Research Article: Systematic Review of the Toxicity of Long-Course Oral Corticosteroids in Children

Date Published: January 26, 2017

Publisher: Public Library of Science

Author(s): Fahad Aljebab, Imti Choonara, Sharon Conroy, Robert S. Phillips.

http://doi.org/10.1371/journal.pone.0170259

Abstract

Long courses of oral corticosteroids are commonly used in children in the management of chronic conditions. Various adverse drug reactions (ADRs) are known to occur with their use. This systematic review aimed to identify the most common and serious ADRs and to determine their relative risk levels.

A literature search of Embase, Medline, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed was performed with no language restrictions in order to identify studies where oral corticosteroids were administered to patients aged 28 days to 18 years of age for at least 15 days of treatment. Each database was searched from their earliest dates to January 2016. All studies providing clear information on ADRs were included.

One hundred and one studies including 33 prospective cohort studies; 21 randomised controlled trials; 21 case series and 26 case reports met the inclusion criteria. These involved 6817 children and reported 4321 ADRs. The three ADRs experienced by the highest number of patients were weight gain, growth retardation and Cushingoid features with respective incidence rates of 21.1%, 18.1% and 19.4% of patients assessed for these ADRs. 21.5% of patients measured showed decreased bone density and 0.8% of patients showed osteoporosis. Biochemical HPA axis suppression was detected in 269 of 487 patients where it was measured. Infection was the most serious ADR, with twenty one deaths. Varicella zoster was the most frequent infection (9 deaths).

Weight gain, growth retardation and Cushingoid features were the most frequent ADRs seen when long-course oral corticosteroids were given to children. Increased susceptibility to infection was the most serious ADR.

Partial Text

Corticosteroids are used widely for their immunosuppressant and anti-inflammatory properties. They may be used individually or in combination with other drugs and are prescribed in both short and long courses depending on the condition being treated and the response of the patient [1]. The adverse effects from short-course use have been described recently and include changes in mood and behaviour, vomiting and sleep disturbance [2]. Long-course use of corticosteroids may lead to additional side effects [3]. Many of the side effects are reversible if the medication is stopped, while others may be permanent [4][5].

A systematic literature search was performed to identify all papers describing toxicity of corticosteroids in children. Six databases were searched up to January 2016: MEDLINE, EMBASE, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed. The databases were searched separately and combined together to remove duplications. The search strategy included all languages and involved the keywords “prednis* or dexamethasone or betamethasone” which are the most frequent medications given orally to children for long periods. “Corticosteroid” was added to cover all other oral corticosteroid medication. The keywords “toxicity* or adverse drug reaction* or adverse event* or side effect* or adverse effect*” were used as recommended by the BMC Medical Research Methodology for systematic reviews of adverse effects [7]. Additionally, the keyword ‘‘safety*”, was used as in a previous systematic review [8]. The terms recommended by search strategies for Medline were used to cover the paediatric age group ‘‘child* or children* or p*ediatric* or infant* or adolescent*” [9]. The terms neonate, newborn and gestation were excluded. The keywords: oral, tablet, syrup and PO (abbreviation meaning by mouth) were used to cover all possibilities of oral administration of corticosteroids.

7,714 articles were identified in total. 101 articles met the inclusion criteria after nine papers were added from manual searches of bibliographies, [13–33] [34–66] [67–87] [88–113] (S1 Appendix 1). The remaining articles were excluded for the reasons shown in Fig 1. Twenty one articles were excluded after quality assessment. Only one RCT contained four criteria with high risks of bias, and this study was excluded from the results [114] (Schaefer 2008, Fig 2). Twelve studies scoring < 70% in the STROBE checklist (range 30–57.5%) were excluded [115–126]. Eight case series were excluded for poor ratings in the Health Technology Assessment checklist [127–134]. Forty three patients died during treatment with oral corticosteroids. Infection was the most serious ADR and was responsible for half of the deaths. The incidence of infection with short course oral corticosteroids in children has previously been reported as (0.9%) [2]. It was significantly higher (8.7%) with long course treatment (P <0.0001). It is already well known that the immunosuppressant effects of corticosteroids in supra-physiological doses can lead to patients having increased susceptibility to infection, to deterioration in those with existing infections or to activation of latent infection [135]. To compound this their anti-inflammatory effects may mask symptoms and allow infections to progress significantly before detection. We believe this is the first study to quantify this greatly increased incidence of infection in patients on long-course rather than short-course oral corticosteroids.   Source: http://doi.org/10.1371/journal.pone.0170259