28, 29 ]. Preliminary data presented from the PROMISE study indicate decreased proportion of self-described constipation (−1.8% from baseline) but a 6% proportion increase of reported diarrhea [ 27 ].

Study Participants

We performed a single-center, prospective observational study in adult patients (age ≥18 years) with CF. The patients were enrolled from August 2021 to June 2022. We included all those with a diagnosis of CF treated with ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg combined with ivacaftor 150 mg per day according to EMA indication criteria. There was no washout period in previously used generation of CFTR modulators. Patients after lungs transplantation or pregnant were not included into the study.

Data Collection

All data were obtained prospectively during outpatient visits at 24-week follow-up. We assessed BMI, body weight, albumin, prealbumin, total protein levels, and FE-1. Fecal specimens were collected at home. At baseline, this was usually at the time of diagnosis. In cases of PS, this was done annually. In case of EPI and any previous CFTR modulator use and any gastrointestinal problems occur, we did not reevaluate FE-1 besides this trial. The controlled FE-1 value was measured at the 24th week of ETI use. PERT dose was assessed for 1 day during week 24, same as number of stools per day. Patients were allowed to set their daily PERT doses according to their behavior modification. Defecation frequency was evaluated by the patients themselves.

Data Analysis

All outcome results are determined in the same local laboratory using the same laboratory methods. All the patients’ body weights were measured on the same digital weighing machine. Weights were measured in kilograms; BMIs were calculated as weight (kg)/height (m 2 ); and the values of albumin, total protein, and prealbumin were measured in grams/liter. A monoclonal ELISA assay was used to test FE-1 levels (ScheBo Biotech AG). FE-1 was reported in micrograms/gram. For purposes of this study, EPI is considered to occur when FE-1 level is < 200 μg/g of stool. PERT doses and stool frequency are patient-reported outcome measures themselves with the notes and mean value was measured. We measured change in lipase substitution in units/kg/day.

Categorical data are described by absolute and relative frequencies. Relative frequencies are calculated from valid (known) data. Continuous data are described by valid N , mean (± standard deviation), and median together with range. Ratio of patients with FE-1 improvement is tested by one-sample binomial test against a 0% reference value. Change of parameters over time is calculated as difference between values at 24 weeks versus baseline values. These differences are tested by paired t test or paired Wilcoxon test (depending on normal distribution of data). The entire analysis was prepared in SPSS Statistics v28, and all hypotheses are tested against a 5% level of significance.

Study Cohort Characteristics

Data in Table 1 characterize the patients and cohort. All patients ( N = 29) were of Caucasian ethnicity. Thirteen (44.8%) were males. At baseline, the mean age was 29.1 years, 15 patients (51.7%) were homozygous for F508del mutation, and other 14 patients (48.3%) were F508del heterozygous. In 4 cases, second pathogenic variant was classified as class I ( 2184insA , 3134del9 , 3143del9 , 3659delC ), 2 cases of class II mutation ( 2143delT, 2185insC ), 1 case of class III ( G551D ), 2 cases of class IV ( 711+5 G>A, R1066G ), and 2 cases of class V ( 3272-26 A>G, 3849+10kb C>T ). Mean FEV 1 was 66.8%, and 24 patients (82.8%) were EPI. One patient in this cohort (3.4%) had been pretreated with ivacaftor monotherapy, 5 (17.2%) with lumacaftor/ivacaftor, and 8 (27.5%) with tezacaftor/ivacaftor before ETI initiation. Fifteen patients (51.7%) were CFTR modulators naïve. In general, during previous CFTR modulator treatment, the nutritional status and gastrointestinal symptoms did not significantly change; however, this was not the purpose of this trial. Prior to initiating treatment, the mean BMI was 23.0 kg/m 2 , mean body weight 66.6 kg, mean albumin 45.9 g/L, mean prealbumin 0.2 g/L, and mean total protein 77.3 g/L. The mean PERT dose at baseline was 7,471 units of lipase/kg/day, and number of stools per day was 2.8.

Descriptive characteristics of patients

Impact of ETI on BMI, Body Weight, and Nutritional Parameters

The mean change in BMI was an improvement by 1.20 kg/m 2 ( p < 0.001). The mean body weight improved by 3.51 kg ( p < 0.001). Mean albumin value increased by 2.81 g/L and prealbumin by 0.06 g/L ( p < 0.001). Total protein decreased by 3.29 g/L after initiating ETI. There was no difference between homozygotes and heterozygotes. All nutritional parameters are summarized in Table 2 .

Change of parameters during 24 weeks

Impact of ETI on Exocrine Pancreatic Function

Results at outcome compared to baseline values were evaluated only among participants with data available at both baseline and follow-up visit. Twenty-two patients (75.8%) were evaluated for FE-1 at the outcome. Of these 22 patients, 1 patient (4.5%) improved FE-1 value from the <200 μg/g range to the ≥200 μg/g range ( p < 0.001) ( Table 3 ). Twenty-one patients did not significantly improve FE-1 levels. In these 21 patients (95.5%), FE-1 levels were in the EPI range both at baseline and at outcome.

FE-1 status at follow-up within interval of week 24 versus baseline ( n = 22)

Impact of ETI on PERT Dose and Defecation Symptoms

The mean change in lipase substitution was a decrease by 1,969 units/kg/day ( p < 0.001). Moreover, 2 patients no longer needed PERT as of the 24-week follow-up. Five patients (17.2%) were pancreatic sufficient at the baseline. At the baseline, however, 24 patients had been pancreatic insufficient, 3 patients were using the PERT regardless that they were pancreatic sufficient, and 3 pancreatic insufficient patients were not using PERT due to intolerance. Two patients discontinued and no longer needed lipase substitution during the observation period. In some cases, PERT dose actually was increased, probably due to weight gain. The frequency of defecation decreased by 1.18 stool per day ( p < 0.001). There was no significant difference between homozygotes and heterozygotes (see Table 2 ).

Poor nutritional status in CF is associated with increased pancreatic dysfunction [ 5 ]. Interventions aiming to improve nutritional status and, by extension, increase survival have comprised a crucial step in treatment. Improvement in BMI and body weight is a benefit of CFTR modulator therapy. This depends on the severity of a given patient’s mutation status and the specific CFTR modulator used. In this research, we demonstrated statistically significant improvement of nutritional parameters after ETI use. We report BMI improvement by mean 1.20 kg/m 2 , while trials showed means in the 0.6–2.02 kg/m 2 range [ 6‒10 ]. We observed mean weight gain of 3.51 kg, which is more than the 1.6–3.4 kg demonstrated in trials [ 6‒10 ]. Petersen et al. [ 10 ] had demonstrated that only patients with EPI and treated with the triple combination had body weight significantly altered. The mechanism of increased nutritional parameters is multifactorial. The treatment improves appetite and food intake, improved lung clearance causes better exercise tolerance and therefore benefits the musculoskeletal system. Decreased chronic inflammation leads to a reduction in energy expenditure needed for the working of respiratory muscle during respiratory exacerbations, and that leads to more proper energy management [ 30 ]. Because persistent inflammation is reduced, we speculate that a lowering of the circulating immunoglobulins causes decreased total protein level. In any case, the total protein marker is not an appropriate index of nutritional status. We demonstrate higher concentration of the serum proteins, which in an absence of inflammation, fairly well correlate to nutrition status. In patients using ivacaftor alone, no significant change in albumin serum value has been reported, but in our cohort, a mean improvement by 2.81 g/L was seen [ 5 ]. In any case, pancreatic insufficiency also significantly affects an individual’s nutritional status.

We are challenged to determine whether CFTR modulator therapy can restore pancreatic function outside of childhood. Trials have shown that the younger a patient is and the closer to borderline pancreatic insufficiency, the more likely it is that pancreatic function can be rescued [ 30, 31 ]. CFTR modulators decrease episodes of pancreatitis in patients with residual pancreatic function by reducing pancreatic ductal mucoid plugging [ 30 ]. The mechanism of improving exocrine pancreatic function is uncertain. It might be caused by improved pancreatic duct cell function with subsequent improvement in acinar cell function or enhanced CFTR-mediated bicarbonate function [ 11, 32 ]. A single study evaluating FE-1 in adults (treated with ivacaftor) found no significant change, but that trial’s duration was only 12 weeks [ 19 ]. In our study, FE-1 was analyzed at week 24 after initiating ETI. On the other hand, Nichols et al. [ 12 ] demonstrated the case of a patient 14 years old who reached exocrine pancreas sufficiency in 7 years after ivacaftor initiation. We demonstrated improvement of exocrine pancreatic function from EPI to PS in 1 adult patient (4.5%). In this case, FE-1 increased by at least 374.4 μg/g (from 45 μg/g to 419.4 μg/g, subsequently 442.1 μg/g) [ 33 ]. To date, only 1 case report in 2018 has been described with improved EPI after ivacaftor treatment [ 20 ]. In our cohort, we have presented the second patient with conversion from pancreatic insufficiency to sufficiency after CFTR therapy (respectively, the first patient with exocrine function improvement after ETI therapy). Improvement of exocrine pancreatic function is age-dependent.

The multicentric PROMISE-GI study, which evaluated a qualitatively similar study group as ours, found mean change by 7.08 μg/g, which was not a significant improvement in PS [ 27 ]. We did not measure absolute FE-1 change in our study because the lower limit in our laboratory is < 50 μg/g and a quantitative assessment would have been inaccurate. We assume that mutation status might play the key role here and that carriers of milder forms of mutations could have greater chances of adjusting pancreatic function.

A single patient within our cohort – a 36-year-old female – presented with exocrine pancreatic function restoration with F508del/3849 + 10 kb C>T mutation [ 33 ]. Patients having this variant are generally likely to be pancreatic sufficient [ 34 ]. Her baseline FE-1 had been 45 μg/g of stool, and PERT substitution had been initiated. At age 35, tezacaftor/ivacaftor combination therapy was initiated. One year later, she started using ETI. In week 24 of treatment, her level of FE-1 was 419.4 μg/g; in week 32, it was 442.1 μg/g. During the tezacaftor/ivacaftor use, FE-1 had not been evaluated. Her PERT was weaned and stopped completely with no adverse event.

The PERT dose assessment is a patient-reported outcome measure. Therefore, the patients’ adherence might be a limitation. We observed decreased need for PERT by a mean 1,969 units of lipase/kg/day, which rather is on the lower limit of the change observed with ivacaftor use (1,202–4,655 units) [ 12, 28, 29 ]. We report significantly decreased number of bowel movements per day by a mean 1.18, whereas the PROMISE-GI study (438 participants) observed no significant change while using a stool-specific questionnaire [ 27 ]. The impact of improved symptoms cannot be distinguished to be attributed solely to PERT or CFTR modulators.

Our study has a number of limitations that need to be considered. First, this is a small cohort of patients. Improvement in exocrine pancreatic function might also have been affected by the previous treatments. FE-1 levels had not been checked during previous CFTR modulator treatments. The FE-1 might be affected by stool consistency; all the stool samples were classified 1–4 within the Boston stool scale. Further research and longitudinal studies are needed to explain the mechanism of improved nutritional status and prove whether highly effective CFTR modulators can restore exocrine pancreatic function in adult patients.

This single-center observational study of 29 adults with CF reveals that ETI therapy was associated with improved metabolic parameters, decreased need of weight-adjusted dose of lipase supplementation and number of stools per day, and, finally, pancreatic function restoration in the case of one adult with the F808del and mild type CFTR mutation. This is only second known report of pancreatic insufficiency restoration in the adult population, respectively, and the first patient treated with ETI who achieved pancreatic function conversion to sufficiency. This prospect of function restoration is very promising, and consideration should be given to repeating FE-1 measurement in patients with improved clinical symptoms and satisfactory weight gains upon treatment. We should consider whether restoration of pancreatic insufficiency in adulthood is possible in patients having mild mutations. Whereas malnutrition and pancreas insufficiency used to be defining characteristics of CF, we need to rethink the understanding of CF, as well as to change the basic paradigms of CF treatment and the designs of future studies.

An approval by an ethical board is not necessary as this is an observational study, and there is no intervention in this study. Written informed consent containing permission for data processing for scientific purposes has been signed by each patient. This study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

The authors declare no conflict of interest.

Publication will be supported by the Czech Pneumological and Physiological Society (open access publication fee grant).

Nela Stastna: writing – original draft, methodology, visualization, formal analysis, and data curation. Lumir Kunovsky and Jan Trna: methodology and writing – review and editing. Michal Svoboda: data curation and formal analysis. Eva Pokojova and Miriam Mala: supervision and data curation. Lukas Homola and Jana Skrickova: supervision. Zaneta Gracova and Barbora Jerabkova: data curation.

The data that support the findings of this study are not publicly available but are available from the corresponding author upon reasonable request.

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Its blockbuster cystic fibrosis treatment costs $300,000 a year. Now Vertex wants to solve the opioid crisis

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Oliver Barnes in New York

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So effective is Vertex Pharmaceuticals’ blockbuster cystic fibrosis (CF) drug, Trikafta, that studies project it could extend the lives of some young patients by up to 45 years. As such, it is not cheap: in the US, it costs $300,000 per patient, per year. But given the transformative nature of the treatment for a disease with a poor prognosis, the high list price has not held back sales for the pharma group.

And, now, the same team of scientists at Vertex’s San Diego laboratory have a second decades-long research project coming to fruition that could unlock another potentially huge market: non-opioid painkillers.

If patients live longer, “it’s good for business”, says David Altshuler, Vertex’s chief scientific officer. The number of people living with CF worldwide is now 105,000, up from 70,000 in 2012, according to estimates from US non-profit the Cystic Fibrosis Foundation — a rise that experts attribute both to Vertex’s drugs and improved diagnostics.

“If you take a life-threatening disease that shortens life and you have a transformative medicine, you not only have the benefit in the short run, but then people live a long time and it’s a positive thing for everyone,” adds Altshuler. These positive effects are evident in Vertex’s revenues, which more than doubled between 2019 and 2022, from $4.2bn to $8.9bn, the period covered by the FT-Statista ranking of the Americas’ 500 fastest-growing companies. Revenues then rose again, to $9.9bn, in 2023.

Since its launch in 2019, Trikafta has generated $26bn in revenues and is expected to hit $10bn in annual sales next year. The Boston-based biotech is also poised to seek regulatory approval this year for its fifth CF treatment, known as the vanza triple, which is also projected to generate nearly $10bn in annual sales, according to investment bank William Blair.

Vertex “is probably going to be one of the fastest-growing top lines outside of the weight-loss drugmakers [Eli] Lilly and Novo [Nordisk],” predicts Debjit Chattopadhyay, a healthcare analyst at Guggenheim Securities. “I’d put Vertex in my pharma top three [to invest in].” This year, Vertex’s market capitalisation surpassed $100bn for the first time.

Daniel Lyons, a portfolio manager at Janus Henderson, a top-25 Vertex shareholder, says the biotech faces “no real competitive threats” to its dominance in CF, with patents extending until at least 2039.

“That gives the company an incredibly profitable base business and they’ve basically reinvested a significant amount of those profits in their pipeline.”

Altshuler says Vertex learnt the importance of continued investment in research from the troubled rollout of its hepatitis C treatment, Incivek. After becoming the fastest drug ever to hit $1bn in annual sales, it was rapidly supplanted by a superior treatment from rival Gilead. “It’s never the case that the first or second medicine is the best — but most companies think that no one’s going to keep with them so they stop,” he says. “We learnt from that: never assume you’re going to win; keep building better and better medicine.”

However, Vertex has come under fire for the hefty price tag of Trikafta, which has meant only 12 per cent of CF patients worldwide have been prescribed the treatment, according to research published in the Journal of Cystic Fibrosis in 2022.

The researchers concluded that “the medicines are so expensive they are essentially unavailable unless reimbursed by government or health system authorities”. Altshuler says the “vast majority” of CF patients worldwide who meet the prescription criteria for Trikafta have been prescribed the drug.

The challenge for Vertex is whether it can reproduce its success in CF in other diseases. The company received regulatory approval last year for the first ever treatment based on Crispr gene editing, which targets sickle cell disease and beta thalassaemia. It also paid $4.9bn this month for Alpine Immune Sciences, which is developing a treatment for an autoimmune kidney disease.

But it is a new generation of non-addictive painkillers that analysts say are the most promising drugs in Vertex’s pipeline.

Vertex hopes to receive US Food and Drug Administration approval for a non-opioid painkiller, known as VX-548, this year after a late-stage clinical study showed it lowered pain with a far lower incidence of side-effects such as nausea and vomiting — and without the risk of addiction.

“Each year, we’re layering on evidence that we’re going to crack another disease open,” says Stuart Arbuckle, Vertex’s chief operating officer. He says Vertex’s $4.8bn R&D budget is not about maximising “shots on goal”; it is instead focused on “a set number” of diseases where Vertex has “super-high conviction that they’re going to work”.

Vertex’s acute pain drug is projected to generate $2.3bn in annual sales by 2030, according to analysts’ consensus forecasts, but the much bigger opportunity is an approved non-opioid painkiller that can serve as an alternative to the prescription opioids that have led to the deaths of hundreds of thousands of Americans.

If you can go from acute to chronic pain, we could be talking about a $10bn-$20bn revenue potential Hartaj Singh, biotech analyst

“Wall Street is all over the place with how to handle chronic pain, because of the dirtiness of the opioid crisis and because people have gotten bullish on pain launches and the pain launches have failed,” says a person at a biotech fund with a shareholding in Vertex.

To overcome competition from cheap generic opioids, Vertex has hired a salesforce of several hundred people — much larger than its team focused on CF — to work on the product’s launch.

Some analysts say non-opioid pain medication could be the next blockbuster class of drugs, with an impact on the industry similar to the weight-loss medications. “Pain could be analogous to another GLP-1 scenario,” says Hartaj Singh, a biotech analyst at equity research company Oppen­heimer — referring to the hormone targeted by the weight-loss drugs. “If you can go from acute to chronic pain, we could be talking about a $10bn-$20bn revenue potential.”

Altshuler recalls how experts dismissed GLP-1s. “What they said . . . ten years ago, was that no medicines for diabetes and obesity are needed — they’re all generic, nothing really works, it’s not going to happen. That turned out to be untrue . . . I can’t promise but, to me, [the pain franchise] looks like [CF] in 2012.”

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The Biology Corner

Biology Teaching Resources

Case Study: Cystic Fibrosis Mutations

This case study is a follow-up to the Cystic Fibrosis Case Study where students explore how changes in transport proteins affects the movement of ions, resulting in a build-up of chloride ions and the symptoms of the disease.

Students were introduced to the idea that different mutations can cause differences in the transport proteins, but in the first version, the origin of these mutations was not discussed.

Eventually, students get to the chapter on DNA, RNA, and protein synthesis, so it’s a good time to circle back to the CF case and explore how mutations in DNA can affect the protein made by the ribosomes.

Students should already have some background in the central dogma, but a review may be in order to remind students how to transcribe DNA to RNA and then use a codon chart to determine the sequence of amino acids. This practice worksheet on using codon charts is something they may have done in freshman biology.

CFTR Mutations

This case explore frameshift mutations, missense mutations, and nonsense mutations. Students are given a section of DNA to transcribe and compare it to mutant DNA. Students should see that changes in DNA can result in changes in the synthesized protein, though some changes are more profound than others.

The link below is a Google Doc designed for remote learning but will work for in-class lessons. An original in-class version is also available, where it doesn’t have the colored text boxes.

Shannan Muskopf

• Open access
• Published: 29 April 2024

Association between arachidonate lipoxygenase 15,c.-292 C > T gene polymorphism and non-cystic fibrosis bronchiectasis in children: a pilot study on the effects on airway lipoxin A4 and disease phenotype

• Mahitab Morsy Hussein   ORCID: orcid.org/0000-0003-2932-9291 1 ,
• Eman Mahmoud Fouda 1 ,
• Yasmine Shehab 1 ,
• Enas Samir Nabih 2 ,
• Ahmed Mohamed Osman 3 &
• Sally Raafat Ishak 1  

Italian Journal of Pediatrics volume  50 , Article number:  90 ( 2024 ) Cite this article

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Persistent airway inflammation is a central feature of bronchiectasis. Arachidonate 15-lipoxygenase (ALOX-15) controls production of endogenous lipid mediators, including lipoxins that regulate airway inflammation. Mutations at various positions in ALOX-15 gene can influence airway disease development. We investigated association between ALOX-15,c.-292 C > T gene polymorphism and bronchiectasis unrelated to cystic fibrosis in Egyptian children. Also, lipoxin A4 (LXA4) level in bronchoalveolar lavage (BAL) was studied in relation to polymorphism genotypes and disease phenotypes determined by clinical, pulmonary functions, and radiological severity parameters.

This was an exploratory study that included 60 participants. Thirty children with non-cystic fibrosis bronchiectasis (NCFB) were compared with 30 age and sex-matched controls. ALOX-15,c.-292 C > T polymorphism was genotyped using TaqMan-based Real-time PCR. LXA4 was measured in BAL using ELISA method.

There was no significant difference between patients and controls regarding ALOX-15,c.-292 C > T polymorphism genotypes and alleles (OR = 1.75; 95% CI (0.53–5.7), P  = 0.35) (OR = 1; 95% CI (0.48-2), p  = 1). BAL LXA4 level was significantly lower in patients, median (IQR) of 576.9 (147.6–1510) ng/ml compared to controls, median (IQR) of 1675 (536.8–2542) ( p  = 0.002). Patients with severe bronchiectasis had a significantly lower LXA4 level ( p  < 0.001). There were significant correlations with exacerbations frequency ( r =-0.54, p  = 0.002) and FEV1% predicted ( r  = 0.64, p  = 0.001). Heterozygous CT genotype carriers showed higher LXA4 levels compared to other genotypes( p  = 0.005).

Conclusions

Low airway LXA4 in children with NCFB is associated with severe disease phenotype and lung function deterioration. CT genotype of ALOX-15,c.-292 C > T polymorphism might be a protective genetic factor against bronchiectasis development and/or progression due to enhanced LXA4 production.

Bronchiectasis is a syndrome characterized by endobronchial suppuration, inflammation, and impaired mucus clearance with the end result of chronic microbial infection and progressive decline in lung function [ 1 ]. Clinically, it is defined by chronic or recurrent wet cough confirmed by evidence of bronchial dilation in high-resolution computed tomography (HRCT) [ 2 ]. While cystic fibrosis (CF) is a major etiology, bronchiectasis unrelated to CF is associated with various pathological conditions. Immunodeficiency disorders, severe infections, aspiration, primary ciliary dyskinesia, and airway anomalies represent the most common etiologies [ 1 ]. It is often classified as idiopathic if underlying cause is undetermined [ 3 ]. Burden of non-CF bronchiectasis (NCFB) is still unclear. A prevalence of 0.2–735 cases per 100,000 children is suggested [ 4 ]. Persistent airway inflammation is a central feature of bronchiectasis [ 5 ] in the presence or absence of bacterial infection [ 6 ]. Studies have characterized inflammatory exudate to include abundant neutrophilic infiltrate, elevated proinflammatory cytokines as interleukin (IL)-8, IL-6, IL-1β, tumor necrosis alpha (TNFα), and anti-microbial peptides as interferon gamma-induced protein − 10 (IP-10) and LL-37 [ 7 ]. Watt and colleagues [ 8 ] also found prolonged airway neutrophil survival in bronchiectasis. The elevated neutrophil count was strongly correlated with impaired lung function and bronchiectasis severity [ 9 ]. Dysregulated inflammatory response to repeated environmental insults has been proposed as host immunologic mechanism contributing to uncontrolled inflammation in pediatric NCFB. However, orchestrator for this is still unknown [ 10 ]. This highlighted the role of endogenous anti-inflammatory pathways in progression of NCFB. Failure of eicosanoid class switching with abnormal lipoxins production has been previously studied in the CF lung [ 11 ]. Lipoxin A4 (LXA4) belongs to a class of newly identified specialized pro-resolving lipid mediators (SPMs) playing a central role in resolution of inflammation as they inhibit neutrophils effector functions [ 12 ]. They are first eicosanoids to be expressed during process of class switching from prostaglandins and leukotrienes (LTB4), followed by resolvins and protectins [ 13 ]. LXA4 biosynthesis involves a multistep enzymatic process initiated by lipoxygenation of arachidonic acid by 15-lipoxygenase (ALOX-15) enzyme in macrophages and airway epithelial cells blocking LTB4 biosynthesis [ 14 ]. Thus, ALOX-15 pathway plays an important role in underlying pathogenesis of airway inflammation [ 15 ] Arachidonic acid 15-lipoxygenase (ALOX-15) gene, located on chromosome 17p13.3, controls transcriptional activity and hence, function of lipoxins [ 16 ] Eleven gene variations were detected. Functional polymorphisms in ALOX-15 gene could alter ALOX-15 enzyme activity and influence disease progression. A functional single nucleotide polymorphism (SNP) resulting from C-to-T substitution at position c.-292 was found to increase gene transcription [ 17 ]. To the best of our knowledge, no previous studies investigated ALOX-15 gene polymorphisms and their influence on lipoxin production in airway of children with NCFB.

Our objective was to investigate the association between ALOX-15,c.-292 C > T gene polymorphism and NCFB in Egyptian children. Also, lipoxin A4 level measured in bronchoalveolar lavage (BAL) was studied in relation to polymorphism genotypes and disease phenotype determined by clinical, pulmonary functions, and radiological severity parameters.

Study design

This pilot study recruited 30 children with NCFB collected from the regular patients of Pediatric Pulmonology clinic, Children’s Hospital, Ain Shams University, Cairo, Egypt from December 2020 to December 2021. Patients were enrolled if they have clinical symptoms consistent with bronchiectasis confirmed radiographically using pediatric criteria for bronchial dilation in high-resolution computed tomography (HRCT) scan and a negative sweat test [ 18 ], age between 1 and 16 years and in a clinically stable state. Exclusion criteria included presence of acute exacerbation at time of enrollement defined as increased respiratory symptoms, mainly cough, increased sputum quantity or purulence for ≥ 3 days, dyspnea or hypoxia irrespective of the duration [ 19 ], confirmed cystic fibrosis (CF) diagnosis, underlying chronic inflammatory conditions, known or suspected chromosomal abnormality, on antibiotics or anti-inflammatory drugs including inhaled and systemic steroids four weeks before the study or immunosuppressive therapy. They were compared with 30 age and sex-matched previously healthy children referred for bronchoscopy in view of suspected foreign body aspiration. Only those with normal airway anatomy, and normal microbiology BAL results were included.

Ethical considerations

Informed consent.

was obtained from participants or their legal guardians before enrollment. This study was performed in line with principles of the Declaration of Helsinki 1975. Approval was granted by Research Ethics Committee of human experimentation, Faculty of Medicine, Ain shams university (FMASU MD 270/2020).

Data collection

All patients were subjected to detailed history taking, laying stress on demographics, disease duration, symptoms suggestive of exacerbation, and frequency of hospitalization due to exacerbations in last 12 months. Vital data and anthropometric parameters, including weight, height, and body mass index (BMI), were recorded and plotted on centiles. Pulse oximetry was used to monitor oxygen saturation.

Routine inflammatory markers as complete blood count (CBC) and C-reactive protein (CRP) were performed at enrollment. Patients and controls with abnormal results were not included.

Non-CF bronchiectasis severity assessment tools

Pulmonary function tests.

Forced spirometry was performed for enrolled subjects using JAEGER apparatus, care fusion, Germany, 2011. Standard methodology for acceptability and repeatability of spirometry was followed according to combined American thoracic society / European respiratory society guidelines [ 19 ]. The following parameters were obtained: forced vital capacity (FVC), forced expiratory volume in first second (FEV1), ratio between FEV1 and FVC (FEV1/FVC), and maximal mid-expiratory flow rate during 25–75% of expiration (MMEF25-75) and results were expressed as percentage (%) of predicted values based on age, sex, ethnicity, weight, and height. Spirometry was interpreted as normal if FEV1 and FVC % predicted were ≥ 80% and FEV1/FVC ratio > 80. Severity of obstructive ventilatory defect was graded based on FEV1% predicted values as follows: mild if > 70%, moderate if < 70 to 50%, severe if < 50 to 30% predicted [ 20 ].

2. Radiological evaluation using Modified Bhalla score and quantitative lung analysis.

High-resolution computed tomography (HRCT) scan was performed for all enrolled patients using a 64-slice CT machine (Optima CT, GE “general electric”, USA). No specific preparations were required. Only in non-cooperative children, general anesthesia was needed to obtain scanning during suspended inspiration. In older children, scanning was taken during full inspiration. Patients were scanned in supine position with arms above the head. Image acquisition was at 1.25 mm thickness, 0.625 mm intervals using 512 × 512 matrix, tube speed 35 mm/rotation with 0.5s rotation time. The KVp and mAs were used as low as possible to limit radiation dose. Image analysis was done by an experienced radiologist blinded to patient’s condition. The following items were recorded: distribution and severity of bronchiectasis, peribronchial thickening, and severity, presence of mucus plugging, sacculations, bullae/emphysema, and consolidation/collapse. Modified Bhalla score [ 21 ] was calculated to assess radiological disease severity. Total score range from 0 to 37.

Post-processing, using Fuji 3D synapse automated software, a quantitative analysis based on CT image (CT volumetry) was performed, where volume of the diseased areas was calculated as a percentage of the total lung volume. This was referred to as percentage of lung volume affected by bronchiectasis [ 22 ].

Pediatric bronchiectasis severity index.

A pediatric-specific score was adapted as an assessment tool of disease severity in studied subjects. It uses a combination of clinical (age, nutritional status, exacerbations, hospital admissions over a year period, and patient compliance), radiological and microbiological features. Depending on calculated score, disease was graded as mild if 0–4, moderate if 5–8, and severe if ≥ 9 [ 23 ]. Chronic airway colonization was determined if a pathogenic microorganism was identified in cultures from BAL and/or induced sputum samples on at least 2 occasions, 3 months apart in the previous 12 months [ 24 ].

Modified medical research council (mMRC) dyspnea scale.

Degree of perceived breathlessness and respiratory dysfunction in daily living activities of enrolled patients was evaluated using mMRC scale. It is a self-reported five-statement questionnaire, ranging from grade 0 (dyspnea only on strenuous exercise) to grade 4 (dyspnea on dressing/undressing) [ 25 ].

Laboratory work-up

Measurement of Lipoxin A4 level in bronchoalveolar lavage fluid (BALF).

All enrolled patients and controls underwent bronchoscopy with bronchoalveolar lavage (BALF) collection according to European respiratory society guidelines [ 26 ]. Bronchoscopy was done under general anesthesia through a laryngeal mask. Standardized protocol for BALF collection under aseptic conditions was followed by wedging in right middle lobe bronchus and lingula, then sterile normal saline (1-2 ml/kg) was instilled and suctioned immediately. Collected samples were transported in sterile containers to laboratory where total and differential cytology was immediately determined, microbiological cultures were performed and a sample was stored at -20◦C for further use. BAL samples were centrifuged for 20 min at 1000xg. The supernatants were collected for measurement of lipoxin A4 concentration using a human lipoxin A4 ELISA kit (E0612Hu, Bioassay Technology Laboratory, China). LXA4 in samples and standards competed with that is coated to wells for the Biotinylated Detection antibody specific to LXA4. After a washing step, an Avidin-Horseradish peroxidase (HRP) conjugate was added and incubated followed by addition of a TMB substrate solution. The reaction was terminated after 10 min by the stop solution. The optical density was measured at 450 nm and concentration of LXA4 was calculated using a standard curve with an intra- & inter-assay CV of 5.6 & 7.7 respectively, a range of 5-2000 ng/ml and sensitivity of 2.47ng/l.

Genotyping of ALOX-15,c.-292 C > T (rs2072510) single nucleotide polymorphism (SNP) using TaqMan-based Real-time PCR.

Venous blood samples were collected from all participants under aseptic conditions in EDTA-containing tubes and stored at -20◦C. DNA was extracted from plasma samples using QIAamp DNA blood kits, catalog no: 51,104 (Qiagen, Hilden, Germany). DNA concentration of 50 ug/ml was determined and DNA purity was detected by determination of A 260 /A 280 ratio. All patients and controls were genotyped for ALOX-15,c.-292 C > T SNP using Applied Biosystems TaqMan SNP genotyping assays ”ALOX-15 C/T rs2072510, catalog no:4,351,379 (ThermoFisher Scientific, Germany) and PCR TaqMan Genotyping Master Mix kit, cat no:4,371,353 (ThermoFisher, Germany). The thermal cycling protocol was optimized as follows: 95◦C for 10 min for AmpliTaq Gold, UP enzyme activation, followed by denaturation step at 95◦C for 15 s and annealing/extension at 60◦C for 1 min for 40 cycles. The qPCR was performed on Applied Biosystems PCR instrument (ThermoFisher Scientific, Germany).

Statistical analysis

There were no previous data to inform a power calculation, so sample size in this pilot study is opportunistic based on availability of samples. 60 participants is a conservative estimate to detect a statistically significant result. Statistical package for social science, version 23.0 (SPSS Inc., Chicago, Illinois, USA) was used for data management and statistical analysis. Quantitative variables were presented as mean, standard deviation (SD), and ranges when parametric, median, and interquartile range (IQR) when non-parametric. Categorical variables were presented as numbers (n) and percentages (%). Chi-square test was used for comparison between 2 groups regarding qualitative data. For comparison between 2 groups with quantitative variables, independent t-test (parametric) and Mann-Whitney test (non-parametric) were used. Kruskall-Wallis test was used for comparison between more than 2 quantitative variables (non-parametric). Alleles frequency was calculated using gene counting method, Chi-square was used to test the difference between groups as regards genotypes and alleles and to prove Hardy-Weinberg equilibrium. Association of Genetic polymorphism with bronchiectasis was assessed by exact logistic regression model, odds ratio (OR), and 95% confidence interval (CI) were calculated. Spearman correlation coefficients were used for correlation analysis. Confidence interval was set at 95%, margin of error accepted was set at 5%. P-value was considered significant if < 0.05.

This study included 30 pediatric patients with non-CF bronchiectasis of post-infectious or idiopathic etiology, they were 18 females (60%) and 12 males (40%), and their ages ranged from 3 to 15 years old with mean (SD) of 8.87 (3.6) years. They were well-matched with controls regarding age and sex.

BAL Lipoxin A4 levels and distribution of ALOX-15,c.-292 C > T gene polymorphism genotypes and alleles among patients and controls are shown in Table  1 .

Patients with NCFB showed a significantly lower level of LXA4, median (IQR) of 576.9 (147.6–1510) ng/ml, when compared to controls ( p  = 0.002) (Figure S1 ). However, this difference was insignificant among CT genotype carriers, median (IQR) 1519 (918.1–2073) ( p  = 0.35) (Figure S2 ). Lipoxin A4 level was significantly higher among CT genotype compared with CC , median (IQR) 546.5 (155.75–971) and TT genotypes, median (IQR) 140.6 (132.7–256) ( p  = 0.005) (Table  2 ).

Clinical and disease severity characteristics of studied patients are illustrated in Table  3 . Bronchiectasis was moderate in 60%, mild in 23%, and sever in 16.7% of patients. 4 patients (14.8%) had normal spirometry results. Obstructive ventilatory defect was graded as mild in 25.9%, moderate in 40.7%, and severe in 18.5% of patients. Neutrophils were predominant cell type in BAL (76.7%). Chronic airway colonization was present in 70% of patients with haemophilus influenzae being most commonly isolated organism.

Table  4 shows that LXA4 was significantly lower in patients with severe disease with median (IQR) of 132.7 (89-138.9) compared to those with mild and moderate disease ( p  < 0.001). Patients with chronic airway infection had lower levels of LXA4, however, this was statistically non-significant. Patients with normal lung functions showed a significantly higher level of LXA4 ( p  = 0.04).

There was significant correlation with FEV1% predicted ( r  = 0.64, p  = 0.001) (Figure S3 ) and frequency of hospitalization due to exacerbations over past 12 months ( r =-0.54, p  = 0.002) (Fig.  1 ).

Correlation between BAL lipoxin A4 and frequency of admissions due to exacerbations over past year ( r = -0.54, p =0.002) r: Spearman correlation coefficient

Comparison between ALOX-15,c.-292 C > T polymorphysim genotypes showed no significant difference as regards disease severity index ( p  = 0.14), abnormal pulmonary function results ( p  = 0.95), radiological severity score, chronic airway infection ( p  = 0.74) and nutritional status ( p  = 0.13) among studied subjects (Table  2 ).

Logistic regression analysis detected no significant association between ALOX-15,c.-292 C > T genetic polymorphism and non-CF bronchiectasis in studied subjects (Table  5 ).

In this study, we attempted to scrutinize the role of ALOX-15 gene polymorphism and LXA4 in pediatric NCFB, an area hitherto not extensively explored. NCFB is multifactorial, predisposed by genetic factors with a poorly understood pathogenesis [ 3 ]. Considerable efforts were made to understand underlying exaggerated and/or dysregulated inflammation in response to challenges from respiratory pathogens. Data from CF or chronic obstructive pulmonary diseases (COPD) were extrapolated, although they are distinctly different entities [ 11 ]. Though previously studied in relation to asthma [ 27 ], COPD [ 28 ], CF [ 29 ], and other systemic diseases [ 30 ], role of LXA4 in NCFB in children has not yet been elucidated. This research presented an insight into the intricate relationship between ALOX-15 gene, LXA4, and pediatric NCFB. It pointed out that low LXA4 level in the airway of children with NCFB was associated with clinical disease severity in the form of reduced lung functions and increased exacerbations frequency. ALOX-15,c.-292 C > T SNP was functional and increased LXA4 level among heterozygous CT carriers. However, its association with NCFB occurrence and its severity was not detected. In our study, BAL lipoxin A4 level was significantly lower in children with NCFB compared to controls ( p  = 0.002). Also, it was significantly lower in patients with severe disease according to pediatric bronchiectasis severity score ( p  = 0) and pulmonary function parameters ( p  = 0.04). There was no significant difference between those with and without chronic airway infection ( p  = 0.81). This was in agreement with Bedi et al. [ 31 ] who studied LXA4 in adult subjects with bronchiectasis. Celik et al. [ 27 ] and Balode et al. [ 28 ] reported same findings regarding LXA4 in relation to asthma and COPD, respectively. Ringholz et al. [ 12 ] and Urbach et al. [ 29 ] studied airway LXA4 in children with CF and it was significantly reduced compared to controls, even in the absence of infection. The documented correlation of low LXA4 levels with disease severity underscores the potential significance of resolving lipid mediators in modulating inflammation and disease progression. LXA4 contributes to active resolution of inflammation by inhibiting LTB4-induced neutrophils recruitment, antagonizing the effect of pro-inflammatory mediators as IL-8, myeloperoxidase, and reactive oxygen species limiting tissue injury. Also, it promotes neutrophil apoptosis in the inflammatory site through enhancement of phagocytosis by macrophages [ 32 ]. Karp et al. [ 33 ] reported that mice treated with LXA4 and challenged with pseudomonas aeruginosa contained the infection effectively. The use of lipoxin gained attention recently in many diseases associated with an excessive inflammatory response as its deficiency has been associated with a wide range of pathologies. Impaired resolution of inflammation may be enhanced by genetic polymorphisms affecting SPM biosynthesis [ 34 ].

The influence of ALOX-15,c.-292 C > T gene polymorphism on NCFB in children was studied. There was no significant difference between patients and controls as regards distribution of ALOX-15,c.-292 C > T genotypes. T allele frequency was equal among patients and controls [OR = 1, 95% CI (0.48-2), p  = 1]. No significant association was detected between ALOX-15,c.-292 C > T polymorphism variants, and occurrence of NCFB which might pose questions about the genetic determinant’s role in disease pathogenesis. Few studies evaluated the effect of ALOX-15 gene polymorphism on LXA4 levels [ 35 ]. Also, its anti-inflammatory role was studied in animals [ 36 ]. Serhan et al. [ 37 ] showed that overexpression of arachidonate 15-LO in transgenic rabbits led to enhanced endogenous anti-inflammation. LXA4 level was significantly higher among heterozygous CT carriers compared to homozygous CC carriers ( p  = 0.005). Wittwer et al. [ 38 ] reported that polymorphism in ALOX-15 gene promotor region that involves C-to -T substitution at position c.-292 leads to higher ALOX-15 enzyme transcription in macrophages from heterozygous CT carriers compared to homozygous CC carriers by creating a new binding site for transcription factor SPI1 resulting in a significant increase in arachidonic acid pathway metabolites. Thus, possible enhancement of endogenous anti-inflammation due to increase in pro-resolving mediators, mainly lipoxins, can be postulated. In conclusion, offering promising insights into the interplay between genetics, lipid mediators, and pediatric NCFB, this pilot study presents a foundation for further extensive investigations to decipher the intricate mechanisms underlying bronchiectasis development and progression. Also, our findings provide a window for ALOX-15 pathway as a potential area of research regarding failure of resolution of inflammation in pediatric NCFB. small sample size, single-center approach, and studying a single molecule from arachidonic acid pathway are the limitations of the present study. Other pro-inflammatory molecules as leukotrienes are also controlled by ALOX-15 enzyme. The multifactorial nature of bronchiectasis requires more comprehensive investigation encompassing broader genetic variations and gene-environment interactions [ 39 ]. Further research in this domain should consider expanding sample size, incorporating multi-omics approaches and exploring gene-enviroment interactions to unravel the complexity of NCFB pathophysiology comprehensively.

Low airway LXA4 in children with NCFB is associated with severe disease phenotype and lung function deterioration. CT genotype of ALOX-15,c.-292 C > T polymorphism might be a protective genetic factor against bronchiectasis development and/or progression due to enhanced LXA4 production.

Abbreviations

High resolution computed tomography

Cystic fibrosis

Noncystic fibrosis bronchiectasis

Tumor necrosis factor-alpha

interferon gamma-induced protein − 10

Arachidonic acid 15 lipoxygenase

Single nucleotide polymorphism

Bronchoalveolar lavage fluid

Body mass index

complete blood count

C reactive protein

Forced vital capacity

Forced espiratory volume in first second

Maximal mid expiratory flow rate during 25–75% of expiration

modified medical research council

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The authors are indebted to the patients and their guardians who agreed to participate in the study.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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E.F., M.H., and S.I. contributed to the study conception, design, and supervision. Material preparation, data collection, and analysis were performed by Y.S, M.H., and S.I. Bronchoscopy and BAL were performed by M.H., and S.I. Genotyping and Laboratory work was performed by E.N. Radiology images analysis was done by A.O. Resources by Y.S. The first draft of the manuscript was written by M.H. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Hussein, M.M., Fouda, E.M., Shehab, Y. et al. Association between arachidonate lipoxygenase 15,c.-292 C > T gene polymorphism and non-cystic fibrosis bronchiectasis in children: a pilot study on the effects on airway lipoxin A4 and disease phenotype. Ital J Pediatr 50 , 90 (2024). https://doi.org/10.1186/s13052-024-01654-5

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Received : 20 September 2023

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