Introduction

Bronchiolitis is the most common acute lower respiratory tract infection of viral origin among infants [1]. It is characterized by cough, rhinorrhea, crackles, wheezes, fever, and hypoxemia [2–4]. Common etiology includes respiratory syncytial virus, rhinovirus, adenovirus, coronavirus, human metapneumovirus, influenza, or parainfluenza [5, 6]. The economic and social implications of bronchiolitis are substantial. In North America, hospitalizations attributable to bronchiolitis have increased twofold over the past two decades [7, 8]. The disease currently accounts for more than 100 thousand hospital admissions annually at an estimated cost of $1.73 billion [9]. In the United Kingdom, 1 in 3 infants will develop bronchiolitis in the first year of life and 2 to 3% of all infants require hospital admissions. In England alone, there were 30,451 secondary care admissions for bronchiolitis between 2011 and 2012 [10].

Despite decades of research, effective pharmacotherapy for bronchiolitis is still lacking. The current treatment is controversial and there are no definitive recommendations for the use of any drug in the routine management of bronchiolitis [6]. Common pharmacological agents such as bronchodilator, corticosteroid, and hypertonic saline have been shown to only provide symptomatic relief [11]. Maintaining hydration and oxygenation of patient remains the cornerstone of management [12]. In the absence of efficacious curative therapy, the use of complementary and alternative medicine (CAM) in bronchiolitis is gaining popularity [13].

Over the past few years, several studies have examined the effects of different CAMs for bronchiolitis, but making sense of this literature requires a comprehensive and systematic synthesis of the available evidence. The aim of the current study was to comprehensively appraise the effectiveness and safety of CAMs for the treatment of bronchiolitis in infants.

Methods

This study was conducted and reported following the process as specified in the PRISMA statement [14].

Results

Study characteristics

Our initial search yielded 1,220 studies, of which 31 underwent full-text evaluation and 11 unique studies were included in this review (Fig 1). They comprised 8 randomized controlled trials [17–21, 28–30] and 3 cohort studies [31–33] conducted in Asia, enrolling a total of 904 inpatient infants presenting with bronchiolitis. Sample size of the studies varied between 24 and 133 participants, with age ranging from 1 to 24 months. The studies were published between 1997 and 2015 in English (n = 9) [17–21, 28–30, 32] and Chinese (n = 2) [31, 33] language. Four studies were multicenter [17, 18, 28, 30] and seven were single-center [19–21, 29, 31–33]. Study duration ranged from one day to one week. In all studies, bronchiolitis was diagnosed by a physician based on symptoms of acute wheezing or respiratory distress. In seven studies, the infants were diagnosed as first time wheezers [17–19, 21, 28–30]. Another one study recruited a combination of wheezing and non-wheezing patients [20]. No specific information was provided in three studies [31–33] (Table 1). Three studies were funded by university or government agencies [18, 28, 30], whilst the other eight studies had no sponsorship [17, 19–21, 29, 31–33]. The main characteristics and results of included studies were summarized in Tables 2 and 3.

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Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram outlining study screening, identification, inclusion and exclusion.

https://doi.org/10.1371/journal.pone.0172289.g001

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Table 1. Definition of bronchiolitis used in the studies identified.

https://doi.org/10.1371/journal.pone.0172289.t001

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Table 2. Characteristics and summary of results of herbal medicine studies.

https://doi.org/10.1371/journal.pone.0172289.t002

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Table 3. Characteristics and summary of results of supplement studies.

https://doi.org/10.1371/journal.pone.0172289.t003

Study quality assessment

Randomized controlled trials.

The methodological quality of the 8 randomized controlled trials (RCTs) was generally moderate. Three trials had all domains judged as low risk of bias [20, 28, 30]. Most trials had an appropriate method of randomization as well as allocation concealment. Seven studies mentioned double blinding, of which only three described details of blinding of patients, personnel, and outcome assessors [20, 28, 30]. All studies were judged to have sufficient reporting of outcomes and have low risk of bias of selective outcome reporting. However, all studies had an unclear risk of other source of bias (Fig 2).

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Fig 2. Assessment of risk of bias according to a recommended tool for randomized controlled trials by the Cochrane Handbook for Systematic Reviews of Interventions.

(a) Risk of bias summary showing review authors’ judgments about each risk of bias domain for 8 randomized controlled trials. (b) Risk of bias graph showing each risk of bias domain presented as percentages across the studies.

https://doi.org/10.1371/journal.pone.0172289.g002

Cohort studies.

The observational study by Feng and colleagues lacked methodological details for quality assessment [32]. The other two studies generally had a good quality of cohort selection and comparability, but, independent blind outcome assessment and adequacy of follow up were not described [31, 33].

Discussion

To our best knowledge, this is the first systematic review that examined the effectiveness and safety of complementary and alternative medicine (CAM) for the treatment of bronchiolitis. Our review found that two studies reported significant benefit associated with the use of CAM in the primary outcome of length of hospital stay. The first study (n = 66) was a cohort study conducted by Wang et al. and reported that Chinese herbal medicine (Shuang Huang Lian) reduced duration of hospitalization by 1.8 days compared to ribavirin [31]. The second study (n = 89) was a randomized controlled trial undertaken by Saad et al. and demonstrated that vitamin D decreased length of stay by 2.5 days compared to placebo [29]. On the contrary, N-acetylcysteine, zinc, and magnesium had no benefit on the length of hospital stay [17, 19, 21, 28]. Studies of Chinese herbal medicine, vitamin D, N-acetylcysteine, and magnesium showed some benefits with respect to clinical severity scores [17, 21, 28] [30], oxygen saturation [30, 33], and symptom resolution [29–31, 33]. Nonetheless, findings from the primary studies should be interpreted cautiously, given the heterogeneity across trials in the CAM treatment studied, outcome reporting, and other differences in trial design and conduct, as well as insufficient, and in some cases lack of rigorous, evidence for the different interventions (e.g., most of the studies of herbal medicine were cohort studies and there was only single study for many of the CAM interventions, of which most had a small sample size).

The current American Academy of Pediatrics (AAP) guidelines recommend that apart from length of hospital stay, parent satisfaction and patient-centered outcomes should be integrated in evaluating the effectiveness of pharmacotherapy for bronchiolitis [6]. No study identified in this review reported a patient-centered outcome. Instead, a number of studies, especially those which examined herbal decoctions used “cure rate” or a global assessment as an outcome. It was uncertain how these criteria were established, but the definitions were not uniform across studies. Furthermore, there is currently no universally validated bronchiolitis scoring system in clinical practice. In our review, Kose et al. [21] used the clinical severity score (CSS) tool developed by Wang et al. [34], whereas Modaresi et al. [28] used respiratory distress assessment instrument (RDAI) as a measure [35]. Albeit these two studies analogously examined magnesium, the use of different clinical severity scoring tools for predicting the course of illness may affect the treatment outcomes due to the dissimilar parameters being assessed.

Variability in measuring and reporting outcomes across studies of bronchiolitis precludes a formal meta-analysis. Our findings provide further evidence of inconsistency and problems with outcome reporting that can be a source of bias in this literature. There is a need to assess outcomes across the CAM studies. However, systematic assessment of treatment efficacy is often complicated by the wide range of outcome measures used by investigators. Therefore, it is necessary to agree on a core outcome set to be measured and reported in future studies assessing the impact of CAM on bronchiolitis. The Agency for Healthcare Research and Quality (AHRQ) recommends future studies to ascertain clinically relevant outcomes, particularly rates of hospitalization, need for more intensive services in the hospital, costs of care, parental satisfaction with treatment, and development of longer-term respiratory problems to facilitate clarity in communication about outcomes and increase the value of existing and future data [36]. Also of potential concern, the findings in this review may be subject to publication bias which is often difficult to detect in systematic reviews with few studies. Due to the heterogeneity in the outcomes assessed, the method of reporting, and the various types of CAM used, assessment of publication bias was not performed. Hence, we were unable to rule out the presence of publication bias in this body of literature.

There was a scarcity of information concerning the quality as well as the complete constituents of the herbal preparations used. A key reason could be the difficulty in standardization of herbal preparations. The manifold constituent nature, age of plants, harvest season, source location, and technique of crude preparation may affect the chemical composition and potency of herb derivatives [37]. Although some manufacturers have commenced to standardize herbal products, there is still a general lack of consistency in the market. On the other hand, research on supplements has been encumbered by the absence of reliable assays to detect micronutrient deficiencies. For instance, the emergence of vitamin D assays from the preliminary competitive protein binding assays through to immunoassay and liquid chromatography-tandem mass spectrometry assay have shown numerous analytical challenges. Immunoassay is the most popular method in consideration of ease of use, cost, and rapidity, however, the accuracy and specificity remain an issue of discussion [38]. The non-existence of reliable assays added challenges in elucidating nutrient-related conditions, theories, pharmacodynamics, and pharmacokinetics of mineral supplements in bronchiolitis.

Another issue was the lack of adverse events reporting. Less than half of the included studies reported adverse events, of which, two reported no adverse events [17, 21]. The adverse events documented were gastrointestinal problems associated with the use of Laggera pterodonta mixture, vitamin D, and zinc. This scarcity of reporting can be considered as reporting bias and as such could have underestimated the magnitude of a problem. There is empirical evidence indicating that adverse events are inadequately reported in CAM trials [39]. It is necessary to improve such reporting of harms to enable accurate, objective, and comprehensive safety data to be given to users even when there have been no observed adverse events.

Potential and theoretical adverse effects may stem from biologically active constituents from herbs, side effects of contaminants, cross-allergenicity, and CAM-drug interactions. For example, three herbal preparations [32, 33] located in this review contained Ephedra herba, which had the active ingredient ephedrine. Some of the common side effects of ephedrine included nausea, vomiting, psychiatric or autonomic symptoms, and palpitations [40], but none of these was reported in the included studies. Therefore, further studies on safety of these preparations are warranted, especially pertaining to CAM-drug interactions as well as risk-benefit assessments.

Thus far, we did not find other evidence from systematic reviews or meta-analyses of CAM for bronchiolitis. A Cochrane review has examined the therapeutic effect of traditional Chinese herbal medicines commonly used in China for acute bronchitis [41]. Nevertheless, our findings are consistent with the Cochrane review in the aspects of sparsity of available evidence and the need for future well-designed RCTs with adequate power in order to formulate a clinical conclusion on the use of any CAM.

Conclusions

This review identified 11 studies evaluating the effectiveness and safety of a variety of CAM interventions among inpatients with bronchiolitis. Five studies did not examine our primary outcome of hospital length of stay. Four of the remaining six studies did not find a significant benefit associated with the primary outcome. Preliminary evidence indicated that Chinese herbal medicine mixtures, vitamin D, N-acetylcysteine, and magnesium might be potentially useful in managing the symptoms of bronchiolitis. However, the evidence was not sufficient or rigorous enough to formulate recommendations for the use of any CAM. Among studies that reported adverse events, no serious harms were noted. There is a need to conduct more high quality studies to better understand the effectiveness as well as safety of CAM for bronchiolitis in infants.

Supporting information

Acknowledgments

We would like to thank Professor Dr. Fook Choe Cheah of the National University of Malaysia for his invaluable input on the draft of this manuscript. We declare no financial or other potential conflict of interest in connection with this article.