Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review

Abstract:

Background: Millions of COVID-19 pediatric survivors are facing the risk of long COVID after recovery from acute COVID-19. The primary objective of this study was to systematically review the available literature and determine the pooled prevalence of, and risk factors for long COVID among the pediatric survivors.

Methods: Studies that assessed the prevalence of, or risk factors associated with long COVID among pediatric COVID-19 survivors were systematically searched in PubMed, Embase, Cochrane Library, medRxiv and bioRxiv up to December 11th, 2022. Random effects model was performed to estimate the pooled prevalence of long COVID among pediatric COVID-19 patients. Subgroup analyses and meta-regression on the estimated prevalence of long COVID were performed by stratification with follow-up duration, mean age, sex ratio, percentage of multisystem inflammatory syndrome, hospitalization rate at baseline, and percentage of severe illness.

Results: Based on 40 studies with 12,424 individuals, the pooled prevalence of any long COVID was 23.36% ([95% CI 15.27-32.53]). The generalized symptom (19.57%, [95% CI 9.85-31.52]) was reported most commonly, followed by respiratory (14.76%, [95% CI 7.22-24.27]), neurologic (13.51%, [95% CI 6.52-22.40]), and psychiatric (12.30%, [95% CI 5.38-21.37]). Dyspnoea (22.75%, [95% CI 9.38-39.54]), fatigue (20.22%, [95% CI 9.19-34.09]), and headache (15.88%, [95% CI 6.85-27.57]) were most widely reported specific symptoms. The prevalence of any symptom during 3-6, 6-12, and >12 months were 26.41% ([95% CI 14.33-40.59]), 20.64% ([95% CI 17.06-24.46]), and 14.89% ([95% CI 6.09-26.51]), respectively. Individuals with aged over ten years, multisystem inflammatory syndrome, or had severe clinical symptoms exhibited higher prevalence of long COVID in multi-systems. Factors such as older age, female, poor physical or mental health, or had severe infection or more symptoms were more likely to have long COVID in pediatric survivors.

Conclusions: Nearly one quarter of pediatric survivors suffered multisystem long COVID, even at 1 year after infection. Ongoing monitoring, comprehensive prevention and intervention is warranted for pediatric survivors, especially for individuals with high risk factors.

Source: Zheng YB, Zeng N, Yuan K, Tian SS, Yang YB, Gao N, Chen X, Zhang AY, Kondratiuk AL, Shi PP, Zhang F, Sun J, Yue JL, Lin X, Shi L, Lalvani A, Shi J, Bao YP, Lu L. Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review. J Infect Public Health. 2023 Mar 7. doi: 10.1016/j.jiph.2023.03.005. Epub ahead of print. PMCID: PMC9990879. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9990879/ (Full text)

COVID-19 long-term sequelae: Omicron versus Alpha and Delta variants

Abstract:

Background: The study aimed to assess the association between three predominant SARS-CoV-2 variants (Alpha, Delta, and Omicron) and the risk of developing long COVID (persistence of physical, medical, and cognitive symptoms more than 4 weeks after infection), post-COVID-19 syndrome (symptoms extending beyond 12 weeks), and viral persistence (testing positive beyond 4 weeks despite clinical resolution).

Methods: Retrospective study of 325 patients hospitalized for COVID-19 with genomic sequencing information. For each SARS-CoV-2 variant, sample characteristics, frequency of symptoms, and long-term sequelae were compared using Chi-squared test, Fisher’s exact test, Kruskal-Wallis test, and Dunn’s test as appropriate. Odds ratios (OR) were calculated using logistic regression models to assess the association of risk factors and sequelae.

Results: The adjusted model showed that the Omicron (vs Alpha) variant (OR, 0.30; 95% CI0.16-0.56), admission to ICU (OR, 1.14; 95% CI 1.05-1.23), and being treated with antiviral or immunomodulatory drugs (OR, 2.01; 95% CI 1.23-3.27) predicted long COVID and post-COVID-19 syndrome. Viral persistence showed no difference between variants.

Conclusions: The Omicron variant was associated with significantly lower odds of developing long-term sequelae from COVID-19 compared with previous variants, while severity of illness indicators increased the risk. Vaccination status, age, sex, and comorbidities were not found to predict sequelae development. This information has implications for both health managers and clinicians when deciding on the appropriate clinical management and subsequent outpatient follow-up of these patients. More studies with non-hospitalized patients are still necessary.

Source: Hernández-Aceituno A, García-Hernández A, Larumbe-Zabala E. COVID-19 long-term sequelae: Omicron versus Alpha and Delta variants. Infect Dis Now. 2023 Feb 27:104688. doi: 10.1016/j.idnow.2023.104688. Epub ahead of print. PMID: 36858287; PMCID: PMC9970656. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9970656/ (Full text)

Is exposure to Epstein-Barr virus a risk factor for long-covid?

Abstract:

Background: A viral etiology to chronic fatigue syndrome (CFS) has long been postulated, and Epstein-Barr Virus (EBV) was the first CFS associated virus. CFS and Long-COVID share features, potentially implicating a similar etiology. This study evaluated if EBV exposure is associated with post-COVID syndrome (Long-COVID)

Methods: Intermountain Healthcare electronic health records were queried to identify patients diagnosed with COVID-19 and tested for EBV between March 6, 2020 and April 13, 2022. A subsequent diagnosis of Long-COVID (ICD-10 U09.9) was evaluated using survival methods.

Results: Overall, 296,959 patients had COVID-19 and 590 had concurrent EBV test results [207 (35.1%) were EBV positive]. Subjects averaged 27.4±18.4 years of age (range: 0-86); 57.6% were female. Hospitalization occurred in 61 subjects (10.3%) within 30 days of COVID-19 diagnosis, with 17 (2.9%) requiring intensive care. Long-COVID was found in 29 (4.9%) subjects (just 10 were among the 61 hospitalized for COVID-19), with 15 (7.2%) EBV positive (Figure) and 14 (3.7%) EBV negative (HR=2.09, 95% CI=1.01, 4.34; p=0.042). EBV risk remained in multivariable analyses. Race, hyperlipidemia, and tobacco use also predicted Long-COVID, with histories of anticoagulant and vitamin D use were protective.

Conclusion: In a large prospectively-collected registry, EBV positivity was associated with an elevated risk of Long-COVID. This suggests that EBV may be a predisposing risk factor for or co-precipitant of Long-COVID.

Source: Horne B, Knowlton K, Le V, et al. IS EXPOSURE TO EPSTEIN-BARR VIRUS A RISK FACTOR FOR LONG-COVID?. J Am Coll Cardiol. 2023 Mar, 81 (8_Supplement) 1784. https://doi.org/10.1016/S0735-1097(23)02228-3 (Full text)

Predictors of Long-COVID-19 and its Impact on Quality of Life: Longitudinal Analysis at 3, 6 and 9 Months after Discharge from a Portuguese Centre

Abstract:

Introduction: Long-COVID-19 impacts health-related quality of life (HR-QoL) but data is scarce. The aim of this study was to describe and prospectively assess the prevalence and risk factors for long-COVID-19 after hospital discharge, and to evaluate its impact on patient HR-QoL.

Material and methods: Single-centre longitudinal study including all COVID-19 patients discharged between December 2020 and February 2021. Patients were contacted remotely at three, six and nine months. Data were collected as follows: 1) Long-COVID-19 symptoms were self-reported; 2) HRQoL were assessed using the 3-level EuroQoL-5D (EQ-5D-3L) questionnaire. Pregnant women, demented, bedridden, and non-Portuguese-speaking patients were excluded.

Results: The three-, six- and nine-month assessments were completed by 152, 117 and 110 patients (median age: 61 years; male sex: 56.6%). Long-COVID-19 (≥ 1 symptom) was reported by 66.5%, 62.4% and 53.6% of patients and HR-QoL assessment showed impairment of at least some domain in 65.8%, 69.2% and 55.4% of patients at three, six and nine months, respectively. Fatigue was the most common long-COVID-19 symptom. Anxiety/depression domain was the most frequently affected in all three time-points, peaking at six months (39%), followed by pain/discomfort and mobility domains. Long-COVID-19 was associated with the impairment of all EQ-5D-3L domains except for self-care domain at each time-point. Neither intensive care unit admission nor disease severity were associated with long-COVID-19 nor with impairment of any EQ-5D-3L domain. After adjusting for sex, age, frailty status, and comorbid conditions, long-COVID-19 remained significantly associated with HR-QoL impairment at three (OR 4.27, 95% CI 1.92 – 9.52, p < 0.001), six (OR 3.46, 95% CI 1.40 – 8.57, p = 0.007) and nine months (OR 4.13, 95% CI 1.62 – 10.55, p = 0.003) after hospital discharge. In a longitudinal analysis, patients reporting long-COVID-19 at three months had an EQ-5D-3L index value decreased by 0.14 per visit (p < 0.001) compared to those without long-COVID-19 and both groups had a non-significant change in mean EQ-5D-3L index over the nine-month period (time-point assessment, Z = 0.91, p = 0.364).

Conclusion: Clinical sequelae associated with long-COVID-19 can persist for at least nine months after hospital discharge in most patients and can impair long-term HR-QoL in more than half of patients regardless of disease severity, and clinicodemographic characteristics.

Source: Gaspar P, Dias M, Parreira I, Gonçalves HD, Parlato F, Maione V, Atalaia Barbacena H, Carreiro C, Duarte L. Predictors of Long-COVID-19 and its Impact on Quality of Life: Longitudinal Analysis at 3, 6 and 9 Months after Discharge from a Portuguese Centre. Acta Med Port. 2023 Feb 24. doi: 10.20344/amp.19047. Epub ahead of print. PMID: 36827994. https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/19047 (Full text)

Vaccination status and long COVID symptoms in patients discharged from hospital

Abstract:

Effective vaccination against coronavirus mitigates the risk of hospitalisation and mortality; however, it is unclear whether vaccination status influences long COVID symptoms in patients who require hospitalisation. The available evidence is limited to outpatients with mild disease.

Here, we evaluated 412 patients (age: 60 ± 16 years, 65% males) consecutively admitted to two Hospitals in Brazil due to confirmed coronavirus disease 2019 (COVID-19). Compared with patients with complete vaccination (n = 185) before infection or hospitalisation, those with no or incomplete vaccination (n = 227) were younger and had a lower frequency of several comorbidities.

Data during hospitalisation revealed that the no or incomplete vaccination group required more admissions to the intensive care unit (ICU), used more corticosteroids, and had higher rates of pulmonary embolism or deep venous thrombosis than the complete vaccination group. Ninety days after hospital discharge, patients with no or incomplete vaccination presented a higher frequency of symptoms (≥ 1) than patients with complete vaccination (40 vs. 27%; p = 0.013).

After adjusting for confounders, no or incomplete vaccination (odds ratio [OR] 1.819; 95% confidence interval [CI] 1.175-2.815), female sex (OR 2.435; 95% CI 1.575-3.764) and ICU admission during hospitalisation (OR 1.697; 95% CI 1.062-2.712) were independently associated with ≥ 1 symptom 90 days after hospital discharge.

In conclusion, even in patients with severe COVID-19, vaccination mitigates the probability of long COVID symptoms.

Source: Nascimento TCDC, do Valle Costa L, Ruiz AD, Ledo CB, Fernandes VPL, Cardoso LF, Junior JMV, Saretta R, Kalil-Filho R, Drager LF. Vaccination status and long COVID symptoms in patients discharged from hospital. Sci Rep. 2023 Feb 11;13(1):2481. doi: 10.1038/s41598-023-28839-y. PMID: 36774419; PMCID: PMC9922040. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922040/ (Full text)

Long COVID-A New Challenge in Medicine: Focus on Pregnancy and Breastfeeding

Abstract:

Long COVID (coronavirus disease) has been described as a new multi-organ disease, which appears to be more prevalent in women than in men. Pregnant and breastfeeding women are a special subgroup of patients to consider with long COVID, as only scarce data have been collected to date. Menstrual changes are commonly observed during or after COVID-19; some studies also attribute slight changes of cycle length to previous inoculation against the virus.
Pregnant women who have a symptomatic infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are at a higher risk for adverse outcomes and pregnancy-associated complications. Moreover, more and robust data are required to evaluate vertical transmission. COVID vaccines are the most effective tool against the pandemic, as they prevent infection, but also appear to be able to ease long COVID symptoms. Vaccines have been proven safe and effective in both pregnant and breastfeeding women. This article aims to present current data on long COVID in pregnant and breastfeeding women and elucidate risk factors and possible treatment options.
Source: Han E, Gyöngyösi M. [Long COVID-A New Challenge in Medicine: Focus on Pregnancy and Breastfeeding]. Journal fur Gynakologische Endokrinologie (Osterreichische Ausg.). 2023 Feb:1-6. DOI: 10.1007/s41974-023-00250-5. PMID: 36747883; PMCID: PMC9893966. https://europepmc.org/article/med/36747883 (Full text available in German)

Correlates of long-COVID-19: the role of demographics, chronic illness, and psychiatric diagnosis in an urban sample

Abstract:

Long-COVID-19 symptoms are an emerging public health issue. This study sought to investigate demographics, chronic illness, and probable psychiatric diagnoses as correlates for long-COVID-19 in an urban adult sample. Self-report Qualtrics surveys were sent to students across City University of New York (CUNY) campuses in New York City in Winter 2021-2022. Binary logistic regressions were used to assess the relation of a range of factors with endorsement of long-COVID-19. Results demonstrated that Latinx participants endorsed higher odds of long-COVID-19, as compared to non-Latinx white participants.

Participants who endorsed having a prior chronic illness and those who met the cut-off for probable psychiatric diagnoses all endorsed higher odds of long-COVID-19. Long-COVID-19 may be more likely among specific subpopulations and among persons with other ongoing physical and mental illness.

Source: Schulder T, Rudenstine S, Ettman CK, Galea S. Correlates of long-COVID-19: the role of demographics, chronic illness, and psychiatric diagnosis in an urban sample. Psychol Health Med. 2023 Feb 8:1-13. doi: 10.1080/13548506.2023.2177684. Epub ahead of print. PMID: 36752386. https://pubmed.ncbi.nlm.nih.gov/36752386/

Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis

Abstract:

Background: The relationship between coronavirus disease 2019 (COVID-19) vaccination and long COVID has not been firmly established. We conducted a systematic review and meta-analysis to evaluate the association between COVID-19 vaccination and long COVID.

Methods: PubMed and EMBASE databases were searched on September 2022 without language restrictions (CRD42022360399) to identify prospective trials and observational studies comparing patients with and without vaccination before severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We also included studies reporting symptomatic changes of ongoing long COVID following vaccination among those with a history of SARS-CoV-2 infection. Odds ratios (ORs) for each outcome were synthesized using a random-effects model. Symptomatic changes after vaccination were synthesized by a one-group meta-analysis.

Results: Six observational studies involving 536,291 unvaccinated and 84,603 vaccinated (before SARS-CoV-2 infection) patients (mean age, 41.2-66.6; female, 9.0-67.3%) and six observational studies involving 8,199 long COVID patients (mean age, 40.0 to 53.5; female, 22.2-85.9%) who received vaccination after SARS-CoV-2 infection were included. Two-dose vaccination was associated with a lower risk of long COVID compared to no vaccination (OR, 0.64; 95% confidence interval [CI], 0.45-0.92) and one-dose vaccination (OR, 0.60; 95% CI, 0.43-0.83). Two-dose vaccination compared to no vaccination was associated with a lower risk of persistent fatigue (OR, 0.62; 95% CI, 0.41-0.93) and pulmonary disorder (OR, 0.50; 95% CI, 0.47-0.52). Among those with ongoing long COVID symptoms, 54.4% (95% CI, 34.3-73.1%) did not report symptomatic changes following vaccination, while 20.3% (95% CI, 8.1-42.4%) experienced symptomatic improvement after two weeks to six months of COVID-19 vaccination.

Conclusions: COVID-19 vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID, while most of those with ongoing long COVID did not experience symptomatic changes following vaccination.

Source: Watanabe A, Iwagami M, Yasuhara J, Takagi H, Kuno T. Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis. Vaccine. 2023 Feb 8:S0264-410X(23)00134-2. doi: 10.1016/j.vaccine.2023.02.008. Epub ahead of print. PMID: 36774332; PMCID: PMC9905096. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9905096/ (Full text)

A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms

Abstract:

Background: Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles.

Methods: 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations.

Results: We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 (“Nasal cluster”) is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 (“Sensory cluster”) is highly correlated with loss of smell or taste, and cluster 3 (“Respiratory/Systemic cluster”) is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01).

Conclusions: We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.

Source: Epsi NJ, Powers JH, Lindholm DA, Mende K, Malloy A, Ganesan A, Huprikar N, Lalani T, Smith A, Mody RM, Jones MU, Bazan SE, Colombo RE, Colombo CJ, Ewers EC, Larson DT, Berjohn CM, Maldonado CJ, Blair PW, Chenoweth J, Saunders DL, Livezey J, Maves RC, Sanchez Edwards M, Rozman JS, Simons MP, Tribble DR, Agan BK, Burgess TH, Pollett SD; EPICC COVID-19 Cohort Study Group. A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms. PLoS One. 2023 Feb 9;18(2):e0281272. doi: 10.1371/journal.pone.0281272. PMID: 36757946; PMCID: PMC9910657. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9910657/ (Full text)

Long COVID in cancer patients: preponderance of symptoms in majority of patients over long time period

Abstract:

Background: An increasing number of observational studies have reported the persistence of symptoms following recovery from acute COVID-19 disease in non-cancer patients. The long-term consequences of COVID-19 are not fully understood particularly in the cancer patient population. The purpose of this study is to assess post-acute sequelae of SARS-CoV-2 infection (PASC) in cancer patients following acute COVID-19 recovery.

Methods: We identified cancer patients at MD Anderson Cancer Center who were diagnosed with COVID-19 disease between March 1, 2020 and Sept 1, 2020 and followed them till May 2021. To assess PASC, we collected patients reported outcomes through questionnaires that were sent to patients daily for 14 days after COVID-19 diagnosis then weekly for 3 months, and then monthly thereafter. We also reviewed patients’ electronic medical records to capture the persistence or emergence of new COVID19-related symptoms reported during any clinic or hospital encounter beyond 30 days of the acute illness and up to 14 months.

Results: We included 312 cancer patients with a median age of 57 years (18-86). The majority of patients had solid tumors (75%). Of the 312 patients, 188 (60%) reported long COVID-19 symptoms with a median duration of 7 months and up to 14 months after COVID-19 diagnosis. The most common symptoms reported included fatigue (82%), sleep disturbances (78%), myalgias (67%) and gastrointestinal symptoms (61%), followed by headache, altered smell or taste, dyspnea (47%) and cough (46%). A higher number of females reported a persistence of symptoms compared to males (63% vs 37%; p=0.036). Cancer type, neutropenia, lymphocytopenia, and hospital admission during acute COVID-19 disease were comparable in both groups. Among the 188 patients with PASC, only 16 (8.5%) were readmitted for COVID-related reasons.

Conclusions: More than one out of two cancer patients, and more likely females, report PASC that may persist beyond 6 months and even one year. The most common symptoms are non-respiratory and consist of fatigue, sleep disturbance, myalgia and gastro-intestinal symptoms. Most of the cancer patients with PASC were managed on outpatient basis with only 8,5% requiring a COVID-19 related re-admission.

Source: Dagher H, Chaftari AM, Subbiah IM, Malek AE, Jiang Y, Lamie P, Granwehr B, John T, Yepez E, Borjan J, Reyes-Gibby C, Flores M, Khawaja F, Pande M, Ali N, Rojo R, Karp DD, Chaftari P, Hachem R, Raad II. Long COVID in cancer patients: preponderance of symptoms in majority of patients over long time period. Elife. 2023 Feb 7;12:e81182. doi: 10.7554/eLife.81182. Epub ahead of print. PMID: 36748905. https://elifesciences.org/articles/81182 (Full text)