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KSR Number: KSRA62396

Prevalence of hypersensitivity reactions in children associated with acetaminophen: a systematic review and meta-analysis

Risk of Bias Assessment

Overall summary: High risk of bias in the review

Bottom Line

Current evidence suggests that around 10% of children or adults who undergo oral challenge to acetaminophen have a true hypersensitivity. However, these conclusions must be interpreted with caution, since the review had significant methodological weaknesses, meaning relevant studies may have been missed and reviewer error and bias cannot be ruled out. Future studies are required to develop biomarkers to predict the risk of immediate and non-immediate hypersensitivity reactions to acetaminophen and determine the mechanisms of acetaminophen hypersensitivity reactions.

Risk of Bias Assessment

Overall summary High risk of bias in the review

High

There were some limitations with the review methods such as the lack of details with regards to eligibility criteria for the study design. Relevant studies may have been missed due to restrictions on publication format, language and date, and the lack of strategies to identify additional studies. No information was provided on the number of reviewers involved in the study selection and data extraction process, therefore reviewer error and bias cannot be ruled out. Study quality was assessed using inappropriate criteria.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably no
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review High

Details of Review

Number of studies 85
Number of participants 1,030
Last search date January 2017
Review type Aetiological
Objective To characterise reported hypersensitivity reactions to acetaminophen in adults and children; and to assess the prevalence of acetaminophen hypersensitivity in children with a suspected acetaminophen allergy.
Population Children and adults.
Outcome Prevalence of acetaminophen hypersensitivity (including immediate and non-immediate reactions).

Articles that had no history consistent with acetaminophen hypersensitivity were excluded; studies evaluating cross-intolerance to acetaminophen in patients reporting non-steroidal inflammatory drugs hypersensitivity were excluded.
Study design Not pre-defined (retrospective and prospective studies were ultimately included).
Exposure Acetaminophen.

Results

Pooled analysis reported that the prevalence of hypersensitivity to acetaminophen in adults or children undergoing oral acetaminophen challenge was 10.10% (95% confidence interval [CI] 6.05 to 14.16; 10 studies, n=259 patients).

Pooled analysis reported that they prevalence of hypersensitivity to acetaminophen among children undergoing oral acetaminophen challenge was 10.06% (95% CI 4.50 to 15.63; 5 studies).

Full Risk of Bias Assessment

The research objective was clearly stated. The inclusion criteria were not explicitly defined with regard to the study design. Studies were restricted based on language (only English and French studies were included), date (only studies published between January 2007 and January 2017 were included) and publication format (conference abstracts were excluded). For the meta-analysis, only studies with a sample size ≥10 were included.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably no
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably no
Concerns regarding specification of study eligibility criteria High

PubMed and EMBASE databases were searched for relevant studies. Only database searching was employed to identify studies, additional methods were not made to retrieve further studies. The search strategy was not reported. Searches were limited to studies published in the English and French language in the past 10 years, i.e. from January 2007 to January 2017. No information was provided regarding the number of authors involved in the study selection process.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably no
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? No information
2.4 Were restrictions based on date, publication format, or language appropriate? Probably no
2.5 Were efforts made to minimise error in selection of studies? No information
Concerns regarding methods used to identify and/or select studies High

No information was provided regarding the number of authors involved in the data extraction process. Sufficient study characteristics appear to have been extracted to allow interpretation of the results. Relevant study results appear to have been extracted. The methodological quality of included studies was assessed using inappropriate criteria. Three reviewers were independently involved in the assessment of risk of bias.

3.1 Were efforts made to minimise error in data collection? No information
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably no
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies High

The synthesis appeared to include all relevant studies. The method of analysis was poorly explained but appeared generally appropriate. Heterogeneity was assessed and found to be high for some analyses. However, heterogeneity was decreased after removing adult studies. Robustness of the findings was not addressed. Publication bias was not assessed; this was considered inappropriate. The quality of individual studies was considered in the synthesis using inappropriate criteria.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably no
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably no
Concerns regarding synthesis and findings High

Keywords