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2.6.1 Summary of findings

My systematic review of the literature identified one RCT, one non-RCT, three cohort studies, and CBA studies on the prevention of RTIs in individuals with DS.

Four assessed passive immunotherapies (three palivizumab, one pidotimod), two looked at prophylactic treatment with oral zinc supplements, and one at the effectiveness of a school-based infection-control programme. Due to a critical risk of bias, four studies were not included as part of the main results (zinc therapy, infection-control programme, and two palivizumab studies).

Pidotimod, an immunostimulant, and palivizumab, a human monoclonal antibody, showed some benefit in individuals with DS, on URTI episodes and RTI hospitalisations respectively, when used prophylactically for three and nine months. They therefore may have a role in preventing RTIs in individuals with DS.

Although the included RCT assessing zinc over six months showed no effect on URTI episodes, the excluded CBA study assessing the effects of zinc over four months showed a significant reduction in episodes. In view of the critical risk of bias in the latter, these results should be interpreted with caution.

2.6.2 Strengths and Weaknesses

I chose a very broad search strategy including DS-related co-morbidities such as CHD, to ensure a thorough and comprehensive search of all potential management options for RTIs in people with DS to inform clinical practice and future research. Whilst this search identified numerous studies (n=17,731 incorporating the 2017 update), the majority did not report on any interventions to prevent or treat RTIs.

Limitations of the review are likely to stem from restricting to studies published in English and publication bias. The latter is owing to anecdotal evidence that most studies on individuals with DS involve small samples, which may limit publication potential. Whilst one may argue that a rigorous approach to assessment of the risk of bias is unnecessary in the light of limited evidence in the field, it was important to clarify both the quality and quantity of evidence to assist in informing current clinical practice and future directions for research.

2.6.3 Comparison with previous research

In contrast to adults and children with DS, there is an abundance of high quality research into medical and surgical interventions for (recurrent) RTIs in the general population. With this high-level evidence, CPGs such as the NICE CPG [CG69] on prescribing antibiotics in RTIs in the general population have been developed (33). Similarly, numerous studies have highlighted the effectiveness of preventative measures for RTIs such as vaccination in the general population (33). However, how these recommendations can be translated to people with DS is unclear since their functional anatomy and immunity profile may both predispose them to RTIs differently and may make them respond differently to treatments.

2.6.4 Implications for practice

I found no randomised controlled trials, controlled before-after studies and cohort studies on therapeutic interventions for RTIs in children with DS, suggesting that there is no high-quality evidence to guide clinicians in managing children with DS.

From the prophylactic treatments identified, I found some evidence for the use of palivizumab in preventing RSV-RTIs. Due to the absence of a true internal comparator in one study (e.g. comparing treated vs. untreated populations between Netherlands and Canada with differing healthcare practices and seasonal patterns), the causal inferences of palivizumab on children with DS are limited.

Furthermore, whilst palivizumab was effective in reducing RSV related RTI hospitalisations, overall RTI-related hospitalisations were unaffected, except in one study that had a critical risk of bias where a reduction was observed. Currently, American Academy of Pediatrics guidance recommends palivizumab as prophylaxis in children with DS only when there are concurrent comorbidities (e.g. CHD, CLD, prematurity) (96). Pidotimod shows encouraging results in preventing RTIs, however as with most immunostimulants it is currently only licensed for research purposes in several European countries and the USA, due to a lack of high quality evidence as to its efficacy and its side effect profile (97).

Finally, with a high quality RCT showing no significant effect of prophylactic zinc therapy in preventing RTIs, it is not recommended for clinical practice (92).

2.6.5 Implications for research

With no high quality, therapeutic intervention studies identified from this systematic review, clinicians are faced with little evidence to guide them in the treatment of RTIs in children with DS. A particularly relevant decision is that of prescribing antibiotics for RTIs where concerns about antimicrobial resistance exist. It is disappointing that, in the two years since the original review took place, no additional studies were identified that met the quality criteria for inclusion.

Whilst randomised controlled trials remain the gold standard in providing robust clinical and cost-effectiveness estimates, due to the fluctuating nature of RTIs, substantial numbers of children with DS would need to be recruited. Cohort studies utilising population wide electronic health records may therefore be a viable alternative.

This exemplifies the need for the subsequent phases of my thesis that focus on establishing RTI healthcare utilisation in primary and secondary care and the effectiveness of antibiotics in preventing hospitalisations in children with DS compared to children without DS using routinely collected EHRs.