The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year … – Nature.com

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 swabs18. 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 therapy15.

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.cepaciawas 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 frame19. 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 CF20. We have demonstrated that over the past 18years, 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 2years 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 group21. 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 significantincrease 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<2years 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 safety21.

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 tobramycin22. 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 examined23. 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 18years. 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 18years. 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 2years of age over time.

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