Consistency of inconsistency in long-COVID-19 pain symptoms persistency: A systematic review and meta-analysis

Abstract:

Introduction: Individuals recovering from acute COVID-19 episodes may continue to suffer from various ongoing symptoms, collectively referred to as Long-COVID. Long-term pain symptoms are amongst the most common and clinically significant symptoms to be reported for this post-COVID-19 syndrome.

Objectives: This systematic review and meta-analysis aimed to evaluate the proportions of persisting pain symptoms experienced by individuals past the acute phase of COVID-19 and to identify their associated functional consequences and inflammatory correlates.

Methods: Two online databases were systematically searched from their inception until 31 March 2022. We searched primary research articles in English, which evaluated individuals after laboratory-confirmed COVID-19 acute phase resolution and specifically reported on pain symptoms and their inflammatory and/or functional outcomes.

Results: Of the 611 identified articles, 26 were included, used for data extraction, and assessed for their methodological quality and risk of bias by two independent reviewers. Pain symptoms were grouped under one of six major pain domains, serving as our primary co-outcomes. Proportional meta-analyses of pooled logit-transformed values of single proportions were performed using the random-effects-restricted maximum-likelihood model. An estimated 8%, 6%, 18%, 18%, 17%, and 12% of individuals continued to report the persistence of chest, gastrointestinal, musculoskeletal joint, musculoskeletal muscle, general body, and nervous system-related pain symptoms, respectively, for up to one year after acute phase resolution of COVID-19. Considerable levels of heterogeneity were demonstrated across all results. Functional and quality-of-life impairments and some inflammatory biomarker elevations were associated with the persistence of long-COVID pain symptoms.

Conclusion: This study’s findings suggest that although not well characterized, long-COVID pain symptoms are being experienced by non-negligible proportions of those recovering from acute COVID-19 episodes, thus highlighting the importance of future research efforts to focus on this aspect.

Source: Kerzhner O, Berla E, Har-Even M, Ratmansky M, Goor-Aryeh I. Consistency of inconsistency in long-COVID-19 pain symptoms persistency: A systematic review and meta-analysis. Pain Pract. 2023 Jul 21. doi: 10.1111/papr.13277. Epub ahead of print. PMID: 37475709. https://onlinelibrary.wiley.com/doi/10.1111/papr.13277 (Full study)

A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls.

Methods: Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17.

Results: Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult.

Conclusions: There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.

Source: Taccori A, Maksoud R, Eaton-Fitch N, Patel M, Marshall-Gradisnik S. A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Transl Med. 2023 Jul 5;21(1):440. doi: 10.1186/s12967-023-04295-0. PMID: 37408028; PMCID: PMC10320942. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320942/ (Full text)

Neuropsychological deficits in patients with persistent COVID-19 symptoms: a systematic review and meta-analysis

Abstract:

Long-term persistent symptoms of COVID-19 affect 30-80% of patients who have recovered from the disease and may continue for a long time after the disease has been overcome. The duration of these symptoms over time might have consequences that affect different aspects of health, such as cognitive abilities.

The main objective of this systematic review and meta-analysis was to objectify the persistent COVID-19 cognitive deficits after acute phase of infection and to summarize the existing evidence. Additionally, we aimed to provide a comprehensive overview to further understand and address the consequences of this disease. Our protocol was registered in PROSPERO (CRD42021260286).

Systematic research was conducted in the Web of Science, MEDLINE, PubMed, PsycINFO, Scopus, and Google Scholar databases from January 2020 to September 2021. Twenty-five studies were included, six of which were analyzed for the meta-analysis, and consisted of 175 patients who had recovered from COVID-19 and 275 healthy individuals. Analyses of cognitive performance of post-COVID-19 patients and healthy volunteers were compared using a random-effects model.

The results showed an overall medium-high effect size (g = -.68, p = .02) with a 95% CI (-1.05 to -.31), with a significantly moderate level of heterogeneity among studies (Z = 3.58, p < .001; I2 = 63%). The results showed that individuals who had recovered from COVID-19 showed significant cognitive deficits compared to controls.

Future studies should carefully assess the long-term progression of cognitive impairments in patients with persistent COVID-19 symptoms, as well as the effectiveness of rehabilitation interventions. Nevertheless, there is an urgent need to know the profile to speed up development of prevention plans as well as specific interventions. Since more information is being obtained and more studies are being conducted on the subject, the need to examine this symptomatology multidisciplinary to achieve greater scientific evidence of its incidence and prevalence has become increasingly clear.

Source: Sobrino-Relaño S, Balboa-Bandeira Y, Peña J, Ibarretxe-Bilbao N, Zubiaurre-Elorza L, Ojeda N. Neuropsychological deficits in patients with persistent COVID-19 symptoms: a systematic review and meta-analysis. Sci Rep. 2023 Jun 26;13(1):10309. doi: 10.1038/s41598-023-37420-6. PMID: 37365191; PMCID: PMC10293265. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10293265/ (Full text)

Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis

Abstract:

Introduction: Myalgic encephalomyelitis is an illness characterized by profound malaise after mental or physical effort occurring in patients already suffering from constant fatigue. On the other hand, widespread pain and widespread allodynia are the core fibromyalgia clinical features.

There is controversy on these two syndromes alikeness. Through the years, different diagnostic and/or classification criteria have been put forward to appraise both fibromyalgia and myalgic encephalomyelitis.

The epidemiology of these two illnesses, and their overlap, may vary accordingly to the used definition. The most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria incorporates three myalgic encephalomyelitis features including fatigue, waking unrefreshed and dyscognition. The objective of this meta-analysis was to define the clinical overlap between fibromyalgia and myalgic encephalomyelitis based on a systematic literature review.

Methods: PubMed, Embase, Lilacs, and Cochrane data bases were searched on January 25, 2021 linking the medical subject heading “Fibromyalgia” to the following terms “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “systemic exertion intolerance disease”.

Our review included all original articles in which the clinical overlap between fibromyalgia and myalgic encephalomyelitis could be quantified based on recognized diagnostic or classification criteria. Articles scrutiny and selection followed the PRISMA guidelines. Each study quality was assessed according to GRADE recommendations. The global clinical overlap was calculated using a fixed effect model with inverse variance-weighted average method.

Results: Twenty one publications were included in the meta-analysis. Reviewed studies were highly dissimilar in their design, objectives, sample size, diagnostic criteria, and/or outcomes yielding a 98% heterogeneity index.

Nevertheless, the clinical overlap between fibromyalgia and myalgic encephalomyelitis was a well defined outcome that could be reliably calculated despite the high heterogeneity value.

All reviewed publications had moderate GRADE evidence level. Most evaluated articles used the old 1990 Wolfe et al. fibromyalgia diagnostic criteria. Myalgic encephalomyelitis and fibromyalgia diagnoses overlapped in 47.3% (95% CI: 45.97-48.63) of the reported cases.

Conclusion: This meta-analysis found prominent clinical overlap between fibromyalgia and myalgic encephalomyelitis. It seems likely that this concordance would be even higher when using the most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria.

Source: Ramírez-Morales R, Bermúdez-Benítez E, Martínez-Martínez LA, Martínez-Lavín M. Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis. Autoimmun Rev. 2022 Aug;21(8):103129. doi: 10.1016/j.autrev.2022.103129. Epub 2022 Jun 9. PMID: 35690247. https://www.sciencedirect.com/science/article/abs/pii/S1568997222000994?via%3Dihub

Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specific test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufficient knowledge about the disease. Prior studies have shown that patients with ME/CFS/SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the differences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls.

Methods: This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases’ inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the difference in serum acylcarnitine levels between the two groups.

Results: The electronic search identified 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had significantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high.

Conclusion: The patient group had significantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition.

Source: Jinushi R, Masuda S, Tanisaka Y, Nishiguchi S, Shionoya K, Sato R, Sugimoto K, Shin T, Shiomi R, Fujita A, Mizuide M, Ryozawa S. Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis. J Transl Med. 2023 Jun 19;21(1):398. doi: 10.1186/s12967-023-04226-z. PMID: 37337273; PMCID: PMC10280864. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10280864/ (Full text)

New-onset type 1 diabetes in children and adolescents as postacute sequelae of SARS-CoV-2 infection: A systematic review and meta-analysis of cohort studies

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents may increase risk for a variety of post-acute sequelae including new-onset type 1 diabetes mellitus (T1DM). Therefore, this meta-analysis aims to estimate the risk of developing new-onset type 1 diabetes in children and adolescents as post-acute sequelae of SARS-CoV-2 infection.

PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched up to March 20, 2023. A systematic review and subsequent meta-analyses were performed to calculate the pooled effect size, expressed as risk ratio (RR) with corresponding 95% confidence interval (CI) of each outcome based on a one-stage approach and the random-effects estimate of the pooled effect sizes of each outcome were generated with the use of the DerSimonian-Laird method. Eight reports from seven studies involving 11 220 530 participants (2 140 897 patients with a history of diagnosed SARS-CoV-2 infection and 9 079 633 participants in the respective control groups) were included. The included studies reported data from four U.S. medical claims databases covering more than 503 million patients (IQVIA, HealthVerity, TriNetX, and Cerner Real-World Data), and three national health registries for all children and adolescents in Norway, Scotland, and Denmark.

It was shown that the risk of new-onset T1DM following SARS-CoV-2 infection in children and adolescents was 42% (95% CI 13%-77%, p = 0.002) higher compared with non-COVID-19 control groups. The risk of developing new-onset T1DM following SARS-CoV-2 infection was significantly higher (67%, 95% CI 32 %-112%, p = 0.0001) in children and adolescents between 0 and 11 years, but not in those between 12 and 17 years (RR = 1.10, 95% CI 0.54-2.23, p = 0.79). We also found that the higher risk for developing new-onset T1DM following SARS-CoV-2 infection only exists in studies from the United States (RR = 1.70, 95% CI 1.37-2.11, p = 0.00001) but not Europe (RR = 1.02, 95% CI 0.67-1.55, p = 0.93). Furthermore, we found that SARS-CoV-2 infection was associated with an elevation in the risk of diabetic ketoacidosis (DKA) in children and adolescents compared with non-COVID-19 control groups (RR = 2.56, 95% CI 1.07-6.11, p = 0.03).

Our findings mainly obtained from US medical claims databases, suggest that SARS-CoV-2 infection is associated with higher risk of developing new-onset T1DM and diabetic ketoacidosis in children and adolescents. These findings highlight the need for targeted measures to raise public health practitioners and physician awareness to provide intervention strategies to reduce the risk of developing T1DM in children and adolescents who have had COVID-19.

Source: Rahmati M, Yon DK, Lee SW, Udeh R, McEVoy M, Kim MS, Gyasi RM, Oh H, López Sánchez GF, Jacob L, Li Y, Koyanagi A, Shin JI, Smith L. New-onset type 1 diabetes in children and adolescents as postacute sequelae of SARS-CoV-2 infection: A systematic review and meta-analysis of cohort studies. J Med Virol. 2023 Jun;95(6):e28833. doi: 10.1002/jmv.28833. PMID: 37264687. https://onlinelibrary.wiley.com/doi/10.1002/jmv.28833

Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis

Abstract:

Introduction: The number of children with mental health problems has more than doubled since the COVID-19 pandemic. However, the effect of long Covid on children’s mental health is still debatable. Recognising long Covid as a risk factor for mental health problems in children will increase awareness and screening for mental health problems following COVID-19 infection, resulting in earlier intervention and lower morbidity. Therefore, this study aimed to determine the proportion of mental health problems post-COVID-19 infection in children and adolescents, and to compare them with the population with no previous COVID-19 infection.

Methodology: A systematic search was done in seven databases using pre-defined search terms. Cross-sectional, cohort and interventional studies reporting the proportion of mental health problems among children with long COVID in the English language from 2019 to May 2022 were included. Selection of papers, extraction of data and quality assessment were done independently by two reviewers. Studies with satisfactory quality were included in meta-analysis using R and Revman software programmes.

Results: The initial search retrieved 1848 studies. After screening, 13 studies were included in the quality assessments. Meta-analysis showed children who had previous COVID-19 infection had more than two times higher odds of having anxiety or depression, and 14% higher odds of having appetite problems, compared to children with no previous infection. The pooled prevalence of mental health problems among the population were as follows; anxiety: 9%(95% CI:1, 23), depression: 15%(95% CI:0.4, 47), concentration problems: 6%(95% CI: 3, 11), sleep problems: 9%(95% CI:5, 13), mood swings: 13% (95%CI:5, 23) and appetite loss: 5%(95% CI:1, 13). However, studies were heterogenous and lack data from low- and middle-income countries.

Conclusion: Anxiety, depression and appetite problems were significantly increased among post-COVID-19 infected children, compared to those without a previous infection, which may be attributed to long COVID. The findings underscore the importance of screening and early intervention of children post-COVID-19 infection at one month and between three to four months.

Source: Mat Hassan N, Salim HS, Amaran S, Yunus NI, Yusof NA, Daud N, et al. (2023) Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis. PLoS ONE 18(5): e0282538. https://doi.org/10.1371/journal.pone.0282538 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282538 (Full text)

Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis

Abstract:

Background: Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, the correlation between IL-6 and long COVID-19 is unknown. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19.

Methods: Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran’s Q test and the Higgins I-squared (I2) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger’s test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results.

Results: An increase in IL-6 levels was observed after SARS-CoV-2 infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30-32.54 pg/ml, I2 = 100%, P < 0.01) for long COVID-19 patients. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75-13.75 pg/ml, I2 = 100%, P < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22-6.42 pg/ml, I2 = 88%, P = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups.

Conclusions: This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on the “early stage” of long COVID-19.

Source: Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty. 2023 Apr 24;12(1):43. doi: 10.1186/s40249-023-01086-z. PMID: 37095536; PMCID: PMC10123579. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123579/ (Full text)

COVID-19 Vaccination for the Prevention and Treatment of Long COVID: A Systematic Review and Meta-analysis

Abstract:

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination.

Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N= 257 817).

Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

Source: Ceban F, Kulzhabayeva D, Rodrigues NB, Di Vincenzo JD, Gill H, Subramaniapillai M, Lui LMW, Cao B, Mansur RB, Ho RC, Burke MJ, Rhee TG, Rosenblat JD, McIntyre RS. COVID-19 Vaccination for the Prevention and Treatment of Long COVID: A Systematic Review and Meta-analysis. Brain Behav Immun. 2023 Mar 27:S0889-1591(23)00079-X. doi: 10.1016/j.bbi.2023.03.022. Epub ahead of print. PMID: 36990297; PMCID: PMC10067136. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067136/ (Full text)

Risk Factors Associated With Post−COVID-19 Condition A Systematic Review and Meta-analysis

Abstract:

Importance  Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.

Objective  To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.

Data sources  Medline and Embase databases were systematically searched from inception to December 5, 2022.

Study Selection  The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.

Data Extraction and Synthesis  Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.

Main Outcomes and Measures  The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.

Results  The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).

Conclusions and Relevance  This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.

Trial Registration  PROSPERO Identifier: CRD42022381002

Source: Tsampasian V, Elghazaly H, Chattopadhyay R, et al. Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisJAMA Intern Med. Published online March 23, 2023. doi:10.1001/jamainternmed.2023.0750 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2802877 (Full text)