key: cord-1041105-aaxos30v authors: Rastogi, Aarushi; Bhaskar, Sonu Menachem Maimonides title: Incidence of white matter lesions in hospitalized COVID‐19 patients: A meta‐analysis date: 2022-02-14 journal: Microcirculation DOI: 10.1111/micc.12749 sha: 0803af493d37ac5e1b7cf895db0b73668df9ccfd doc_id: 1041105 cord_uid: aaxos30v OBJECTIVE: Novel coronavirus disease 2019 (COVID‐19) has been found to be associated with encephalopathy and brain imaging abnormalities. The identification of incident white matter lesions, known to be associated with cerebral microcirculatory failure and cerebrovascular disease, in COVID‐19 patients is of clinical and scientific interest. We performed a meta‐analysis to investigate the incidence of white matter lesions (WMLs) in hospitalized COVID‐19 patients. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for studies on brain imaging abnormalities in hospitalized COVID‐19 patients. The terms used included “white matter lesions,” “white matter hyperintensity,” “COVID‐19,” “coronavirus,” and “SARS‐CoV‐2.” A random‐effects meta‐analysis was conducted to obtain a pooled estimate of WML prevalence in hospitalized COVID‐19 patients. RESULTS: A total of 4 eligible studies involving 362 patients (144 with WMLs and 218 without) were included in the meta‐analysis. We found the pooled estimate of WML prevalence to be 20% (ES 0.20; 95% CI 0.00–0.54; p = .03). CONCLUSIONS: The estimated pooled prevalence rate of WMLs was approximately 20% in hospitalized COVID‐19 patients, albeit lower than the crude prevalence rate (39.8%). There is mounting evidence that coronavirus disease 2019 is associated with central nervous system involvement, 1, 2 with several reports of patients exhibiting neurological manifestations and brain imaging abnormalities. 3 Among the notable neuroimaging, findings in this population are white matter lesions (WMLs). WMLs, also referred to as leukoaraiosis or white matter hyperintensity (WMH), are areas of hyperintensity in cerebral white matter as seen on magnetic resonance imaging (MRI). [4] [5] [6] Cerebrovascular dysfunction and cerebral microcirculatory failure have been implicated in hypoperfusion and white matter damage. 7 While WMLs have been reported in the setting of COVID-19, 3, 8 there are limited data surrounding their incidence in patients with COVID-19. This metaanalysis sought to obtain a pooled estimate of the prevalence of WMLs in hospitalized COVID-19 patients. Our primary hypothesis is that there is a high prevalence of WMLs in hospitalized patients with COVID-19. The databases of EMBASE, PubMed, and Cochrane Central Register of Clinical Trials databases were used as the search engines. Articles published between January 2020 and June 2021 were included in the search. The search terms included: "white matter lesions" or "leukoaraiosis" or "white matter hyperintensity" and "COVID-19" or "coronavirus" or "SARS-CoV-2." Additionally, studies were limited to those that were in the English language and conducted on humans. The search was conducted on the July 10, 2021. The complete search strategy is available in the Appendix S1 (Search Strategy). The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flowchart shows the studies included in the meta-analysis ( Figure 1 ). This study adheres to the guidelines outlined in the Meta-analysis of Observational Studies in Epidemiology (MOOSE) (Table S1) and PRISMA 2020 (Table S2) checklists. Studies were eligible for inclusion if they met the following criteria: (1) age ≥18 years; (2) patients with a confirmed diagnosis of COVID-19 in the hospital; (3) patients who received brain imaging; (4) availability of data on non-specific WMLs in patients; and (5) studies with a sample size of >20 patients. The exclusion criteria were (1) studies not in English; (2) animal studies; (3) duplicated publications; (4) fulltext articles not available; (5) systematic reviews, meta-analyses, or letters; and (6) studies presented in the abstract form, with relevant data on white matter lesions not available. Titles and abstracts were first screened on Endnote to identify and exclude articles that were outside the field of interest, were systematic reviews or meta-analyses, or mismatched the eligibility criteria for other reasons. The remaining articles then underwent a comprehensive assessment to determine whether they should be included in the systematic review or meta-analysis. The reference list of obtained articles was also examined. The screening was conducted independently by two experienced investigators. In case of disagreement between authors, a consensus was reached through discussion. A data extraction sheet was used to extract the following data from each study: 1) baseline demographics: author, country, and year of publication; 2) study population: age of patients, sample The methodological quality of each study was assessed independently by two researchers using modified Jadad analysis. 10 The modified Jadad scale evaluates study quality based on randomization, blinding, description of withdrawals/dropouts, inclusion/exclusion criteria, assessment of adverse events, and methods used for statistical analysis. Using this scale, studies may be scored from 0 to 8. Studies included in the meta-analysis all obtained a score of 3. Each study was also separately assessed for risk of funding bias using a 4-point scale that scored studies from 0 (low potential for bias) to 3 (high potential for bias). 11 The absence of industry funding was not taken to signify an absence of bias, but the presence of industry funding or conflicts of interest was assumed to be an indicator of bias. None of the included studies were found to have high potential for bias. All statistical analyses were performed using STATA (Version 13.0, StataCorp LLC). This study investigated the proportion of white matter lesions in patients with COVID-19. The "metaprop" STATA command was used to pool proportions by performing a random-effects meta-analysis of proportions obtained from the individual studies. 12 Random-effects modeling was performed using the DerSimonian and Laird method. Forest plots were generated to study overall effects. To stabilize the variances, Freeman-Tukey double arcsine transformation was applied to calculate the pooled estimates. The heterogeneity was estimated from the inverse-variance fixed-effect model and quantified using the I 2 measure (I 2 < 40% = low, 30%-60% = moderate, 50%-90% = substantial, and 75%-100% = considerable). An estimate of between-study variance (tau-squared or τ 2 ) was also reported. The significance tests, in terms of Z-statistics and p-values, were reported. A p-value <.05 was considered significant. This meta-analysis included 4 case series reporting on brain imaging findings in COVID-19 patients, with a cumulative cohort of 362 patients. 13 All four included studies reported on the incidence of WMLs in COVID-19 patients. A pooled estimate of 20% was found (ES 0.20; 95% CI 0.00-0.54; z = 2.15; p = .03) (Figure 2 and Table S4 ). Notably, there was considerable heterogeneity between the included studies (I 2 = 96.86%, p < .001). The estimate of between-study variance (τ 2 ) was 0.50. The estimated pooled prevalence was lower than the crude prevalence rates (39.8%) observed in this study. Due to the limited epidemiological data surrounding leukoaraiosis, its prevalence in the general population is poorly elucidated. Two recent studies conducted in hospitalized cohorts in China found WMLs to be present in 58.3% and 81.4% of patients, respectively. 17, 18 Moreover, community-based samples in healthy populations from Australia and the Netherlands have also shown high incidences, at 50.9% and 95%, respectively. 19, 20 Importantly, subjects in the cohort from the Netherlands were significantly older than those included in other studies. Conversely, WML prevalence in a young (16-65) and healthy cohort from the United States of America was shown to be as low as 5.3%. 21 Similarly, a study in a cohort aged 1-45 in China also reported a relatively low prevalence of 25.94%. 22 When considering these historically reported rates, the 20% prevalence found in our study is lower than expected for our cohort of COVID-19 patients with a mean age of 63.2 years. The reasons for this finding are unclear. However, our results must be interpreted within the context of our study's limitations. Our study has several limitations. First, due to the limited literature on brain imaging findings in COVID-19 patients, our meta-analysis included only 4 studies and thus may have been underpowered to detect significant effects. Notably, a separate analysis of studies with sample sizes of 15 and above was also conducted, [13] [14] [15] [16] 23, 24 and yielded a pooled estimate of WML prevalence of 42% (ES 0.42; 95% CI 0.17-0.68; p < .001) ( Figure S1 ). Thus, it is possible that examination of results from a greater COVID-19 has been linked to encephalopathy and abnormalities on brain imaging. The observation of incident WMLs in COVID-19 patients is of clinical, public health and scientific relevance. To fully elucidate the possible involvement of COVID-19 in WML pathogenesis, more research on the relationship of COVID-19 with WMLs is needed. We would like to acknowledge the support from the administrative staff and NSW wide partnering clinicians and investigators. Funding The authors declare that they have no conflicts of interest. SMMB conceived the study, contributed to the planning, drafting, and revision of the manuscript; and supervision of the student. 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