Composition Vendor Newgen KnowledgeWorks (P) Ltd. PLoS ONE plos plosone PLOS One 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0314892 PONE-D-24-52453 Research Article Medicine and health sciencesMedical conditionsInfectious diseasesViral diseasesCOVID 19 Biology and life sciencesPhysiologyPhysiological parametersBody weightObesity Biology and life sciencesPhysiologyPhysiological parametersBody weight Medicine and health sciencesEpidemiologyMedical risk factors Biology and life sciencesNeuroscienceCognitive scienceCognitive psychologyPerceptionSensory perceptionSmell Biology and life sciencesPsychologyCognitive psychologyPerceptionSensory perceptionSmell Social sciencesPsychologyCognitive psychologyPerceptionSensory perceptionSmell Biology and life sciencesNeuroscienceSensory perceptionSmell Medicine and health sciencesClinical medicineSigns and symptomsHeadaches Biology and life sciencesPhysiologyPhysiological processesSleep Biology and life sciencesNeuroscienceCognitive scienceCognitive neuroscienceCognitive neurologyNeuropsychological testing Biology and life sciencesNeuroscienceCognitive neuroscienceCognitive neurologyNeuropsychological testing Medicine and health sciencesNeurologyCognitive neurologyNeuropsychological testing Biology and life sciencesNeuroscienceNeuropsychologyNeuropsychological testing Biology and life sciencesPsychologyNeuropsychologyNeuropsychological testing Social sciencesPsychologyNeuropsychologyNeuropsychological testing Excess weight is associated with neurological and neuropsychiatric symptoms in post-COVID-19 condition: A systematic review and meta-analysis Excess weight and neuro-symptoms in post-COVID-19 condition https://orcid.org/0000-0002-9161-6403 Ronca Débora Barbosa Conceptualization Formal analysis Funding acquisition Writing – original draft 1 2 3 ¤ * Mesquita Larissa Otaviano Conceptualization Formal analysis Investigation Writing – review & editing 1 Oliveira Dryelle Investigation 4 Figueiredo Ana Cláudia Morais Godoy Formal analysis Supervision Writing – review & editing 2 5 Wen Jun Writing – review & editing 6 7 Song Manshu Writing – review & editing 3 ‡ de Carvalho Kênia Mara Baiocchi Conceptualization Project administration Supervision Writing – original draft Writing – review & editing 1 4 ‡ Faculty of Health Sciences, Graduate Program of Public Health, University of Brasília, Brasília, Brazil Health Department of Federal District, Brasília, Brazil School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia, Faculty of Health Sciences, Graduate Program of Human Nutrition, University of Brasília, Brasília, Brazil Superior School of Health Sciences, Brasília, Brazil Faculty of Hospitality and Tourism Management, Macau University of Science and Technology, Macau SAR, China Faculty of Business and Law. Curtin University, Perth, Western Australia, Australia Yon Dong Keon Editor Kyung Hee University School of Medicine, KOREA, REPUBLIC OF * E-mail: d.ronca@ecu.edu.au, deboraronca@gmail.com

The authors have declared that no competing interests exist.

Current address: School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia

‡ Co-corresponding authors.

 752025 2025 20 5 e0314892 17112024 2432025 2025 Ronca et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background/purpose

Excess weight has been identified as a potential risk factor for post-COVID-19 condition (PCC). This systematic review and meta-analysis aimed to investigate whether excess weight is associated with the development or experience of neurological and neuropsychiatric symptoms in PCC.

 Methods

We conducted a comprehensive search of eight databases (PubMed, Embase, Scopus, Web of Science, VHL, Google Scholar, ProQuest, and medRxiv) for studies published up to July 2023. Studies were included if they assessed PCC symptoms in relation to nutritional status, specifically the development of neurological and neuropsychiatric symptoms more than 12 weeks post-infection. The analysis compared exposure and controls groups (excess weight vs. normal weight; obesity vs. non-obesity). Data were synthesized using a random-effects model.

 Results

Of the 10,122 abstracts screened, 18 studies (n = 139,091 adults) were included. These studies included 79,050 individuals with excess weight vs 57,926 normal-weight individuals and 30,694 individuals with obesity vs 107,612 non-obese individuals. The presence of excess weight in PCC was significantly associated with persistent depression (RR = 1.21; 95% CI: 1.03–1.42), headache (OR = 1.23; 95% CI: 1.10–1.37), memory issues (RR = 1.43; 95% CI: 1.24–1.65), sleep disturbance (RR = 1.31; 95% CI: 1.16–1.48), and vertigo (RR = 1.21; 95% CI: 1.04–1.41). Obesity was significantly associated with persistent headache (OR = 1.45; 95% CI: 1.37–1.53), numbness (RR = 1.61; 95% CI: 1.46–1.78), smell disorder (OR = 1.16; 95% CI: 1.11–1.22), taste disorder (OR = 1.22; 95% CI: 1.08–1.38), and vertigo (RR = 1.44; 95% CI: 1.35–1.53).

 Conclusions

Excess weight, including overweight and obesity, is associated with experiencing neuro-symptoms related to PCC. Individuals with these conditions urgently need enhanced personalized care management in current post-pandemic context.

 http://dx.doi.org/10.13039/501100002322 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Finance Code 001 https://orcid.org/0000-0002-9161-6403 RoncaDébora Barbosa Health Sciences Teaching and Research Foundation 5/2020 – FEPECS/DE https://orcid.org/0000-0002-9161-6403 RoncaDébora Barbosa http://dx.doi.org/10.13039/501100024253 Western Australian Future Health and Innovation Fund, Government of Western Australia WANMA/Ideas2023-24/10 SongManshu http://dx.doi.org/10.13039/501100003593 Conselho Nacional de Desenvolvimento Científico e Tecnológico 302740/2022-8 de CarvalhoKênia Mara Baiocchi This research received a grant from the Research Support Program at the Superior School of Health Sciences, Brasília, Brazil, funded by the Health Sciences Teaching and Research Foundation (Grant and Acceptance Term No. 5/2020 – FEPECS/DE) (DBR). This study was also partially financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil – Finance Code 001 (DBR). MS is supported by the Western Australian Future Health Research and Innovation Fund (Grant ID WANMA/Ideas2023-24/10). KMBC is supported by National Council for Scientific and Technological Development CNPq (Grant n. 302740/2022-8). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability All relevant data are within the paper and its Supporting Information files. Outbreaks COVID-19 Introduction

A growing body of evidence suggests that a subset of COVID-19 survivors develop persistent, debilitating symptoms and may face a long road to complete recovery [1–4]. These symptoms have been shown to affect multiple organ systems, as evidenced by respiratory, cardiovascular, neurological, and mental health manifestations. This emergent condition has several names: long-COVID; post-acute sequelae of SARS-CoV-2 syndrome; and, as per the World Health Organization (WHO), post-COVID-19 condition (PCC). Although PCC has varying definition in the literature, it is generally described as involving persistent symptoms or new symptom onset, typically 12 weeks from the acute phase of COVID-19 [5,6], presenting a novel challenge to healthcare systems [7]. Recently, it was defined as an infection-associated chronic condition that occurs after SARS-CoV-2 infection [8].

To date, no comprehensive effective treatment has been recognized for PCC, and the common strategies are based on symptoms relief [9,10]. Among PCC’s range of symptoms, long-term COVID-19 neurological and neuropsychiatric manifestations are of particular interest given the higher incidence of nervous system related sequalae’s after post-viral epidemics [11]. Prior reviews revealed that smell and taste disorders, headache, sleep disturbance, anxiety and depression were among the most commonly reported persistent symptoms in the general population. However, these studies only follow participants for a few weeks after SARS-CoV-2 infection and do not meet the criteria for PCC [12–15]. The severity of the COVID-19 acute phase has been associated with the development of long-term COVID-19 neuropsychiatric symptoms [16]. The body mass index (BMI) has been regarded as a potential risk factor for PCC, although the association of excess weight (EW) with the development of specific neurological and neuropsychiatric symptoms remains unclear [17,18]. Moreover, studies that reported the prevalence of persistent neurological and neuropsychiatric symptoms up to one year after COVID-19 onset exhibited considerable heterogeneity and did not perform subgroups analyses according to nutritional status [2,19]. An increased number of PCC symptoms that longer persist may be experienced by individuals with EW and might be associated to worsen health and poor quality of life [20].

It is noteworthy that EW is a chronic suboptimal heath condition characterized by excessive fat deposits and is considered a global public health problem. It represents a major risk factor for other chronic conditions and encompasses overweight, a suboptimal body weight that represents a risk to health, and obesity, a metabolic disease [21,22]. A complex yet costly care of individuals with EW is required, with appropriate multidisciplinary, long-term support [21]. In 2020, the overweight and obesity pandemic collided with the COVID-19 pandemic. These conditions’ joint negative effects have increased the incidence of related diseases, leading to potentially adverse clinical and social consequences [23–26]. Obesity was found to be associated with poor COVID-19 outcomes, such as hospital admissions, intensive care admissions, and lethality rates [27–29]. Although the COVID-19 pandemic has come under control, the multisystemic nature of this disease and its long-term impacts have yet to be elucidated [12,30].

Although there is literature on the most reported neurological and neuropsychiatric symptoms of PCC, few studies reported the risk of PCC symptoms according to nutritional status and no previous review has explored the association of EW and the development of specific neurological or neuropsychiatric symptoms among COVID-19 survivors. Elucidating the long-term neuro-outcomes of COVID-19, along with its suite of symptoms and high-risk populations, is urgently needed to facilitate the development of reliable and personalized care management strategies. Although a universal definition has been recently stablished by the National Academies of Sciences, Engineering, and Medicine and the terminology of Long COVID has been encouraged to improve communication [8], the present study applied the definition of Post-COVID-19 Condition as proposed by WHO [5], since it was the most common used terminology among included studies. Therefore, this systematic review addresses whether EW is associated with the development or experience of specific persistent neurological or neuropsychiatric symptoms among COVID-19 survivors.

 Materials and methods

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [31]. It is a subset of broad research aimed at investigating the role of EW in the development of persistent symptoms of PCC. This review was registered at the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42023433234).

Search strategy and eligibility criteria

Two authors (DBR and LOM) searched seven electronic databases (MEDLINE, EMBASE, SCOPUS, Web of Science, VHL, Google Scholar, ProQuest) and a preprint server (medRxiv) on 3 July 2023. The search strategy was reviewed by two reviewers according to the criteria of the Peer Review of Electronic Search Strategies (PRESS) checklist [32]. The search strategy included the following terms: (“long COVID-19” OR “post-acute covid 19 syndrome” OR “COVID-19” OR “SARS-CoV-2” OR “post-COVID-19 condition” OR “long hauler”) AND (“excess of weight” OR “overweight” OR “obesity” OR “body mass index”) AND (“signs and symptoms” OR “COVID-19 sequelae” OR “headache” OR “loss of smell” OR “cognitive dysfunction” OR “anxiety” OR “depression” OR “sleep disorder” OR “brain fog).” The full search strategy is detailed in supporting information (S1 Table). Additionally, some articles were hand-searched to identify potentially eligible studies which might not be electronically retrieved, including those published in 2024 (S2 Table).

Studies were considered eligible for inclusion if they (a) had observational designs; (b) primarily focused on adults; (c) classified focal populations based on the presence of excess weight/obesity versus normal weight/non-obesity, using either measured BMI or self-reported data; and (d) had a mean (or median) follow-up of at least 12 weeks after the acute phase of COVID-19. Survivors could be (a) hospitalized or non-hospitalized, (b) inpatient or outpatient, and (c) mixed population (hospitalized and outpatient) recruited in the community, outpatient clinic or heath care system.

We exclude editorials, clinical trials, reviews, opinions, books or book chapters, conference abstracts, case reports, and correspondence articles. Studies were also excluded if they included mostly pregnant or nursing women; evaluated the health effects of COVID-19; assessed excess weight as a risk factor for acute-phase severity or mortality; investigated clusters of symptoms rather than specific symptoms; or if they lacked a control group (i.e., COVID-19 survivors who did not report persistent symptoms). Additionally, studies were excluded if they evaluated long-term sequelae of COVID-19 in a specific population (e.g., individuals with specific comorbidities) to ensure that our analysis remained focused on the general population of COVID-19 survivors.

All included studies adhered to ethical guidelines and were approved by their respective ethical committees.

 Screening process, study selection, and data extraction

The same two authors (DBR and LOM) independently screened the titles and abstracts of studies obtained from database searches and removed duplicates. The Rayyan app [33], a semi-automation tool, was used to streamline the review process. This was followed by a full-text review of the retained articles to ensure they met eligibility criteria (S2 Table). Fig 1 presents the flowchart for the included studies.

10.1371/journal.pone.0314892.g001Flow diagram of included studies.

The study population of interest comprised COVID-19 survivors. Exposure was defined as EW or obesity based on BMI measurement, data from electronic medical records, or self-reported information. Two exposure groups were defined according to WHO guidelines [34]: 1) an excess weight group (BMI ≥ 25 kg/m2) and 2) an obesity group (BMI ≥ 30 kg/m2). Both Asian and Caucasian populations were included in the analysis, with corresponding BMI cut-offs applied: for Asian-Pacific populations, the thresholds were BMI ≥ 23 kg/m2 for EW and BMI ≥ 25 kg/m2 for obesity, as previously defined in the included studies [35,36].

We adopted WHO’s definition of PCC as outlined by Soriano et al. (2021) [5]. Symptoms were measured with predefined questionnaires/scales or reported during interviews (in person, by phone, or online). Due to varying definitions of illness onset (baseline), we accepted definitions that included 12 weeks from the onset of COVID-19 symptoms, COVID-19 diagnosis, hospital admission, or discharge after the acute phase. For the follow-up period, we considered studies where the sample median (or mean) of persistent symptoms was reported at least 12 weeks (84 days) after the baseline, with a minimum interquartile range (IQR) of 10 weeks (or a standard deviation (SD) of ± 24 days) from baseline. This cut-off was necessary to include studies evaluating long-term sequelae of COVID-19. Given the varied terminology used for symptoms across studies, we re-grouped symptoms into neurological and neuropsychiatric categories as shown in Fig 2.

10.1371/journal.pone.0314892.g002Reported neurological and neuropsychiatric symptoms related to Post-COVID-19 condition (PCC).

a Neurological and neuropsychiatric symptoms reported in included studies were grouped into one category with synonyms presented in brackets.

Specific data were exported from each study into a predefined data collection form, including authors; publication year; country; aim of the study; study design; mean follow-up period; study population; exposure groups; assessment of outcome; evaluated symptoms; frequency of symptoms (n, %) among exposure and control groups; and the effect measure of the association of EW and the neurological/neuropsychiatric symptom. (S3 and S4 Table). Corresponding authors of relevant articles published were contacted if any data were absent (S5 Table).

 Quality assessment

The ROBINS-E tool for observational research was used to determine the risk of bias in the included studies [37]. ROBINS-E is a domain-based tool that evaluates seven domains (confounders, exposure measurement, participant selection, post-exposure interventions, missing data, outcome measurement, and selection of reported results) and then a general assessment of the study. Traffic plots with a final analysis of studies’ risk of bias, by domain, is generated. For this research, two authors (DBR and DO) initially appraised the risk of bias. Disagreements were discussed and resolved in collaboration with a third researcher (LOM). The ROBINS-E tool was not applied as a study eligibility criterion.

We assessed the certainty of evidence via the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework [38–40] regarding the development of PCC-related neurological and neuropsychiatric symptoms among individuals with EW and obesity. The GRADE system measures key domains that impact the overall quality of evidence, including imprecision, inconsistency, indirectness, risk of bias, and publication (reporting) bias. The certainty of evidence was downgraded if these factors were identified. Moreover, the magnitude of the effect, dose-response gradient, and possible adjustment for confounding were also considered in the evaluation, which upgraded the quality of the evidence. Judgements for each GRADE domain were based on the information generated and synthesised in this systematic review. We assessed the certainty of evidence for all evaluated outcomes (symptoms) and scored it as follows: high certainty = ≥4 points (strong confidence that the true effect is close to the estimated effect); moderate certainty = 3 points (The true effect is likely to be close to the estimated effect, but there is some uncertainty); low certainty = 2 points (The true effect may be substantially different from the estimated effect); very low certainty = 1 point (The true effect is highly uncertain due to serious study limitations or inconsistencies).

 Statistical analysis

The frequency of reported symptoms and the associated risk of development were determined for EW vs normal weight groups and for obesity vs non-obesity groups, classified by BMI when available (normal weight: BMI of 18–24.9 kg/m2; excess weight: BMI > 25 kg/m2; obesity: BMI > 30 kg/m2; non-obesity group: BMI < 30 kg/m2), taking into account different cut-off values previously defined for the Asian population in studies [35,36]. Each symptom was considered an individual outcome. For this purpose, we collected data of the frequency (n, %) of each neurological and neuropsychiatric symptoms related to PCC reported and the risk of developing persistent symptoms (as measured by the odds ratio [OR] or the adjusted OR) at follow-up in included studies.

We performed meta-analytic calculations using STATA software (SE/17). Pooled risk ratios (RRs) with their 95% confidence intervals (CIs) were computed from the raw data of included cohort and cross-sectional studies, while pooled odds ratios (OR) were computed for reported symptoms identified in case-control studies. A random effects model meta-analysis was conducted to account for the statistical and methodological heterogeneity of the data. We used a two-sample binary-outcome summary dataset format with DerSimonian–Laird estimation when fewer than five studies were available [41]; when more than five studies were available, we adopted restricted maximum-likelihood estimation and to conduct pooled RR analysis. Statistical heterogeneity was assessed using the I2 statistic, following thresholds recommended by Cochrane: 0%-40% (no important heterogeneity); 30%-60% (moderate heterogeneity); 50%-90% (substantial heterogeneity); and, 75–100% (considerable heterogeneity) [42]. Forest plots were generated for all outcomes. Publication bias was not assessed due to the limited number of included studies in each meta-analysis. A value of p < 0.05 was considered statistically significant.

 Results

Of the 10,122 abstracts screened, 211 full-text registers were reviewed, and 65 studies were considered eligible. Data on neurological and neuropsychiatric symptoms according to individuals’ nutritional status were available for 18 studies (including one preprint [43]), all of which were entered into our meta-analysis.

Selected studies originated from 23 countries across Asia (China [35,36], India [44], Indonesia [45], Japan [46], Malaysia [43] and Saudi Arabia [47]), Europe (Denmark [48,49], England [50], Germany [51], Italy [52], Poland [53], Spain [54] and Switzerland [55]), and North and South America (Argentina [56], Brazil [56], Chile [56], Dominican Republic [56], Ecuador [56], Mexico [56], Panama [56], Paraguay [56], Peru [56] and United States of America [57,58]), comprising both developed and developing countries. Among the included studies, two employed case–control design [54,57], six involved retrospective or prospective cohorts [36,45,52,53,55,58], and 10 involved cross-sectional studies [35,43,44,47–51,56]. The populations investigated varied: three studies evaluated individuals in outpatient settings [49,55,57], five involved hospitalized patients [35,36,45,52,54], and ten included individuals either hospitalized or outpatient settings during COVID-19 acute-phase [43,44,46,47,50,51,53,56,58]. The classification of individuals according to nutritional status also varied: four studies compared symptoms between individuals with EW and those with normal weight [35,43,45,47], five studies evaluated obesity versus non-obesity [36,51–54], eight studies presented data for individuals with normal weight, overweight and obesity [44,48–50,55–58], and one study only provided the mean BMI of the sample without specifying the number of individuals in exposure and control groups [46]. In total, our meta-analysis included 79,050 people with EW and 30,694 with obesity in exposure groups, while 57,926 normal weight individuals and 107,612 non-obese individuals comprised control groups. Sample sizes ranged from 32 [57] to 78,566 [50] COVID-19 survivors. Two Chinese studies applied different cut-off points for nutritional status classification (EW as BMI ≥ 23 kg/m2; obesity as BMI ≥ 25 kg/m2) [35,36]. Exposure was assessed via anthropometric measures [35,36,44,53,56,57], electronic medical record data [45,49,52,54], and self-reported comorbidity/BMI [43,46–48,50,55,58]. PCC neurological and neuropsychiatric symptoms were evaluated using questionnaires [36,44,46–50,53–55,57], validated scales [35,43,51,52,54,57], or self-report instruments [45,50,51,56,58]. The mean time from COVID-19 onset (baseline) to long-term symptom assessment was 25.8 weeks (range: 12 weeks [45,47,49,50,52] to 52 weeks [one year] [35]). Table 1 outlines the features of the included articles.

10.1371/journal.pone.0314892.t001Characteristics of included studies.
Author, Year Country Study aim Study design;Follow-upa Study population Categories of nutritional status Assessment type Main neurological (N) and neuropsychiatric (NP) symptoms evaluated
Alkwai, H.M. et al., 2022 [47] Saudi Arabia To analyze the persistence of COVID-19 symptoms and return to the usual state of health Cross-sectional;12 weeks after COVID-19 infection Mixed populationbn = 108 (male = 23)Age range: 18–65 years Overweight(n = 32)Normal weight (n = 181) Online surveySelf-reported comorbiditiesSymptom questionnaire N: Concentration issues, headache, memory issues, numbness, smell disorder, taste disorder, vertigoNP: mood change, sleep disturbance
Blümel, J.E. et al., 2022 [56] Nine Latin-Americancountriesc To study the development of long-term symptoms and the impacts of COVID-19 on mental health and quality of life in middle-aged women Cross-sectional;32 weeks after COVID-19 infection Mixed populationbSample of interest/ study samplen = 304/1,238 (female only)Age: 53.0 (range: 40–64 years) Obesity (n = 41)Overweight(n = 124)Normal weight (n = 139) In-person interviewMeasured BMIReported symptoms N: anorexia, cognitive deficit, headache, memory issues, numbness, smell disorder, taste disorder, vertigoNP: anxiety, sleep disturbance
Bungenberg, J. et al.,2022 [51] Germany To identify and compare persistent self-reported symptoms in initially hospitalized and non-hospitalized patients after infection Cross-sectional;13.4 weeks for non-hosp. and 41 weeks for hosp. patients after acute symptoms Mixed populationbn = 50 (male = 22)Age: 50.5 (range: 40–64 years) Obesity (n = 7)Non-obesity(n = 43) In-person interviewReported symptoms and scales N: cognitive deficit, memory issues, smell disorder, taste disorder, vertigoNP: sleep disturbance
Carter, S.J. et al., 2022 [57] United States of America To compare functional status, mood state, and physical activity in leisure time among positive COVID-19 and controls Case–control;12.1 weeks after COVID-19 diagnosis Outpatientn = 32 womanSARS-CoV-2 group = 17Age: 55 ± 11 years Obesity (n = 4)Overweight(n = 6)Normal weight (n = 7) In-person interviewMeasured BMIQuestionnaire and Profile of Mood States N: Cognitive deficit, headache, memory issues, smell disorder, taste disorder
Chudzik, M. et al., 2022 [53] Poland To analyse the prevalence of self-reported smell and/or taste disorders and to identify risk factors for the disease Cohort;28.8 weeks starting 14 days after last COVID-19 symptom Mixed population bn = 2,218 (male = 1,410)Age: 53.8 ± 13.5 years Obesity(n = 692)Non-obesity(n = 1,485) In-person interview Measured BMIHealth questionnaire N: Smell and taste disorders
Desgranges, F. et al., 2022 [55] Switzer-land To compare the prevalence of symptoms persisting for more than 3 months and to identify predictors of persistent symptoms Cohort;21.4 weeks after initial consultation (IQR: 17.2–29.1) OutpatientSample of interest/ study samplen = 418/507 (male = 157)Age: 41 (range: 31–54 years) Obesity (n = 72)Overweight/obesity(n = 189)Healthy weight (n = 229) Electronic medical recordsTelephone interviewsSelf-reported BMISurvey with predefined symptoms N: Headache, loss of balance, memory issues, numbness, smell disorder, taste disorderNP: sleep disturbance
Epsi, N.J. et al., 2024 [58] United States of America To improve the definition of PCC with a data-driven approach to phenotyping. Cohort24 weeks post-infection Mixed population bn = 1,988 (male = 1,201)Age: 69,5% were between 18–44 years old Obesity (n = 710)Overweight(n = 842)Normal weight (n = 436) Electronic patient records and self-reported BMIOnline surveySurvey with predefined symptoms N: Smell and taste disorder
Farhanah, N. et al., 2022 [45] Indonesia To determine persistent symptoms and evaluate quality of life in COVID-19 patients 3 months after discharge Cohort;12 weeks after hospital discharge Hospitalizedn = 104 (male = 55)Age: 48.9 (range: 18–65 years) Excess weight (n = 41)Normal weight(n = 63) Electronic medical recordsTelephone interviewsReported symptoms N: headache, smell disorder, sweating, taste disorderNP: sleep disturbance
Fernández-de- Las-Peñas, C. et al, 2021 [54] Spain To investigate the association of obesity with long‐term post‐COVID symptoms in hospitalized COVID‐19 survivors Case-control;28.8 weeks after hospital discharge Hospitalizedn = 264 (male = 159)Age: 52.0 ± 14.5 years Obesity (n = 88)Non-obesity (n = 176) Electronic medical recordsTelephone interviewsList of symptoms Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI) N: Concentration issues, cognitive deficit, headache, memory issues, numbness, sleep disturbance, smell and taste disordersNP: anxiety, depression
Gaur, R. et al., 2022 [44] India To assess the extent of disability following COVID-19 infection Cross-sectional;15.5 weeks after COVID-19 infection Mixed populationbn = 97 (male = 61)Age: 48.7 ± 15.6 years Obesity (n = 32)Overweight (n = 27)Normal weight (n = 38) In-person interviewMeasured BMIQuestionnaire N: Headache, vertigoNP: Sleep disturbance
Li, Z. et al., 2023d [35] China To investigate the mental health status of COVID-19 survivors 1 year after discharge and reveal related risk factors Cross-sectional;52 weeks (12 months) after hospital discharge Hospitalizedn = 535 (male = 216)Age: 50.8 ± 14.4 years BMI ≥ 23 (n = 221)BMI 18.5–22.9 (n = 295) Self-reported surveyMeasured BMIQuestionnaire, General Anxiety Disorder-7 scale, Patient Health Questionnaire (PHQ)-9, PSQI N: Anxiety, depressionNP: Sleep disturbance
Miyazato, Y. et al., 2022 [46] Japan To explore the factors involved in PCC development in a cohort of patients recovering from COVID-19 at a hospital in Japan Cross-sectional;35.5 weeks after symptom onset or COVID-19 diagnosis Mixed populationbn = 457(male = 226)Age: 47 (IQR: 39–55 years) BMI as continuous variable Online surveySelf-reported BMIQuestionnaire with list of symptoms N: Smell and taste disorders
Moy, F.M. et al., 2022 [43] Malaysia To investigate mental health status in the form of depression among COVID-19 survivors and its associated factors Cross-sectional;27.3 weeks after COVID-19 infection Mixed populationbSample of interest/ study samplen = 567/732 (male = 302)Age: 40.2 ± 10.9 years Overweight/obese (n = 315)Normal weight/underweight (n = 246) Online survey Reported BMIPHQ-9 NP: Depression
Shang, L. et al., 2021d [36] China To determine whether obesity has a long‐term impact on COVID‐19 recovery Cohort;46.1 weeks after hospital discharge Hospitalizedn = 118 (male = 48)Age: 53.0 (IQR: 44–61 years) Obesity (n = 53)Non-obesity (n = 65) In-person interview Measured BMIQuestionnaire N: Smell disorderNP: sleep disturbance
Sørensen, A.I.V, et al., 2022 [48] Denmark To estimate the risk difference between COVID-19 positive and negative individuals; to evaluate the duration of symptoms; to explore the influence of risk factors on persistent symptoms Cross-sectional;38 weeks after COVID-19 test. Mixed populaitonb (96% of outpatient)Sample of interest/ study samplen = 61,002/152,880 (male = 25,172)Age: 49.0 (IQR: 39–60 years) Obese (n = 9,950)Overweight (n = 19,264)Normal weight (n = 25,285) Online survey and electronic recordsSelf-reported BMIWeb-based questionnaire N: Headache, smell disorder, taste disorder, vertigo
Van-Wijhe, M. et al., 2022 [49] Denmark To investigate the occurrence and risk factors for long-COVID symptoms and health-related quality of life Cross-sectional;12 weeks after positive PCR test OutpatientSample of interest/ study samplen = 742/7420 (male = 245)Age: 48.2 ± 15.0 Obesity (n = 148)Overweight (n = 226)Normal weight (n = 368) Electronic patient records and online surveyQuestionnaire N: Concentration issues, headache, memory issues, smell disorder, taste disorder, vertigo
Vassalini, P. et al., 2021 [52] Italy To assess the prevalence of depressive symptoms and related risk factors at 3 months after hospitalization for COVID-19 infection Cohort12 weeks after hospital discharge Hospitalizedn = 115 (male = 62)Age: 47 (IQR: 48–66 years) Obesity (n = 5)Non-obesity (n = 110) Electronic medical records and telephone interviewsPHQ-9 NP: Depression
Whitaker, M. et al, 2022 [50] England To estimatesymptom prevalence; to investigate co-occurrence of symptoms andassess risk factors for persistence of symptoms Cross-sectional;12 weeks after symptom onset Mixed population bSample of interest/ study samplen = 78,566/606,434 (male = 37,600)Age: 80% of sample between 25 and 65 years old Obesity (n = 18,892)Overweight (n = 27,986)Normal weight (n = 30,639) Survey (online/telephone)Self-reported BMIQuestionnaire and self-reported symptoms N: Headache, memory issues, numbness, smell disorder, taste disorder, vertigoNP: sleep disturbance

BMI: body mass index; PCR: polymerase chain reaction; IQR: interquartile range.

aMean or median of follow-up time, in weeks;

bHospitalized and outpatient;

cArgentina, Brazil, Chile, Dominican Republic, Ecuador, Mexico, Panama, Paraguay, and Peru;

dDifferent cut-off values were used to define excess weight and obesity in Asian populations.

Half of the studies [35,36,43,46,49,53–55,58] tested for differences in the prevalence or risk of developing PCC neurological and neuropsychiatric symptoms based on nutritional status. One study found that BMI was inversely associated with the risk of developing smell and taste disorders [46]. Positive associations between EW and anxiety [35], depression [35,43], and sleep disturbance [54,55] were also reported, with obesity being independently associated with sleep disturbance [54]. Table 2 displays data on the frequency and risk of developing neurological and neuropsychiatric symptoms of PCC from studies that examined differences between exposure and control groups. Other studies [44,45,47,48,50–52,56,57] did not test for differences in the prevalence or risk of specific persistent neuropsychiatric symptoms. Data on symptom frequency by nutritional status are available in the supporting information (S6 Table).

10.1371/journal.pone.0314892.t002Frequency of neuropsychiatric symptoms related to post-COVID condition and the risk of their development in included studies.
Author, year Frequency (%) of PCC Symptoms bynutritional status Significantly higher frequency of symptoms in the exposure groups? Effect of nutritional status on the risk/or protection from developing a PCC symptom<?Note To TS: Single?> Exposure increased the risk of symptoms?
Excess weight versus Normal weight (Yes/ No) aOR (95%CI) (Yes/ No)
Exposure groups Control group
Desgranges, F. et al., 2022 Smell and taste disorders NA NA NA 1.01 (0.61–1.67); p = 0.96 No
Headache 0.79 (0.48–1.75); p = 0.79 No
Loss of balance 1.46 (0.35–6.09); p = 0.61 No
Memory issues 1.79 (0.93–3.44); p = 0.08 No
Numbness 2.74 (0.79–9.50); p = 0.11 No
Sleep disturbance 2.08 (1.03–4.21); p = 0.04* Yes
Epsi, N.J. et al., 2024 Smell and taste disorder 0.01 0.02 No 0.89 (0.37–2.12) No
Li, Z. et al., 2023a Anxiety 16.3 13.8; p = 0.000* Yes NA NA
Depression 21.7 19.0; p = 0.052* No
Sleep disturbance 51.1 43.3; p = 0.018* Yes
Miyazato, Y. et al., 2022 Smell disorder NA NA NA 0.94 (0.89–0.99); p = 0.014* Yes
Taste disorder 0.93 (0.88–0.98); p = 0.012* Yes
Moy, F.M. et al., 2022 Depression 51.7 42.3; p = 0.026* Yes 1.83 (1.18-2.82) Yes
Van-Wijhe, M. et al., 2022 Concentration issues NA NA NA 1.01 (0.70-1.47) No
Headache 1.09 (0.75-1.58) No
Memory impairment 0.94 (0.62-1.42) No
Taste disorder 0.85 (0.61-1.32) No
Smell disorder 0.72 (0.45-1.05) No
Vertigo 0.95 (0.64-1.42) No
Obesity versus Non-obesity (Yes/ No) OR (95%CI) (Yes/ No)
Exposure groups Control group
Chudzik, M.et al., 2022 Smell and taste disorder 3.1 5.1 No 0.65 (0.35–1.22); p = 0.185 No
Epsi, N.J. et al., 2024 Smell and taste disorder 0.01 0.02 No 0.76 (.29–1.99) No
Fernández-de- las-Peñas, C. et al, 2021 Ageusia 8.0 6.8 Yes NA NA
Anosmia 2.3 6.8 No NA NA
Anxiety 15.9 9.7 Yes 1.75 (0.82–3.72); p = 0.146 No
Cognitive deficit 9.1 6.8 Yes NA NA
Concentration issues 13.6 9.1 Yes NA NA
Depression 13.6 15.9 No 0.83 (0.40–1.73); p = 0.628 No
Headache 8.0 5.7 Yes NA NA
Memory impairment 18.2 14.8 Yes NA NA
Sleep disturbance 45.5 25.6 Yes 2.10 (1.13–3.83); p = 0.020* Yes
Shang, L. et al., 2021a Sleep disturbance 39.6 44.6; p = 0.590 No NA NA
Smell disorder 7.5 7.7; p = 0.970 No
Van-Wijhe, M. et al., 2022 Concentration issues NA NA NA 0.96 (0.62-1.49) No
Headache 1.06 (0.69-1.65) No
Memory impairment 0.92 (0.56-1.50) No
Taste disorder 1.00 (0.65-1.55) No
Smell disorder 0.83 (0.53-1.55) No
Vertigo 0.90 (0.56-1.45) No

* Statistically significant; NA: non-available information; excess-weight group (BMI ≥ 25 kg/m2); normal-weight group (BMI < 25 kg/m2); obesity group (BMI ≥ 30 kg/m2); non-obesity group (BMI < 30 kg/m2). a Different cut-off values were used to define excess weight and obesity in Asian populations (excess weight ≥ 23 kg/m2; obesity ≥25 kg/m2).

 Excess weight and neuro-symptoms of PCC

We assessed the risk ratios (RRs) and odds ratios (ORs) for the EW group. Among neuropsychiatric symptoms, excess weight was significantly associated with persistent depression (RR = 1.21; 95% CI: 1.03–1.42; I2 = 0.00) and sleep disturbance (RR = 1.31; 95% CI: 1.16–1.48; I2 = 17.83%) (Fig 3). Moreover, significant positive association was observed between excess weight and headache (OR = 1.23; 95% CI: 1.10–1.17; I2 = 40.36%), memory issues (RR = 1.43; 95% CI: 1.24–1.65; I2 = 0.00), numbness (RR = 1.37; 95% CI: 1.24–1.51; I2 = 0.00), and vertigo (RR = 1.21; 95% CI: 1.04–1.41; I2 = 59.53%) (Fig 4A; Fig 4B and Fig 4C). Due to the limited number of studies, we were not able to perform meta-analysis for anorexia, mood change, concentration issues and swelling symptoms.

10.1371/journal.pone.0314892.g003Forest plots of excess weight and risk ratio (RR) for neuropsychiatric symptoms.

a Applied a different BMI cut-off (Excess weight > 23kg/m2)..

 10.1371/journal.pone.0314892.g004A. Forest plots of excess weight and pooled results (RR and OR) for neurological symptoms. B. Forest plots of excess weight and pooled results (RR and OR) for neurological symptoms. C. Forest plots of excess weight and pooled results (RR and OR) for neurological symptoms.

Four studies employed multivariate logistic regression and reported the risk of developing headache, smell disorder, memory impairment and taste disorder. These data were included in the meta-analysis. Pooled results revealed a significant association indicating that persistent taste disorder was inversely associated with BMI (OR 0.93; 95%CI 0.88–0.98; I2 = 0,00). No significant associations were found for other evaluated symptoms (S1 Fig).

 Obesity and neuro-symptoms of PCC

Our pooled risk analysis for obesity and neurological symptoms (Fig 5A; Fig 5B and Fig 5C) showed that obesity was associated with a range of neurological symptoms: headache (OR = 1.45; 95% CI: 1.37–1.53; I2 = 0.00); numbness (RR = 1.61; 95% CI: 1.46–1.78; I2 = 0.00); smell disorder (0R = 1.16; 95% CI: 1.11–1.22; I2 = 1.26%); taste disorder (0R = 1.22; 95% CI: 1.08–1.38; I2 = 58.60%); and vertigo (RR = 1.44; 95% CI: 1.35–1.53; I2 = 0.00). No statistically significant association was found between obesity and the risk of developing PCC-related neuropsychiatric symptoms (S2 Fig).

10.1371/journal.pone.0314892.g005A. Forest plot of obesity and pooled results (RR and OR) for neurological symptoms. B. Forest plot of obesity and pooled results (RR and OR) for neurological symptoms. <sup>a</sup> Applied a different BMI cut-off (obesity >25 kg/m<sup>2</sup>). C. Forest plot of obesity and pooled results (RR and OR) for neurological symptoms.

Substantial heterogeneity was observed in our meta-analysis for the non-significant association between obesity and anxiety (I2 = 67.34%), while moderate heterogeneity was observed for sleep disturbance (I2 = 51.27%), smell and taste disorder (I2 = .51.43%) and taste disorder (I2 = 58.60%) in pooled results comparing individuals with obesity and the control group. Meanwhile, moderate heterogeneity was observed when evaluating excess weight as the exposure group for headache (I2 = 40.36%), taste disorder (I2 = 53.46%), and vertigo (I2 = 59.53%). Other analysis showed no significant heterogeneity. Subgroup analyses could not be performed due to an insufficient number of studies evaluating the same outcome by nutritional status.

 Risk-of-bias assessment

We assessed the risk of bias for both evaluated effect measures (frequency and OR). Results for studies reporting the frequency of PCC symptoms are presented in Fig 6; while findings for studies reporting OR are displayed in Supporting Information (S3 Fig). Among the 18 studies evaluated, seven were judged to have a high risk of bias due to self-reported exposure data [43,46–48,50,55,58]. The ROBINS-E tool indicated that no further evaluation of a study was required for studies with inappropriate measurement of exposure or outcome; therefore, this tool was applied only to the remaining 11 studies [35,36,44,45,49,51–54,56,57].

10.1371/journal.pone.0314892.g006Summary plot and traffic light plot illustrating the risk of bias in the included studies.

The domain most affecting the assessment was control for confounders (Domain 1 [D1]). Few studies employed appropriate designs (e.g., randomization or matching) [49,54,57] or analytical methods (e.g., stratification) [35,51–53]; only one study had an overall low risk of bias [53]. Concerns were also noted regarding exposure measurement (Domain 2 [D2]), particularly when data were obtained from electronic medical records without reporting time-related information [54].

Findings from the GRADE assessment are presented in Table 3 and supporting information (S7 Table). The quality of evidence was downgraded from high to very low for headache, taste disorder, and vertigo (with excess weight as the exposure group) and for anxiety, taste disorder and sleep disturbance (with obesity as exposure group) due to high risk of bias, imprecision of results, and publication bias. For the other outcomes, the quality of evidence was rated as low, having been downgraded from high due to risk of bias and publication bias. Depression and cognitive issues among individuals with obesity and the control group were rated as moderate certainty of evidence, downgraded from high due to publication bias.

10.1371/journal.pone.0314892.t003Overall certainty of the evidence assessment for the association of neurological and neuropsychiatric symptoms of Post-Covid-19 Condition and excess weight.
Certainty assessment № of patients Effect
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Excess weight normal weight Relative(95% CI) Absolute(95% CI) Certainty
Depression (follow-up: range 27 weeks to 52 weeks; assessed with: Scales)
2 non-randomised studies seriousa not serious not seriousa not serious publication bias strongly suspectedb 211/536 (39.4%) 160/541 (29.6%) RR 1.21(1.03 to 1.42) 62 more per 1000(from 9 more to 124 more) ☐☐⃝⃝Lowa,b
Sleep disturbance (follow-up: range 12 weeks to 52 weeks; assessed with: Questionnaire and scales)
6 non-randomised studies seriousa not serious not serious not serious publication bias strongly suspectedb 3861/47449 (8.1%) 1958/31420 (6.2%) RR 1.31(1.16 to 1.48) 19 more per 1000(from 10 more to 30 more) ☐☐⃝⃝Lowa,b
Headache (follow-up: range 12 weeks to 387 weeks; assessed with: Questionnaire and self-reported)
7 non-randomised studies seriousa not serious not serious seriousc publication bias strongly suspectedb 7248 cases 132.751 controls 4475/76399 exposed 2773/56352 unexposed RR 1.15(1.07 to 1.22) 0 fewer per 1000(from 0 fewer to 0 fewer) ☐⃝⃝⃝Very lowa,b,c
Memory issues (follow-up: range 12 weeks to 32 weeks; assessed with: Questionnaire)
3 non-randomised studies seriousa not serious not serious not serious publication bias strongly suspectedb 563/7041 (8.0%) 267/4831 (5.5%) RR 1.43(1.24 to 1.65) 24 more per 1000(from 13 more to 36 more) ☐☐⃝⃝Lowa,b
Numbness (follow-up: range 12 weeks to 32 weeks; assessed with: Questionnaire)
3 non-randomised studies seriousa not serious not serious not serious publication bias strongly suspectedb 1141/47075 (2.4%) 550/30959 (1.8%) RR 1.37(1.24 to 1.51) 7 more per 1000(from 4 more to 9 more) ☐☐⃝⃝Lowa,b
Taste disorder (follow-up: range 12 weeks to 38 weeks; assessed with: Questionnaire and self-reported)
5 non-randomised studies seriousa not serious not serious seriousc publication bias strongly suspectedb 4914/76330 (6.4%) 3445/56307 (6.1%) RR 1.11(1.00 to 1.23) 7 more per 1000(from 0 fewer to 14 more) ☐⃝⃝⃝Very lowa,b,c
Vertigo (follow-up: range 12 weeks to 38 weeks; assessed with: Questionnaire and self-reported)
5 non-randomised studies seriousa not serious not serious seriousc publication bias strongly suspectedb 2795/76348 (3.7%) 1764/56282 (3.1%) RR 1.21(1.04 to 1.41) 7 more per 1000(from 1 more to 13 more) ☐⃝⃝⃝Very lowa,b,c

CI: confidence interval; OR: odds ratio; RR: risk ratio;

a. The risk of bias of included studies is related to the measurement of exposure (self-reported) or the control of confounders, particularly regarding the severity of COVID-19 acute phase;

b. There are less than 10 studies included in the metanalyses therefore we were unable to evaluate publication bias;

c. Metanalyses showed moderate heterogeneity among included studies.

 Discussion

Although it has been suggested that individuals with increased BMI are at higher risk of PCC, the associations between EW and specific PCC related neurological and neuropsychiatric symptoms remained unclear. Our review reveals that EW is significantly associated with a range of persistent and PCC symptoms, including headache, vertigo, smell and taste disorder, sleep disturbance and depression. These findings suggest that EW might contribute to the development of these symptoms that persist for more than 12 weeks after COVID-19 onset. Moreover, this study is opportune as we transition into the post-pandemic period facing the challenges of managing the co-occurrence of pandemics, including overweight/obesity, mental health issues, and the burden of PCC.

Increased BMI has been identified as a determinant of adverse outcomes during both the acute and chronic phases of COVID-19 [18,27,29]. This contrasts with the role of sex in the disease course since the pattern of acute phase symptoms by sex is distinct from that of PCC, which tends to affect more females [20,59]. Additionally, the chronic phase of COVID-19’s has been variously defined, with some studies indicating symptoms lasting for at least 4 weeks [12] and others extending to more than 12 weeks [5,6]. Differentiating these time frames is crucial to distinguish between acute illness and potential sequelae of irreversible tissue damage, which may present with varying degrees of impairment [60]. In our review, we used the cut-off criterion to ensure that we focused on long-term or chronic outcomes of COVID-19. The mean follow-up time from illness onset in the included studies was 25.8 weeks (ranging from 12 to 52 weeks). A large systematic review [2] evaluated the prevalence of persistent symptoms among COVID-19 survivors at different follow-up periods. It identified sleep disorder and concentration difficulties as the most common symptoms at 3–6 months (24%, 95% CI: 8%–44%; 22%, 95% CI: 15%–31%, respectively), with sleep disorder being most prevalent at over 12 months. However, unlike our results, this review had a high degree of between-study heterogeneity and did not include BMI in subgroups analysis.

Long-term neurological symptoms significantly decrease the quality of life for individuals, a situation that might be exacerbated by a pre-exiting comorbidities [61]. Moreover, symptoms related to comorbidities often overlap with those of PCC, leading individuals with obesity to attribute their symptoms to their metabolic disease rather than to persistent manifestations of COVID-19 [62,63]. Additionally, overweight individuals also report health complaints, including headache and sleeplessness, associated to their subclinical disease state also known as suboptimal health status, which can be exacerbated by PCC symptoms [22]. The co-occurrence of these complex conditions can have deleterious effects, impairing people’s daily functioning and increasing the demand on healthcare systems. Our results highlight a significantly positive association for persistent headache, vertigo, numbness and taste disorder in individuals with EW or obesity. These results are consistent with recent study demonstrating that obesity increased the risk for memory disorders and neurological cluster of symptoms (headaches, expectoration, myalgias, fatigue, and taste and smell disorders) among COVID-19 survivors [64]. This underscores the role of excessive body weight (fat deposits) in PCC. It is worth noting that patients with PCC have reported that head pain worsens with physical exercise while a decrease in physical activity coupled with increase in sedentary behaviour are generally known to contribute to weight gain [65,66]. Moreover, taste disorders may influence unhealthy weight-related behaviours, such as consuming more palatable, ultra-processed foods high in salt, sugar, and additives. These foods can further impair gustatory function and exacerbate unhealthy symptoms [67,68]. Vertigo which impairs daily functioning by increasing the risk of falls may also be associated with depression [69,70]. To date, the diagnosis of PCC relies on clinical judgement as no defined biomarkers currently exist to confirm the condition [8]. Furthermore, a widely agreed-upon treatment for PCC has yet to emerge. This highlights gaps in scientific knowledge and the urgent need for government agencies, especially of low and middle-income countries, to develop evidence-based clinical practice guidelines and training programs for health-care workers, especially in primary care services to improve diagnosis and enable more comprehensive patients care [71]. Therefore, healthcare systems and public policies should focus on multidisciplinary rehabilitation services to address the long-term impacts of COVID-19 on survivors, specifically through concomitant personalized management of weight, neurological and neuropsychiatric issues. Cognitive behaviour therapy (CBT) and programs that combine both physical and mental rehabilitation may improve cognitive function and patient recovery and are among as the most effective interventions recently recommended for PCC treatment [72]. Social and occupational support should also be addressed to contribute to compassionate and effective care of patients [71].

The high prevalence of persistent complex concurrent symptoms may create a vicious circle between physical and neuropsychiatric symptoms, increasing the risk for depression [73–78]. A significant positive association between obesity and depressed mood has been observed across multiple COVID-19 periods, similar to findings in other coronavirus outbreaks [11,16,66]. During the COVID-19 pandemic, a systematic review of longitudinal studies identified obesity/overweight as a risk factor for depression (pooled RR = 1.2; 95% CI: 1.11–1.31). However, no significant association was found when obesity/overweight was self-reported (pooled RR = 1.03; 95% CI: 0.99–1.26) [79]. In this study, we observed a significantly positive association for persistent depression with EW. This findings aligns with Aminian et al. [80] who reported that the need for diagnostic test to assess neuropsychiatric problems (a proxy for symptoms) was significantly higher in individuals with increased BMI compared to those with normal weight. Although our pooled RR for EW and depression included data from two studies conducted with Asian populations [35,43] featuring different BMI assessments (measured and self-reported) and BMI cut-offs (excess weight defined as BMI ≥ 23 kg/m2 and obesity as BMI ≥ 25 kg/m2), both studies used a validated depression scale (PHQ-9), and the results were not heterogeneous.

It remains uncertain whether neurological and neuropsychiatric manifestations related to PCC are directly attributable to the virus itself or if they develop indirectly (such as, through an immune response or medical therapy). These symptoms may also involve both the central and peripheral nervous systems [16]. Additionally, the role of EW in the progression of COVID-19 is not fully understood, though it may be linked to an exaggerated inflammatory response or pre-existing genetic factors that these conditions share [81–83]. The adipose tissue plays a role in SARS-CoV-2 entry and deposition, and it may serve as a reservoir for virus spread. The nature of adipocytes and elevated fatty acid levels may enhance virus replication and contribute to delayed viral clearance, which is associated with persistent symptoms [84]. EW is also a recognized risk factor for various chronic conditions and the number of pre-existing comorbidities has been associated to the development of PCC symptoms up to two years after COVID-19 onset, in both hospitalized and non-hospitalized patients [85]. Our results underscore the importance of identifying at-risk individuals and highlight the need for timely personalized interventions for COVID-19 survivors. These findings could inform the development of predictive and preventive management plans for future waves of SARS-CoV-2 or other epidemics.

Our quality assessment results indicate that the included studies suffer from methodological issues, particularly in measuring exposure. Studies that classified individuals’ nutritional status based on self-reported data were found to have a high risk of bias, which contributed to downgrade in the overall quality of evidence for the evaluated symptoms. Self-reported data are subject to recall bias, social desirability bias, and variations in individual interpretation of symptoms, which may affect the accuracy of the findings. Moreover, during the height of the pandemic, online health surveys were often used when other research methods were infeasible [86]. However, this design might not adequately capture exposure and could therefore influence the precision of outcomes. Future research should aim to complement self-reported data with objective clinical assessments to enhance the validity of the results and address these potential biases. Issues could also arise in data from medical records as time-related information was not reported. While a few included studies adopted recommended strategies to reduce bias in survey design, which enhanced the rigor of their findings, controlling confounding variables remained a significant concern. In particular, inadequate control of factors such as the severity of COVID-19 acute-phase, sex, previous existing comorbidities and duration of symptoms was frequently observed. Moreover, significant issues also arise from studies relying on self-reported symptoms without using structured questionnaire or validated scales. Although screening tools have been proposed to identify individuals with PCC they often do not consider neuropsychiatric symptoms [87] or key cognitive symptoms [88] that significantly affect individuals’ quality of life. The increased heterogeneity observed among studies evaluating anxiety, headache, taste disorder and vertigo has led to imprecision in the results. Additionally, the limited number of available studies to be included in the meta-analysis made it impossible to assess publication bias, further contributing to the downgrading of the overall quality of evidence for these outcomes from high to very low. The inability to assess publication bias also reduced the certainty of evidence of all evaluated outcomes and highlight the significant knowledge gap regarding risk factors associated with PCC. Very low and low overall certainty of evidence suggests that the estimated effects may differ substantially from the true effects and highlights the need for caution when drawing conclusions and applying the results to clinical practice. Therefore, future research is urgently needed to investigate the combined effects of these chronic conditions.

It is important to acknowledge certain limitations when interpreting the findings of our research. Most of the included studies were cross-sectional which limits the ability to determine cause and effect relationships. The inconsistency in naming PCC symptoms among studies resulted in a relatively low number of studies reporting the same symptom which also precluded subgroup comparisons between hospitalized and outpatient populations. Moreover, the varying symptoms’ terminologies applied and the use of clusters of symptoms analysis among eligible studies might have led to underestimation of the results. We included studies that used non-validated questionnaires to assess symptoms, as it was necessary given that PCC is an emerging condition and validated screening tools have yet to be developed. Although the cut-off for study inclusion regarding time to follow-up (i.e., > 12 weeks) allowed us to track long-term outcomes from COVID-19 and address a gap in the literature, the follow-up period ranged from 12 to 52 weeks post-infection, the varying risk of PCC symptoms throughout different follow-up periods was not investigated in subgroup analysis due to limited number of studies. The available data did not allow for reliable subgroup analyses based on demographic variables (e.g., age, sex, follow-up period) or COVID-19 severity as well. Additionally, the inclusion of both obesity and non-obesity as comparisons groups led to the interchange of overweight individuals between exposure and control groups. Nevertheless, defining EW and obesity as exposure groups was crucial given the syndemic context. This approach enabled the evaluation of the risk of developing persistent symptoms among different levels of excessive fat and highlighted that both suboptimal health status (overweight) and illness (obesity) predisposed individuals to PCC-related neuro-symptoms. However, the inherent differences among these groups should be considered in health, disease prevention and diagnoses. Furthermore, the issues related to body fat assessment should be noted as BMI remains the most widely used screening tool for measuring adiposity. Although it is a simple and non-invasive measure often related to the gold standard fat assessment BMI does not accounts for age, nor does it for ethnic backgrounds and the types or distribution of adipose tissue [89]. In addition, high visceral fat exhibits more angiotensin-converting enzyme-2 (ACE2) levels than subcutaneous adipose tissue, thereby it is more susceptible to SARS-CoV-2 entry and replication, resulting in higher viral load [84,90]. Thus, future research should focus on longitudinal evaluation of COVID-19 survivors incorporating objective assessment of symptoms and adiposity.

Despite these limitations, our review has several scientific and clinical strengths. Notably, the number of investigated outcomes allowed for a pioneering evaluation of the association of EW with both the physical and psychological long-term manifestations of COVID-19. Additionally, the comprehensive definition of PCC that we applied during our article search (to account for varied terminology), along with the inclusion of each neurological and neuropsychiatric symptom specified in our search strategy, ensured a thorough screening process. We also underscored the importance of addressing EW as a global health concern, given its interplay with neurological and neuropsychiatric manifestations, and infectious diseases such as COVID-19. Moreover, this systematic review contributes to the growing body of literature on post-COVID-19 condition by detailing the range of neurological and neuropsychiatric symptoms experienced by adults with both post-COVID-19 condition and excess weight. By revealing these association, our study underscores the significant physical and mental health burden faced by COVID-19 survivors with excess weight and obesity, offering critical insight to guide rehabilitation efforts. Therefore, the management of EW should be considered in the treatment of neurological and neuropsychiatric symptoms due to the significant impact that these combined conditions have on individuals’ health.

 Conclusions

Our systematic review and meta-analysis demonstrate that EW is significantly associated with post-COVID-19 neurological and neuropsychiatric symptoms, including headache, memory issues, numbness, smell and taste disorders, vertigo, depression, and sleep disturbance. These findings underscore for the importance of developing multidisciplinary rehabilitative strategies tailored to individual needs to improve care management and support the overall health of affected individuals. Our results provide evidence-based guidance for healthcare professionals and policymakers in managing PCC and contribute to ongoing global efforts to understand its underlying mechanisms, epidemiology, and identification.

 Supporting information Database search strategy.

(DOC)

 Description of identified records and reasons for exclusion.

(XLSX)

 Data extracted from included studies (n = 18)<sup>a,b</sup>.

a All data was extracted by DBR and LOM; b Due to the number of columns the table was split in two to enable the presentation of all data extracted; PCR: polymerase chain reaction; NA: Data non-available.

(DOCX)

 Data extracted from included studies for meta-analysis.

PTotal: Total population; POB: Population with obesity; PNOB: Non-obesity population; POW: Population with overweight; PEW: population with excess weight; PEUT: Eutrophic population; NSymptomOB: n of individuals with obesity that reported the symptom; NSymptomNOB: n of non-obesity individuals that reported the symptom; NSymptomOW: n of individuals with overweight that reported the symptom; NSymptomEUT: n of eutrophic individuals that reported the symptom; NSymptomEW: n of individuals with excess weight that reported the symptom; NOSymptomOB: n of individuals with obesity that did not report the symptom; NOSymptomNOB: n of non-obesity individuals that did not report the symptom; NOSymptomOW: n of individuals with overweight that did not report the symptom; NOSymptomEUT: n of eutrophic individuals that did not report the symptom; NOSymptomEW: n of individuals with excess weight that did not report the symptom.

(DOCX)

 Author contact details and requested data<sup>a</sup>. <sup>a</sup>All corresponding authors of included studies were contacted by e-mail by Debora Barbosa Ronca (DBR – <email xlink:type="simple">deboraronca@gmail.com</email>); BMI: body mass index; PCR: polymerase chain reaction.

(DOCX)

 Frequency of neurological and neuropsychiatric symptoms of Post-COVID-19 Condition from included studies that did not test for statistical differences according to nutritional status.

Excess weight group (BMI ≥ 25 kg/m2); NW: Normal Weight group (BMI < 25 kg/m2); Obesity group (BMI ≥ 30 kg/m2); NOb: Non-obesity group (BMI < 30 kg/m2).

(DOCX)

 Assessment of the overall certainty of the evidence for the association of neurological and neuropsychiatric symptoms of PCC between exposure and control groups.

A) Excess weight versus normal weight; B) Obesity versus non-obesity group. CI: confidence interval; OR: odds ratio; RR: risk ratio; a. The risk of bias of included studies is related to the measurement of exposure (self-reported) or the control of confounders, particularly regarding the severity of COVID-19 acute phase; b. There are less than 10 studies included in the metanalyses therefore we were unable to evaluate publication bias;.c. Metanalysis showed substantial heterogeneity among included studies; d. Metanalysis showed moderate heterogeneity among included studies.

(DOCX)

 Forest-plots of the association of excess weight and the risk of neurological and neuropsychiatric symptoms.

(DOCX)

 Forest-plots of obesity and odds ratio (OR) for neuropsychiatric symptoms.

(TIF)

 Traffic light plots of risk of bias of included studies that reported the risk of developing neuro-symptoms, assessed using the Robbins-e tool.

(DOCX)

We would like to thank the researchers who shared information and enabled more precise results in this study. We would also like to acknowledge students and collaborators of the PENSA research group at the University of Brasília and the Centre for Precision Health at Edith Cowan University for their support.

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Nat Commun. 2022;13:5722. doi: 10.1038/s41467-022-33218-8 36175400 10.1371/journal.pone.0314892.r001 Author response to Decision Letter 0 Submission Version 0

17 Nov 2024

 10.1371/journal.pone.0314892.r002 Decision Letter 0 Yon Dong Keon Academic Editor 2025 Dong Keon Yon This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

9 Dec 2024

PONE-D-24-52453Excess weight increases the risk for neurological and neuropsychiatric symptoms in post-COVID-19 condition: A systematic review and meta-analysisPLOS ONE

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An explanation of how missing data were handled.

This information can be included in the main text, supplementary information, or relevant data repository. Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected. 

3. Please include a caption for figure 3.

Additional Editor Comments:

Please address the excellent comments from the reviewers.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This systematic review and meta-analysis studied the association between excess weight and post-acute neuropsychiatric sequelae of COVID-19. Despite conducting a rigorous research study, drawing the cause-and-effect relationship between excess weight and post-acute neuropsychiatric sequelae of COVID-19 is statistically inappropriate due to the inclusion of cross-sectional studies. I also suggest using odds ratios instead of relative risks. Other comments are as follows:

- Page 3 line 61: "Although PCC has no uniform definition in the literature". PCC has a universal definition according to the National Academies of Sciences, Engineering, and Medicine (N Engl J Med. 2024 Nov 7;391(18):1746-1753.)

- Page 9 line 214: "Statistical heterogeneity was assessed using the I2 statistic". How was substantial heterogeneity defined? This will affect your decision on downgrading the certainty of evidence due to the inconsistency of the results.

Reviewer #2: Major Comments

1. Provide a detailed discussion on the clinical applicability of the findings to post-COVID-19 care for patients with excess weight.

2. Justify the exclusion of studies focusing on comorbidities and their potential influence on the outcomes.

3. Elaborate on the impact of high risk of bias and heterogeneity, as highlighted in the ROBINS-E and GRADE assessments.

4. Perform subgroup analyses for demographic variables (e.g., age, sex) and COVID-19 severity to refine interpretations.

5. Address methodological limitations of included studies, particularly regarding exposure measurement and confounder control.

6. Clarify the choice of random-effects models and provide details on the handling of missing data in the meta-analyses.

7. Integrate findings with the broader literature on post-COVID-19 conditions and obesity.

Minor Comments

1. Ensure figure captions are precise and consistent with the content.

2. Clearly define terms such as "suboptimal health condition" with appropriate citations.

3. Streamline data presentation in tables and shift less critical details to supplementary materials.

4. Expand on ethical considerations, particularly for studies relying on self-reported data.

5. Update references to include recent, high-impact studies relevant to the research question.

6. Ensure the funding statement explicitly addresses the minimization of funder influence.

Figures and Data

1. Standardize formatting across all forest plots to enhance clarity and interpretability.

2. Include additional plots (e.g., funnel plots, sensitivity analyses) to assess and mitigate publication bias.

**********

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #2: No

**********

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 10.1371/journal.pone.0314892.r003 Author response to Decision Letter 0 Submission Version 1

17 Feb 2025

On January 28th 2025

1. Please ensure that you refer to Figure 3 in your text as, if accepted, production will need this reference to link the reader to the figure

An appropriate caption has been included for Fig 3 (Lines 308-309). The figure 3 is also referred in the text (line 300).

2. Please provide a numbered table of all those 10125 studies identified in the literature search, including those that were excluded from the analyses

A new file encompassing all studies identified in the literature search, including those excluded from the analyses, has been added to the manuscript as supplementary material (S2 Table). This is also referenced in the main text (see Line 154). We also included this information in our updated cover letter, to highlight our response to the editor’s request after the revised submission. It is worth mentioning that the included file (.xlxs format) has two sheets, named “Databases” and “Citation searching”. The “Databases” sheet encompasses 10,122 records identified from databases and the “Citation searching” sheet encompasses 30 studies identified from citation searching. For all the excluded studies, the reasons for exclusion were described. Moreover, an updated PRISMA flowchart was uploaded as figure 1 due to a minor typing error identified (instead of 10,125 records screened from databases, 10,122 records were screened – as indicated in the abstract (line 38) and results sessions (line 234).

On December 09th 2024:

Journal requirements:

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

Response: The financial disclosure has been included in the updated cover letter as follows: “This research received a grant from the Research Support Program at the School of Health Sciences, Brasília, Brazil, funded by the Health Sciences Teaching and Research Foundation (Grant and Acceptance Term No. 5/2020 – FEPECS/DE) (DBR). This study was also partially financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil – Finance Code 001 (DBR). MS is supported by the Western Australian Future Health Research and Innovation Fund (Grant ID WANMA/Ideas2023-24/10). KMBC is supported by National Council for Scientific and Technological Development CNPq (Grant n. 302740/2022-8). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response: The manuscript has been revised to meet PLOS ONE's style requirements, including file naming conventions. We hope this amended version meets the journal's expectations.

2. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:

- A numbered table of all studies identified in the literature search, including those that were excluded from the analyses.

Response: A new file encompassing all studies identified in the literature search, including those excluded from the analyses, has been added to the manuscript as supplementary material (S2 Table). This is also referenced in the main text (see Line 154). We also included this information in our updated cover letter, to highlight our response to the editor’s request after the revised submission. It is worth mentioning that the included file (.xlxs format) has two sheets, named “Databases” and “Citation searching”. The “Databases” sheet encompasses 10,122 records identified from databases and the “Citation searching” sheet encompasses 30 studies identified from citation searching. For all the excluded studies, the reasons for exclusion were described. Moreover, an updated PRISMA flowchart was uploaded as figure 1 due to a minor typing error identified (instead of 10,125 records screened from databases, 10,122 records were screened – as indicated in the abstract (line 38) and results sessions (line 234).

- For every excluded study, the table should list the reason(s) for exclusion.

Response: A file listing all studies identified in the literature search, along with the reasons for exclusion, has been added to the manuscript (S2 Table and Line 154).

- If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed.

Response: All included studies have been previously published or are available as preprints.

A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study:

- Name of data extractors and date of data extraction;

- Confirmation that the study was eligible to be included in the review;

- All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses.

Response: Supplementary files (S3 Table and S4 Table) containing the data extracted from the included studies, along with the names of data extractors, extraction dates, eligibility confirmation, and all relevant data, have been included with the manuscript (S3 Table, S4 Table, and Line 188).

If data or supporting information were obtained from another source (e.g. correspondence with the author of the original research article), please provide the source of data and dates on which the data/information were obtained by your research group.

Response: A supplementary file (S5 Table) with details on the type and dates of data obtained from another source has been included in the manuscript (S5 Table and Line 189).

If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome. Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome.

Response: The reviewer is right about the importance of presenting the risk of bias and GRADE for each study, including all items of the instruments and for each outcome. We applied the ROBBINS-E tool to assess the risk of bias for the included studies, taking into account both frequency and odds ratio measures of effect. The completed risk of bias assessment is shown in Fig. 6 and S3 Fig. Additionally, we used the GRADE tool to assess the quality/certainty of evidence for all investigated outcomes (symptoms), as presented in Table 3 and S7 Table. It is worth mentioning that Table 3 presents the certainty of evidence for the main outcomes evaluated by GRADE, according to Cochrane recommendations, which emphasize patient-important outcomes (Cochrane Handbook 2012, Section 5.4a).

An explanation of how missing data were handled.

Response: This systematic review included studies that reported the frequency (n, %) of persistent neurological and neuropsychiatric symptoms associated with post-Covid-19 condition (PCC), categorized by nutritional status among COVID-19 survivors. Studies were eligible if they reported data on one or more symptoms of the evaluated outcomes. The meta-analyses were conducted using all available data for each symptom, with separate analyses for each outcome. Corresponding authors were contacted to share data on symptom frequencies by nutritional status (S6 Table). For studies that did not report data for a specific symptom, that study was excluded from the corresponding meta-analysis, ensuring that missing data was not an issue. As such, no imputation of missing data was necessary. Additionally, due to the limited number of studies reporting the same outcome (e.g., anxiety, headache) across exposure/control groups (obesity vs. non-obesity, excess weight vs. normal weight), we were unable to perform the Egger’s test to evaluate publication bias. (Lines 229-230). Finally, considering the differences in symptoms terminology among eligible studies and issues regarding how missing data were handled we included as limitation of our study that this inconsistency in naming PCC symptoms might have led to underestimation of results due to limited data of persistent symptoms according to nutritional status (Lines 513-515).

This information can be included in the main text, supplementary information, or relevant data repository. Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected.

Response: We ensure that we have provided all the underlying data required for publication in this journal.

3. Please include a caption for figure 3.

Answer: An appropriate caption has been included for Fig 3 (Lines 308-309). The figure 3 is also referred in the text (line 300).

Additional Editor Comments:

Please address the excellent comments from the reviewers.

Response: Indeed, the reviewers' comments were excellent, which contributed to the improvement of the manuscript. We are grateful for that.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This systematic review and meta-analysis studied the association between excess weight and post-acute neuropsychiatric sequelae of COVID-19. Despite conducting a rigorous research study, drawing the cause-and-effect relationship between excess weight and post-acute neuropsychiatric sequelae of COVID-19 is statistically inappropriate due to the inclusion of cross-sectional studies. I also suggest using odds ratios instead of relative risks. Other comments are as follows:

Answer: We appreciate the reviewer’s comments. As suggested, odds ratios (ORs) are commonly reported in cross-sectional studies when logistic regression is used to assess the association between risk factors and outcome while controlling for confounders. When the outcome is rare (<10%), the OR and risk ratio (RR) are approximately equal, and the OR can be used to approximate the RR (allowing the OR to serve as an approximation of the RR) (Ref.: Wilber ST & Fu R., 2010). We acknowledge as a limitation of our study that the inclusion of cross-sectional studies limits the ability to establish causal relationships (Lines 509-510). However, our data reveals a significant association between excess weight and persistent neurological and neuropsychiatric symptoms in post-COVID-19 Condition. In response to the reviewer’s suggestion, we have revised the manuscript to replace terms related to “risk” with “is associated with/association” for greater clarity. The title of the manuscript was also updated to avoid misunderstandings. Additionally, to address the concern about statistical appropriateness, we reviewed all pooled analysis involving case-control included studies (Carter SJ, et al., 2022 and Fernandes-De-Las-Penas C, et al. 2021) and recalculated the results as Odds Ratios (ORs) instead of Risk Ratios (RRs). Specifically, pooled ORs were calculated for the following comparisons: obesity versus non-obesity groups for cognitive impairment, headache, memory issues, smell disorder, taste disorder, smell and taste disorder, anxiety, depression and sleep disturbance; and excess weight versus normal weight for headache, smell and taste disorder. We have also updated the Methods section to clarify our approach: “We performed meta-analytic calculations using STATA software (SE/17). Pooled risk ratios (RRs) with their 95% confidence intervals (CIs) were computed from the raw data of included cohort and cross-sectional studies, while pooled odds ratios (OR) were computed for reported symptoms identified in case-control studies” (Lines 217-220).

References:

1. Wilber ST, Fu R. Risk ratios and odds ratios for common events in cross-sectional and cohort studies. Acad Emerg Med. 2010 Jun;17(6):649-51. doi: 10.1111/j.1553-2712.2010.00773.x. PMID: 20624147.

2. Fernández‐de‐las‐Peñas C, Torres‐Macho J, Elvira‐Martínez CM, Molina‐Trigueros LJ, Sebastián‐Viana T, Hernández‐Barrera V. Obesity is associated with a greater number of long‐term post‐COVID symptoms and poor sleep quality: A multicentre case‐control study. Int J Clin Pract 2021; 75: e14917.

3. Carter SJ, Baranauskas MN, Raglin JS, Pescosolido BA, Perry BL. Functional Status, Mood State, and Physical Activity Among Women With Post-Acute COVID-19 Syndrome. Int J Public Health 2022; 67: 1604589.

- Page 3 line 61: "Although PCC has no uniform definition in the literature". PCC has a universal definition according to the National Academies of Sciences, Engineering, and Medicine (N Engl J Med. 2024 Nov 7;391(18):1746-1753.)

Response: We appreciate the reviewer’s comment. While a universal definition of PCC was proposed by the National Academies of Sciences, Engineering, and Medicine in November 2024, various broad and non-specific definitions were used in the literature to capture the diverse manifestations of PCC. For instance, the Centers for Disease Control and Prevention (CDC) defined as any signs, symptoms, or conditions persisting for at least four weeks after infection, whereas the World Health Organization (WHO) defined it as the continuation or development of new, otherwise unexplained symptoms three months after the initial SARS-CoV-2 infection. All included studies followed different criteria and definitions of PCC, as the universal definition by the National Academies of Sciences, Engineering, and Medicine was published only in November 2024. Thus, we updated our manuscript and included this important reference in our introduction sections. Moreover, considering the available references during the time of our study and the proposed universal definition, we changed the phrase “Although PCC has no uniform definition in the literature” to “Although PCC has varying definition in the literature” (line 61) and also included information regarding varying terminologies in lines 103-107.

References:

WHO. A clinical case definition of post-COVID-19 condition by a Delphi consensus - The Lancet Infectious Diseases, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00703-9/fulltext (accessed 15 October 2023).

- Page 9 line 214: "Statistical heterogeneity was assessed using the I2 statistic". How was substantial heterogeneity defined? This will affect your decision on downgrading the certainty of evidence due to the inconsistency of the results.

Response: We defined substantial heterogeneity based on the thresholds recommended by Cochrane: 0%-40% (no important heterogeneity), 30%-60% (moderate heterogeneity), 50%-90% (substantial heterogeneity), and 75-100% (considerable heterogeneity). This information was included in the Methods section of the revised manuscript (Line 225-228). To determine the degree of heterogeneity, we considered the I2 value, visual inspection of forest plot, the confidence interval, the direction of the effects, and the clinical and methodological differences among the included studies.

References:

Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane Handbook for Systematic Reviews of Interventions, https://training.cochrane.org/handbook/current (accessed 12 June 2024).

Reviewer #2: Major Comments

1. Provide a detailed discussion on the clinical applicability of the findings to post-COVID-19 care for patients with excess weight.

Response: We have expanded the Discussion section of the manuscript to include a detailed analysis of the clinical applicability

Submitted filename: Response to Reviewers.docx

 10.1371/journal.pone.0314892.r004 Decision Letter 1 Yon Dong Keon Academic Editor 2025 Dong Keon Yon This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

12 Mar 2025

PONE-D-24-52453R1Excess weight is associated with neurological and neuropsychiatric symptoms in post-COVID-19 condition: A systematic review and meta-analysisPLOS ONE

Dear Dr. Ronca,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 26 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Kind regards,

Dong Keon Yon, MD, FACAAI, FAAAAI

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Please see my minor comments

#1. Studies published up to July 2023 were searched independently across eight electronic databases (PubMed ..... Please describe it) to evaluate the risk of developing...

#2. post-COVID infection -> post-COVID-19 condition or SARS-CoV-2 infection

#3. I am simply curious—what is the reason for the omission of this particular paper?

https://pubmed.ncbi.nlm.nih.gov/38918517/

#4. Please describe GRADE system in method section in more dtail.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

**********

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 10.1371/journal.pone.0314892.r005 Author response to Decision Letter 1 Submission Version 2

21 Mar 2025

Journal requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: We carefully reviewed our reference list and made the necessary corrections. We identified five studies with published errata and/or corrections. In all cases, the authors confirmed that these were minor errors that did not affect the studies’ findings or conclusions. These studies were published in prestigious scientific journals (The New England Journal of Medicine, Nature Reviews Microbiology, The Lancet and PLOS ONE, General Hospital Psychiatry). Accordingly, we updated our reference list to reflect this information, as detailed below. Both the original and updated reference lists have been included in the cover letter, with the corrected references highlighted. We confirm that we did not cite any retracted papers.

References updated:

1) Blumenthal D et al., 2020.

Original: Blumenthal D, Fowler EJ, Abrams M, Collins SR. Covid-19 — Implications for the Health Care System. N Engl J Med 2020; 383: 1483–1488.

Updated: Blumenthal D, Fowler EJ, Abrams M, Collins SR. Covid-19 — Implications for the Health Care System. [published correction appears in N Engl J Med. 2020 Oct 22;383(17):1698. N Engl J Med 2020; 383: 1483–1488.

2) Davis HE et al., 2023

Original: Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023; 21: 133–146.

Correction reference included: Davis HE, McCorkell L, Vogel JM, Topol EJ. Author Correction: Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023; 21: 408–408.

3) Swinburn BA, et al., 2019

Original: Swinburn BA, Kraak VI, Allender S, Atkins VJ, Baker PI, Bogard JR, et al. The Global Syndemic of Obesity, Undernutrition, and Climate Change: The Lancet Commission report. Lancet Lond Engl. 2019 393(10173):791–846. DOI: 10.1016/S0140-6736(18)32822-8.

Errata reference included: Errata in: Department of Error. Lancet Lond Engl. 2019 393(10173):746. DOI: 10.1016/S0140-6736(19)30384-8.

4) Hassan NM, et al., 2023

Original: Hassan NM, Salim HS, Amaran S, Yunus NI, Yusof NA, Daud N, et al. Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis. PLOS ONE. 2023 18(5):e0282538. DOI: 10.1371/journal.pone.0282538.

Correction reference included: PLOS ONE Staff. Correction: Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis. PLoS One. 2023 Dec 14;18(12):e0296160. doi: 10.1371/journal.pone.0296160. Erratum for: PLoS One. 2023 May 17;18(5):e0282538. doi: 10.1371/journal.pone.0282538. PMID: 38096220; PMCID: PMC10721052.

5) van der Feltz-Cornelis C, et al., 2024.

Original: van der Feltz-Cornelis C, Turk F, Sweetman J, Khunti K, Gabbay M, Shepherd J, et al. Prevalence of mental health conditions and brain fog in people with long COVID: A systematic review and meta-analysis. Gen Hosp Psychiatry. 2024 88:10–22. DOI: 10.1016/j.genhosppsych.2024.02.009.

Correction reference included: van der Feltz-Cornelis CM, Turk F, Sweetman J, Khunti K, Gabbay M, Shepherd J, et al. Corrigendum to ‘Prevalence of mental health conditions and brain fog in people with long COVID: A systematic review and meta-analysis’ [General Hospital Psychiatry volume 88 (2024)10-22 10.1016/j.genhosppsych.2024.02.009]. Gen Hosp Psychiatry. 2025 92:112. DOI: 10.1016/j.genhosppsych.2024.09.006.

Additional Editor Comments:

Please see my minor comments

#1. Studies published up to July 2023 were searched independently across eight electronic databases (PubMed ..... Please describe it) to evaluate the risk of developing...

Response: This sentence was included in the original version of the manuscript but was updated in the revised version. It was replaced with the following: “We conducted a comprehensive search of eight databases, including PubMed and Embase, for studies published up to July 2023.” To meet the editor’s requirements, we explicitly listed the eight databases in the abstract (lines 32–34): “We conducted a comprehensive search of eight databases (PubMed, Embase, SCOPUS, Web of Science, VHL, Google Scholar, ProQuest, and medRxiv) for studies published up to July 2023.” The discrepancy may have occurred because both the original and revised manuscripts were included in the revised submission, and we did not withdraw the original version. We apologize for any confusion and appreciate the opportunity to clarify. We hope that the updated sentence aligns with the editor’s comments.

#2. post-COVID infection -> post-COVID-19 condition or SARS-CoV-2 infection

Response: We change the sentence accordingly (line 73).

#3. I am simply curious—what is the reason for the omission of this particular paper?

https://pubmed.ncbi.nlm.nih.gov/38918517/

Response: Although this well-designed study aimed to explore the risk of neuropsychiatric complications following a COVID-19 diagnosis using nationally representative data (South Korean and Japanese populations), it did not meet the established eligibility criteria of our systematic review. The study analysed clusters of neuropsychiatric events according to nutritional status (Body Mass Index – BMI) rather than assessing specific symptoms individually, as required by our criteria (Supplementary Information, Tables S7 and S27). For instance, Tables S7 and S27 presented a stratified analysis of the long-term risk of neuropsychiatric events by BMI but did not report the risk for each of the 13 evaluated categories separately. To meet our eligibility criteria, the study would have needed to provide data for each category stratified by BMI, similar to the subgroup analyses in Tables S9 and S10, which assessed long-term hazard ratios (HR) for neuropsychiatric disorders according to COVID-19 severity and vaccination status. Due to variations in the symptom clusters analysed across studies, we excluded studies that examined clusters of symptoms according to nutritional status. Furthermore, the title/abstract of the study “Short- and long-term neuropsychiatric outcomes in long COVID in South Korea and Japan” did not mention “excess weight,” “overweight,” “obesity,” or “body mass index.” These terms represented Exposure in our predefined PECO framework and were included in our search strategy. Their absence from the title/abstract prevented the identification and retrieval of the study through our search. The exclusion criteria of our systematic review are detailed in the Methods section (lines 137–146), and the search strategy is outlined in the Methods section (lines 121–127) and Supporting Information (S1).

#4. Please describe GRADE system in method section in more detail.

Response: We appreciate the editor’s comments and have updated the Methods section of our study to provide a more detailed description of the GRADE system (lines 200-215).

Submitted filename: Response_to_Reviewers_auresp_2.docx

 10.1371/journal.pone.0314892.r006 Decision Letter 2 Yon Dong Keon Academic Editor 2025 Dong Keon Yon This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 2

24 Mar 2025

Excess weight is associated with neurological and neuropsychiatric symptoms in post-COVID-19 condition: A systematic review and meta-analysis

PONE-D-24-52453R2

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Additional Editor Comments (optional):

This is an excellent paper.

Reviewers' comments:

 10.1371/journal.pone.0314892.r007 Acceptance letter Yon Dong Keon Academic Editor 2025 Dong Keon Yon This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PONE-D-24-52453R2

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