Association between chemosensory dysfunctions and inflammatory biomarkers in patients with SARS-CoV-2 infection: a systematic review and meta-analysis

This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline (Moher et al. 2010). Institutional review board approval and informed consent were not required for this systematic review and meta-analysis.

Search strategy

Searches for studies were performed in PubMed, Embase, and Web of Science databases from January 1, 2020 to May 12, 2022. A gray literature search was conducted using Google Scholar (first 100 results) and the preprint server medRxiv. The search was limited to studies published in full-text versions, without language restriction. The reference lists of all eligible studies and reviews were also evaluated to identify additional studies for inclusion. The structured search strategies used for each database and gray literature were detailed in the supplementary file.

Study selection and eligibility criteria

Two independent investigators (E.G.M.M. and R.M.A.) screened the searched studies based on each paper’s title and abstract. Relevant studies were read in full and selected according to the eligibility criteria. Disagreements between the two reviewers were resolved by consensus or by a third reviewer (P.R.S.M.-F.).

Studies were considered eligible if they satisfied the following criteria: (i) they were an observational study; (ii) participants were diagnosed with SARS-CoV-2 infection by real-time reverse transcription-polymerase chain reaction (RT-PCR); (iii) they provided information on hematological (white blood cells [WBC], neutrophils, and lymphocytes), biochemical (lactate dehydrogenase [LDH]), infection-related indices and cellular immunity (C-reactive protein [CRP], interleukin[IL]-6, IL-8, IL-10, TNF-α, ferritin, and procalcitonin), and coagulation function (D-dimer) in patients with COVID-19 and experiencing smell and/or taste disorders; (iv) comparison group included patients with COVID-19, but without chemosensory dysfunctions. Case series and studies with insufficient data on inflammatory biomarkers were excluded.

Data extraction and risk of bias assessment

Two authors (E.G.M.M. and P.R.M.F.) extracted the data from the all reports and cross-checked them for accuracy. Using a standardized data extraction sheet, the following information were extracted: country, eligible population, clinical characteristics, assessment of chemosensory dysfunction, and laboratory findings. Means and standard deviations (SD) of inflammatory biomarker levels were extracted from each study. Where data were not presented in tables or text, and authors could not be reached, data were extracted using WebPlotDigitizer (Web Plot Digitizer, V.3.11. Texas, USA: Ankit Rohatgi, 2017). If the means and SD were not directly reported in the publication, indirect methods of extracting estimates were used (Hozo et al. 2005; Wan et al. 2014).

The Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies of the National Institutes of Health (NIH) (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools) was used to grade the quality of each study.

Data synthesis and complementary analyses

A meta-analysis was conducted using the inverse-of-variance method and a fixed or random-effects model depending on the presence of heterogeneity. Statistical heterogeneity was quantified by the I2 index (Higgins and Thompson 2002) using the following interpretation: 0%, no between-study heterogeneity; < 50%, low heterogeneity; 50–75%, moderate heterogeneity; > 75%, high heterogeneity. In the presence of heterogeneity, we used the random-effects model, otherwise, the fixed-effects model was used.

Effect sizes were reported as standardized mean difference (SMD) with 95% confidence intervals (CI). Cohen’s classification was used to interpret the magnitude of effect size as follows: SMD = 0.2, small; SMD = 0.5, moderate; SMD = 0.8, large (Cohen 1988). A negative effect size indicated that the inflammatory biomarker levels were lower among patients with chemosensory dysfunction. Although funnel plot asymmetry was not evaluated in this meta-analysis due to the limited number of included studies (Simmonds 2015), we reduced the potential for publication bias by planning a comprehensive search including gray literature without restrictions. All analyses were conducted using RStudio software (version 2021.09.1).

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