COVID

Research

16 pages, 1734 KB

Open AccessArticle

Expression of IFN-γ, TNF-α and Interleukins in the Nasopharyngeal Cells and Mononuclear Cells of Mexican Patients with Influenza or SARS-CoV-2

by María F. González-Delgado, Alberto González-Zamora, José J. Alba-Romero, Edgar H. Olivas-Calderón and Rebeca Pérez-Morales

COVID 2026, 6(3), 38; https://doi.org/10.3390/covid6030038 - 28 Feb 2026

Viewed by 1050

Abstract

Respiratory viral infections such as influenza and SARS-CoV-2 induce complex immune responses characterized by dysregulated cytokine production, which may influence disease severity and lead to post-infection immunometabolic alterations. However, comparative data on local epithelial and systemic immune responses during acute infection and recovery [...] Read more.

Respiratory viral infections such as influenza and SARS-CoV-2 induce complex immune responses characterized by dysregulated cytokine production, which may influence disease severity and lead to post-infection immunometabolic alterations. However, comparative data on local epithelial and systemic immune responses during acute infection and recovery remain limited. Objective: To evaluate the expression of IFN-γ, TNF-α, and interleukins IL-2, IL-4, IL-6, and IL-10 in nasopharyngeal epithelial cells from patients with influenza and SARS-CoV-2 infection, as well as in peripheral blood mononuclear cells (PBMCs) from individuals who recovered from COVID-19. Methods: A total of 120 participants were distributed into four groups (control, influenza, asymptomatic SARS-CoV-2 infection, and symptomatic COVID-19; n = 30 per group), in addition to 90 individuals who had recovered from COVID-19. COVID-19 and influenza diagnoses were established by the treating physician based on clinical presentation and confirmed by RT–qPCR. Cytokine gene expression was quantified by real-time PCR, and hematological and biochemical parameters were measured using automated analyzers. Results: The asymptomatic SARS-CoV-2 group showed significantly increased expression of IFN-γ (p = 0.0001), TNF-α (p = 0.0007), and IL-4 (p = 0.01). Individuals who recovered from COVID-19 exhibited elevated erythrocyte and leukocyte counts, along with increased glucose, glycated hemoglobin, triglycerides, and very-low-density lipoprotein levels, while no significant alterations in liver function markers were observed. Conclusions:Influenza and SARS-CoV-2 infections are associated with distinct epithelial cytokine expression profiles during acute infection, and COVID-19 recovery is characterized by persistent immunometabolic alterations, suggesting prolonged systemic effects beyond viral clearance. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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9 pages, 290 KB

Open AccessArticle

Developing a Long COVID Case Definition: Using Machine Learning to Distinguish Long COVID Based on Symptom Presentation

by Leonard A. Jason, Jacob Furst, Lauren Ruesink and Ben Z. Katz

COVID 2025, 5(12), 205; https://doi.org/10.3390/covid5120205 - 14 Dec 2025

Cited by 1 | Viewed by 1176

Abstract

Efforts have been made to develop a case definition for Long COVID, with results differing on whether the case definition should be specific and exclusive, or broad and easily generalizable. Each of these methods has been subject to limitations. As most efforts have [...] Read more.

Efforts have been made to develop a case definition for Long COVID, with results differing on whether the case definition should be specific and exclusive, or broad and easily generalizable. Each of these methods has been subject to limitations. As most efforts have focused on symptoms, inclusion criteria have often relied on the binary occurrence of a symptom. The current study uses a more detailed measure that considers the frequency and severity of symptoms in a sample of individuals with Long COVID and matched controls who recovered from acute SARS-CoV-2 infection. Patients were diagnosed with Long COVID in a systematic process involving their completion of quantitative questionnaires, qualitative interviews, a physical examination, and general laboratory testing to rule out other diagnoses. Since samples were comparatively small given the number of symptoms investigated, Leave One Out Cross-Validation (LOOCV) was used to develop LASSO regression models to determine which symptoms best distinguished Long COVID from recovered controls. An ideal threshold for classifying Long COVID based on symptomatology was developed using a receiver operator characteristics (ROC) curve. The model presented in this article identified Long COVID with high accuracy. The importance of smell/taste was lessened in the current study, and gastrointestinal symptoms took on greater prominence in our study. It is possible to achieve high accuracy in differentiating those with Long COVID from those who have recovered. It is important to specify criteria of Long COVID and to measure symptoms comprehensively to identify those with Long COVID. Reliably identifying those who have developed Long COVID will help in the formulation of treatment strategies. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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11 pages, 783 KB

Open AccessArticle

Factors Associated with the Presence of Post-COVID Syndrome in Older Patients with Arterial Hypertension

by Venera Kudabaeva, Timur Tastaibek, Almagul Mansharipova, Arystan Seidalin and Nargiza Nassyrova

COVID 2025, 5(12), 197; https://doi.org/10.3390/covid5120197 - 28 Nov 2025

Viewed by 836

Abstract

Background: Diagnosing post-COVID syndrome (PCS) in older adults with hypertension is difficult due to heterogeneity and multimorbidity. We aimed to identify factors associated with PCS. Methods: An observational study was conducted from June 2024 to April 2025. Patients aged 60–89 years with arterial [...] Read more.

Background: Diagnosing post-COVID syndrome (PCS) in older adults with hypertension is difficult due to heterogeneity and multimorbidity. We aimed to identify factors associated with PCS. Methods: An observational study was conducted from June 2024 to April 2025. Patients aged 60–89 years with arterial hypertension were enrolled; PCS was verified according to the national protocol. Between-group comparisons used standard tests. Multivariable logistic regression with pre-specified clinical predictors estimated independent associations. Results: A total of 291 patients with arterial hypertension were included in the study. Patients were grouped by PCS status (PCS = 101; controls = 190). In multivariable analysis, female sex (OR 3.64; 95% CI 1.22–10.82), younger age (OR 0.93; 95% CI 0.89–0.98), lower systolic blood pressure (SBP) (OR 0.98; 95% CI 0.96–1.00), and rhythm disturbances (OR 2.63; 95% CI 1.07–6.49) were associated with PCS; other predictors were not significant. Model discrimination was moderate (AUC 0.728; 95% CI 0.668–0.787; Brier score 0.193) with positive net benefit across thresholds ~0.10–0.65. Conclusions: In older hypertensive adults, female sex, younger age, lower SBP, and rhythm disturbances indicate higher PCS likelihood, supporting risk-stratified monitoring and management. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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15 pages, 685 KB

Open AccessArticle

Post-Traumatic Stress Disorder, Anxiety, and Depression in Post-COVID-19 Patients Undergoing Psychotherapy: A Nonrandomized Clinical Trial

by Marilúcia M. Carrijo, Miriã C. Oliveira, Washington A. O. Canedo, João Pedro R. Afonso, Heren N. C. Paixão, Larissa R. Alves, Renata K. Palma, Iranse Oliveira-Silva, Carlos H. M. Silva, Rodrigo F. Oliveira, Deise A. A. P. Oliveira, Rodrigo A. C. Andraus, Rodolfo P. Vieira, Gianluca Castelnuovo, Paolo Capodaglio and Luís V. F. Oliveira

COVID 2025, 5(11), 184; https://doi.org/10.3390/covid5110184 - 25 Oct 2025

Viewed by 1818

Abstract

Global estimates show a 17.9% prevalence of neuropsychiatric disorders in individuals recently hospitalized with COVID-19. Cognitive behavioral therapy (CBT) has been proposed as a nonpharmacological strategy to mitigate these effects. This study examined the potential effects of CBT on anxiety, depression, post-traumatic stress [...] Read more.

Global estimates show a 17.9% prevalence of neuropsychiatric disorders in individuals recently hospitalized with COVID-19. Cognitive behavioral therapy (CBT) has been proposed as a nonpharmacological strategy to mitigate these effects. This study examined the potential effects of CBT on anxiety, depression, post-traumatic stress disorder (PTSD), and quality of life (QoL) in post-COVID-19 patients. This prospective, nonrandomized, single-center clinical trial involved 15 patients (mean age 53.4 years) who underwent weekly CBT sessions for six weeks. Between-group differences in anxiety and depression scores were non-significant (p > 0.05); however, significant intragroup improvements were observed in anxiety (p = 0.01), depression (p = 0.01), and PTSD (p = 0.01) after the intervention. Thus, CBT was associated with reduced anxiety, depression, and PTSD as well as improved quality of life in post-COVID-19 patients. Improvements in QoL were noted mainly in the domains of functional capacity, vitality, emotional aspects, and mental health. While these findings suggest that CBT may be beneficial for post-COVID-19 patients, the small sample size, absence of a control group, and short follow-up period limit the strength of our conclusions. Therefore, the results should be considered preliminary, and further randomized controlled trials with larger sample sizes are warranted. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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15 pages, 552 KB

Open AccessArticle

Persistence of Cognitive Difficulties in Adults Three Years After COVID-19 Infection

by Antonio de Pádua Serafim, Victor Linking Magalhães Campos, Fabiana Saffi, Cristiana Castanho de Almeida Rocca and Ricardo Silva dos Santos Durães

COVID 2025, 5(9), 153; https://doi.org/10.3390/covid5090153 - 11 Sep 2025

Viewed by 9517

Abstract

The COVID-19 pandemic has left millions worldwide with persistent cognitive difficulties, making long-term studies essential to understand their trajectory and inform rehabilitation strategies. This research is presented within the context of Long COVID, emphasizing that cognitive symptoms (including deficits in attention, memory, and [...] Read more.

The COVID-19 pandemic has left millions worldwide with persistent cognitive difficulties, making long-term studies essential to understand their trajectory and inform rehabilitation strategies. This research is presented within the context of Long COVID, emphasizing that cognitive symptoms (including deficits in attention, memory, and executive functions) are reported even in non-hospitalized individuals, yet longitudinal evidence beyond two years remains scarce. An observational, cross-sectional, and retrospective design was applied to a sample of 297 adults with their cognition assessed, divided into mild, moderate, and severe COVID-19 groups, and evaluated using standardized cognitive tests. Findings showed that cognitive performance declined with increasing severity of COVID-19 symptoms, particularly in divided attention, working memory, executive control, verbal fluency, recognition memory, and general intelligence. Age consistently predicted lower scores across cognitive domains, especially in moderate and severe groups, whereas education level did not exert a significant protective effect. The study shows that cognitive deficits can persist at least three years after infection, affecting older adults and those with the more severe symptoms. These results highlight the need for long-term neuropsychological monitoring and individualized rehabilitation strategies to mitigate impacts on autonomy and quality of life. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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Review

Jump to: Research, Other

23 pages, 1230 KB

Open AccessReview

Spatial Memory and COVID-19: Cognitive Patterns, Assessment Approaches, and Neural Substrates

by Tania Llana, Sara Garces-Arilla and Marta Mendez

COVID 2026, 6(4), 60; https://doi.org/10.3390/covid6040060 - 28 Mar 2026

Viewed by 366

Abstract

COVID-19 is increasingly recognized as a multisystemic disease with significant neurocognitive consequences. However, its specific impact on spatial memory, a cognitive domain essential for daily navigation and functional independence, remains insufficiently explored. This narrative review provides a critical synthesis of current evidence regarding [...] Read more.

COVID-19 is increasingly recognized as a multisystemic disease with significant neurocognitive consequences. However, its specific impact on spatial memory, a cognitive domain essential for daily navigation and functional independence, remains insufficiently explored. This narrative review provides a critical synthesis of current evidence regarding spatial and visuospatial memory alterations across acute and post-acute phases, and post COVID-19 condition (PCC). Clinical findings, conventional and emerging assessment tools ranging from static tasks to immersive virtual reality environments, as well as potential neurobiological mechanisms, were considered. Results suggested that spatial memory is frequently compromised after COVID-19 disease, with deficits being most pronounced at longer retention intervals and within navigational contexts. Neuroimaging and biomarker data further reveal selective vulnerability in the medial temporal lobe, characterized by hippocampal atrophy, hypoperfusion, and disrupted functional connectivity. Importantly, traditional neuropsychological tools may underestimate these impairments due to limited ecological validity. Therefore, implementing multimodal assessment frameworks that integrate navigational paradigms is essential to enhance diagnostic sensitivity and facilitate the development of targeted rehabilitation strategies for PCC patients. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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21 pages, 2189 KB

Open AccessReview

Persistent Viral Reservoirs in Post-COVID Patients: Current Evidence and Clinical Implications

by Hae-Jin Park, Jung Min Cho, Eun-Mi Ahn and Jaehoon Bae

COVID 2026, 6(3), 54; https://doi.org/10.3390/covid6030054 - 19 Mar 2026

Viewed by 2215

Abstract

The COVID-19 pandemic has led to an unprecedented global health crisis, with millions recovering from acute infection but experiencing lingering symptoms, collectively referred to as post-acute sequelae of COVID-19 (PASC), or “long COVID.” While the precise mechanisms underlying long COVID remain elusive, one [...] Read more.

The COVID-19 pandemic has led to an unprecedented global health crisis, with millions recovering from acute infection but experiencing lingering symptoms, collectively referred to as post-acute sequelae of COVID-19 (PASC), or “long COVID.” While the precise mechanisms underlying long COVID remain elusive, one hypothesis gaining traction is the persistence of viral reservoirs in various tissues. Despite evidence of viral RNA and proteins detected in post-acute patients, the concept of viral reservoirs in the context of long COVID remains a subject of debate. This review explores the current scientific evidence for the existence of persistent SARS-CoV-2 in human tissues beyond the acute infection phase, focusing on the molecular mechanisms by which the virus may evade immune surveillance. We examine the role of immune dysregulation, chronic inflammation, and viral persistence in tissues such as the lungs, heart, brain, and gut. Additionally, we explore how these persistent viral elements may be associated with ongoing symptoms in long COVID and discuss the biological plausibility of these links. Finally, we discuss the clinical implications of viral persistence in post-COVID care, potential therapeutic strategies, and the need for further research to resolve the open questions surrounding this phenomenon. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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Graphical abstract

33 pages, 558 KB

Open AccessReview

Overview and Pathophysiology of Long COVID

by Elisa Perego

COVID 2026, 6(3), 53; https://doi.org/10.3390/covid6030053 - 18 Mar 2026

Viewed by 4399

Abstract

Long COVID is the disease entity triggered and potentially driven by SARS-CoV-2 infection. It is an heterogeneous condition characterized by dozens of different symptoms, signs and sequelae, which can affect all organs and body systems and evolve over the disease course. Clinical manifestations [...] Read more.

Long COVID is the disease entity triggered and potentially driven by SARS-CoV-2 infection. It is an heterogeneous condition characterized by dozens of different symptoms, signs and sequelae, which can affect all organs and body systems and evolve over the disease course. Clinical manifestations of Long COVID can vary from individual to individual and across the broader patient population. Pathology can range from asymptomatic and subclinical manifestations to fatal outcomes. Over 400 million people worldwide are estimated to suffer, or have suffered, from Long COVID, making the sequelae of SARS-CoV-2 infection one of the greatest public health challenges of the 21st century. This article provides an updated overview of epidemiology, definitions, main concepts and terminology for Long COVID. It also summarizes key evidence of pathology and disease mechanisms in major organs and body systems, such as the immune system, cardiovascular system, endothelium, heart, lungs, central nervous system, peripheral nervous system, gastrointestinal system, hapatobiliary system, pancreas and kidney. Heterogeneity in manifestations, potential risk of death and the degree of disability in several disease subsets call for timely diagnosis of each Long COVID types and a fuller understanding of their pathophysiological underpinnings. Further research is recommended to better understand pathobiology, develop effective clinical trials, and identify treatments and scalable biomarkers. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

22 pages, 361 KB

Open AccessReview

A Case Definition of a New Disease: A Review of the US Working Definition (USG) and 2024 NASEM Definition for Long COVID

by Elisa Perego

COVID 2025, 5(8), 135; https://doi.org/10.3390/covid5080135 - 15 Aug 2025

Cited by 2 | Viewed by 4629

Abstract

SARS-CoV-2 infection can be followed by prolonged symptoms, signs and sequelae, collectively known under the term Long COVID. Hundreds of millions are estimated to suffer from Long COVID. Long COVID, therefore, is a public health crisis that deserves the utmost urgency from all [...] Read more.

SARS-CoV-2 infection can be followed by prolonged symptoms, signs and sequelae, collectively known under the term Long COVID. Hundreds of millions are estimated to suffer from Long COVID. Long COVID, therefore, is a public health crisis that deserves the utmost urgency from all relevant stakeholders, from policymakers to advocacy groups, researchers and healthcare providers. The development of effective definitions and guidelines for Long COVID is crucial to support patients and carers. In this review, I address the following two case definitions of Long COVID developed in the US as a case study for a broader discussion on the sequelae of SARS-CoV-2 infection: the U.S. Government (USG) working definition for Long COVID and the NASEM definition published in 2024. In the first part of this review, I provide a critical appraisal of the USG in light of research, pathophysiology and lived experience, building upon my intervention as a patient expert on a National Academies of Sciences, Engineering, and Medicine (NASEM) panel for defining Long COVID, which examined the USG. In the second part, I raise some pressing concerns to address when approaching Long COVID as a disease entity and as a concept, which I originally submitted to NASEM. In the third part, I offer a critical appraisal of the NASEM definition, the most recent benchmark for Long COVID in the US. The review highlights the importance of broad, expansive and inclusive definitions for Long COVID, accounting for the disease’s heterogeneous, fluctuating and multi-system manifestations. Clinical case definitions for Long COVID must retain their focus on the broader spectrum and scope of the disease entity, while incorporating feedback from people with lived experience, advocates and patient-researchers. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

Other

Jump to: Research, Review

10 pages, 444 KB

Open AccessSystematic Review

A Scoping Review of Long COVID and Menopause

by Gabrielle Humphreys, Ethan Berry, Lawrence D. Hayes, Sam Jensen, Roisin Moodley and Nilihan E. M. Sanal-Hayes

COVID 2026, 6(1), 7; https://doi.org/10.3390/covid6010007 - 24 Dec 2025

Viewed by 1242

Abstract

Background: According to the National Institute for Health and Care Excellence (NICE), long COVID refers to symptoms persisting for four weeks or more after acute infection, with over 100 identified, including fatigue, cognitive dysfunction, and breathlessness. Women aged 45–54 are disproportionately affected, overlapping [...] Read more.

Background: According to the National Institute for Health and Care Excellence (NICE), long COVID refers to symptoms persisting for four weeks or more after acute infection, with over 100 identified, including fatigue, cognitive dysfunction, and breathlessness. Women aged 45–54 are disproportionately affected, overlapping with the typical age for perimenopause and menopause. This scoping review aimed to provide an overview of existing research on the intersection between long COVID and the menopausal transition. Methods: Five database (CINAHL ultimate, MEDLINE, ScienceDirect, Cochrane, and Scopus) searches yielded 387 articles; after removing 40 duplicates and screening 347 titles and abstracts, fourteen studies were reviewed in full, with seven meeting the inclusion criteria (examined both long COVID and menopause in their scope and are written in English language). Results: This scoping review identified a significant symptomatic overlap between long COVID and menopause reported by participants, particularly fatigue, cognitive difficulties, mood changes, and sleep disturbances. Preliminary evidence also suggests that hormonal fluctuations may influence symptom severity, though biological mechanisms remain insufficiently understood. Methodological limitations restrict generalisability, underscoring the need for longitudinal symptom tracking, diverse samples, and biomarker-informed studies. Recognising the intersection of long COVID and menopausal transition is essential for improving assessment, management, and targeted care for affected women. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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7 pages, 198 KB

Open AccessBrief Report

Neurodivergence as a Risk Factor for Post-COVID-19 Syndrome

by Rachael K. Raw, Jon Rees, Amy Pearson and David R. Chadwick

COVID 2026, 6(1), 1; https://doi.org/10.3390/covid6010001 - 19 Dec 2025

Viewed by 1145

Abstract

Objectives: Neurodivergent (ND) individuals (e.g., autistic people) are more likely to experience health problems that are characterised by ‘Central Sensitisation’ (CS). Recent research suggests that a so-called ‘Long-COVID’ syndrome might also be explained by a heightened response to internal physiological stimuli, much like [...] Read more.

Objectives: Neurodivergent (ND) individuals (e.g., autistic people) are more likely to experience health problems that are characterised by ‘Central Sensitisation’ (CS). Recent research suggests that a so-called ‘Long-COVID’ syndrome might also be explained by a heightened response to internal physiological stimuli, much like in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The primary objective of this study was to establish whether individuals who scored highly on a measure of CS would be more likely to experience long-term symptoms of COVID-19. A secondary aim considered if having a Type D personality was also linked to ongoing COVID-19 symptoms. Method: Using a standardised assessment tool, we examined whether traits associated with autism would predict long-term COVID-19 symptoms in 267 Healthcare Workers (HCWs). We also used a measure of Type D personality to establish if negative affect and social inhibition were related to Long-COVID. Results: A higher number of autistic traits predicted COVID-19 symptoms that lasted more than 12 weeks regardless of formal autism diagnosis. A personality measure also showed that negative affect was associated with experiencing COVID-19 symptoms for 4–12 weeks, though the direction of causality in this case is uncertain. Conclusions: Our main findings were (i) more HCWs scored above threshold for neurodivergence than those who were self-declared as having been diagnosed as neurodivergent; (ii) while there was no association between long-term COVID-19 and self-declared neurodivergent status, scores for the ‘sensory reactivity’ item of a standardised autism scale was predictive of COVID-19 symptoms lasting beyond 12 weeks post-infection; and (iii) HCWs with Type D Personality were not more likely to experience long-term COVID-19. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

10 pages, 677 KB

Open AccessSystematic Review

Does Low-Dose Oral Naltrexone Alleviate Symptoms of Long COVID? A Systematic Review and Meta-Analysis

by Aung Du and Andrew Dang Khai Nguyen

COVID 2025, 5(12), 198; https://doi.org/10.3390/covid5120198 - 29 Nov 2025

Viewed by 4340

Abstract

Long COVID, a condition marked by persistent symptoms following COVID-19 infection, poses significant challenges in regard to clinical management. While emerging pharmacological treatments have demonstrated limited benefits in isolated studies, clinical experience and the literature suggest that low-dose naltrexone (LDN) may be a [...] Read more.

Long COVID, a condition marked by persistent symptoms following COVID-19 infection, poses significant challenges in regard to clinical management. While emerging pharmacological treatments have demonstrated limited benefits in isolated studies, clinical experience and the literature suggest that low-dose naltrexone (LDN) may be a promising therapeutic option. Therefore, in this systematic review, we aim to synthesise findings from the available literature and evaluate the overall safety and efficacy of LDN as a potential treatment for long COVID. A literature search was conducted using a combination of key terms—‘COVID’, ‘COVID-19’, ‘SARS-COV-2’, and ‘Naltrexone’— and the following databases: MEDLINE, Web of Science (Clavirate), Embase, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Cumulative Index in Nursing and Allied Health Literature (CINAHL). The methodology is available on the PROSPERO database (CRD42025630362). Screening identified five eligible articles. Four studies were included, but only two provided comparable data suitable for meta-analysis. Meta-analysis demonstrated statistically significant improvements in fatigue, brain fog, and headaches. Preliminary evidence suggests LDN has potential benefits in the treatment of long COVID, particularly with respect to fatigue, brain fog, and headaches, but more robust studies, such as randomised controlled trials, are urgently needed to confirm LDN’s safety and efficacy. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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11 pages, 222 KB

Open AccessStudy Protocol

Therapeutic Potential of Repetitive Transcranial Magnetic Stimulation (TMS) in Long COVID: A Systematic Review and Meta-Analysis Protocol

by Nilihan E. M. Sanal-Hayes, Kate Slade, Marie Mclaughlin, Ethan Berry, Emma Swift and Lawrence D. Hayes

COVID 2025, 5(12), 196; https://doi.org/10.3390/covid5120196 - 27 Nov 2025

Viewed by 1949

Abstract

The cumulative global incidence of long COVID is around 400 million individuals, yet effective treatment options remain limited. A recent systematic review published in 2025 highlighted promising results for non-invasive brain stimulation in alleviating long COVID symptoms. Given the growing use of repetitive [...] Read more.

The cumulative global incidence of long COVID is around 400 million individuals, yet effective treatment options remain limited. A recent systematic review published in 2025 highlighted promising results for non-invasive brain stimulation in alleviating long COVID symptoms. Given the growing use of repetitive transcranial magnetic stimulation (rTMS) for people with long COVID, a focused meta-analysis on the therapeutic effectiveness of rTMS is warranted. To address this gap, this protocol outlines the planned procedures for a systematic review and meta-analysis. A comprehensive search will be conducted across CINAHL Ultimate, MEDLINE, ScienceDirect, and Scopus. Retrieved studies will be managed using Rayyan, with two independent reviewers screening titles and abstracts, followed by full-text review. Data extraction will follow PRISMA and Cochrane guidelines using a standardised form, with dual independent extraction and reconciliation of discrepancies. Risk of bias will be assessed using Cochrane RoB 2.0. Meta-analytical procedures will include calculation of standardised effect sizes (e.g., Hedges’ g), use of random-effects models, and assessment of heterogeneity via I², Cochran’s Q, and tau². Subgroup and moderator analyses will explore variations in rTMS protocols, participant characteristics, and symptom domains. Sensitivity analyses and meta-regression will be conducted where data permit. Results will be visualised using forest and funnel plots, and the GRADE framework will be used to assess the quality of evidence. Full article

(This article belongs to the Special Issue Long COVID: Pathophysiology, Symptoms, Treatment, and Management)

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