Respiratory Syncytial Virus Infection in Children: The Roles of Complementary and Alternative Medicine and Immune Globulin Prophylaxis

Introduction
Respiratory syncytial virus (RSV) is the most prevalent pathogen of paediatric respiratory tract illness. It is the leading cause of bronchiolitis, which accounts for considerable health burden for infants and young children worldwide. Notwithstanding, it has been challenging to determine the best possible management for an infant presenting with this illness owing to a lack of effective pharmacotherapy. In recent years, the scientific literature concerning the efficacy of complementary and alternative medicine (CAM) in the treatment of bronchiolitis is increasing. The survey by the National Center for Complementary and Integrative Health (NCCIH) has shown 1 in 10 children use some form of CAM. However, there have been no comprehensive reviews delineating CAM used in bronchiolitis. In terms of preventive therapy, palivizumab (Synagis®), an anti-RSV F protein-specific humanised monoclonal antibody, is approved by the Food and Drug Administration for prophylaxis among high risk infants. The high cost of palivizumab has restricted the majority of infant population from receiving the vaccination, particularly in resource-limited countries.
Objectives
The primary aim of this research was to review the complementary and alternative medicine for bronchiolitis and to evaluate the impact of a controlled palivizumab prophylaxis program among high risk premature infants in Malaysia.
Methods
This research consisted of two parts. Part 1 was a systematic review of published clinical literature about CAM for the treatment of bronchiolitis. In Part 2, a prospective surveillance follow-up was conducted to monitor the incidence of RSV-associated respiratory tract infections within the first two years of life in premature infants after hospital discharge and compare the incidence and burden of RSV positive respiratory tract infections between premature infants who were administered and those not administered palivizumab immunoprophylaxis. Preterm infants born at or before 35 weeks’ gestation were monitored monthly for symptoms of respiratory illness based on a standardised questionnaire upon discharge from NICU, UKM Medical Centre, from June 1, 2014 to September 30, 2016. A controlled palivizumab program limited the vaccination to infants born ≤28 weeks’ gestation or birth weight ≤1kg or diagnosed to have chronic lung disease (oxygen dependency at 36 weeks’ postmenstrual age). Nasopharyngeal swabs were taken from infants presenting with acute respiratory illness for RSV analysis using polymerase chain reaction.
Significance of this study
This study has provided a critical appraisal and provocative review on the use of CAM for the treatment of bronchiolitis. The best available evidence highlighted in the review aids healthcare providers in their judgments, guidance and counselling to patients and caregivers who have been using or considering herbs and supplements either as alternative or adjunct therapies for RSV disease, in addition to provide recommendations for future research. The evidence gleaned from the palivizumab surveillance study will facilitate the estimation of RSV disease burden in Malaysia and assist government health officials in making decision about the introduction of palivizumab vaccination to the national immunisation program.
Results
The systematic review identified 11 clinical studies (8 randomised controlled trials and 3 cohort studies) examining four herbal preparations and four supplements used either as adjunctive or alternative therapy for bronchiolitis in 904 infants. Most studies were of moderate quality. Among six studies reporting on length of stay, a significant benefit was found for Chinese herbal medicine compared to ribavirin in one cohort study (n=66) and vitamin D compared to placebo in one randomised controlled trial (n=89). Studies of Chinese herbal medicine, vitamin D, N-acetylcysteine and magnesium showed some benefits with respect to clinical severity scores, oxygen saturation and other symptoms, although data were sparse for any single intervention and the outcomes assessed and reported varied across studies. Only five studies reported on adverse events; no serious adverse events were reported. The available evidence was not strong enough to formulate recommendations for the use of any CAM, although all appeared to be generally safe.
In the palivizumab surveillance study, a total of 196 premature infants were recruited. Palivizumab group (n=55) had mean birth weight of 1.13 kg and gestational age of 28.71 weeks, versus 1.86 kg and 32.67 weeks in the non-prophylaxis group (n=141) (p<0.001). At 1, 3 and 6 months, it was found that infants who received palivizumab showed a significantly lower incidence of respiratory-related clinic visit than those without prophylaxis (p<0.05). Data at 9, 12, 15 and 18 months of follow-up demonstrated that the first respiratory event occurred significantly earlier in no prophylaxis group as compared to palivizumab group (p<0.05). By 18 months, 21 and 24 months of follow-up, the burden of respiratory illness on health care resources was similar between palivizumab and control groups. The proportion of infants in each group who acquired RSV infection was significantly different at 6, 15 and 18 months of follow-up, with higher incidence being reported among the untreated participants (p<0.05).
Conclusions
The review of the scientific literature found very little evidence for a treatment effect of CAM in childhood bronchiolitis. Given the burden of the disease, further large, randomised controlled trials of CAM are needed. In the context of preventive therapy, palivizumab immunoprophylaxis minimised the rate of severe and RSV-positive respiratory illnesses in the high risk extremely preterm infant group. A controlled program targeting the most at risk premature infants could feasibly be introduced in a budget-constrained environment of a developing country with tropical climate.