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Canadian Journal of Cardiology

One-Year Risk of myocarditis after COVID-19 infection: a systematic review and meta-analysis

Published:December 12, 2022DOI:https://doi.org/10.1016/j.cjca.2022.12.003

      Abstract

      Background

      Acute myocarditis has been described as a relatively rare cardiovascular complication of COVID-19 infection. However, data regarding the risk of myocarditis during the post-acute phase of COVID-19 are scant. We assess the risk of incident myocarditis in COVID-19 survivors within one year from the index infection by a systematic review and meta-analysis of the available data.

      Methods

      Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022, and reporting the long-term risk of incident myocarditis in COVID-19 survivors. Myocarditis risk data were pooled using the Mantel–Haenszel random effects models with Hazard ratio (HR) as the effect measure with 95% confidence interval (CI). Heterogeneity among studies was assessed using Higgins and Thomson I2 statistic.

      Results

      Overall, 20.875.843 patients (mean age 56.1 years, 59.1% males) were included in this analysis. Of them, 1.245.167 survived to COVID-19 infection. Over a mean follow-up of 9.5 months, myocarditis occurred to 0.21 [95% CI: 0.13- 0.42) out of 1000 patients survived to COVID-19 infection compared to 0.09 [95% CI: 0.07-0.12] out of 1000 control subjects. Pooled analysis revealed that recovered COVID-19 patients presented an increased risk of incident myocarditis (HR: 5.16, 95% CI: 3.87-6.89, p<0.0001, I2=7.9%) within one year from the index infection. The sensitivity analysis confirmed yielded results.

      Conclusion

      Our findings suggest that myocarditis represents a relatively rare but important post-acute COVID-19 sequelae.

      Graphical abstract

      Key words

      Introduction

      Acute myocarditis (AM) has been described as a relatively rare complication of COVID-19 infection [
      • Ammirati E.
      • Lupi L.
      • Palazzini M.
      • Hendren N.S.
      • Grodin J.L.
      • Cannistraci C.V.
      • Schmidt M.
      • Hekimian G.
      • Peretto G.
      • Bochaton T.
      • Hayek A.
      • Piriou N.
      • Leonardi S.
      • Guida S.
      • Turco A.
      • Sala S.
      • Uribarri A.
      • Van de Heyning C.M.
      • Mapelli M.
      • Campodonico J.
      • Pedrotti P.
      • Barrionuevo Sánchez M.I.
      • Ariza Sole A.
      • Marini M.
      • Matassini M.V.
      • Vourc'h M.
      • Cannatà A.
      • Bromage D.I.
      • Briguglia D.
      • Salamanca J.
      • Diez-Villanueva P.
      • Lehtonen J.
      • Huang F.
      • Russel S.
      • Soriano F.
      • Turrini F.
      • Cipriani M.
      • Bramerio M.
      • Di Pasquale M.
      • Grosu A.
      • Senni M.
      • Farina D.
      • Agostoni P.
      • Rizzo S.
      • De Gaspari M.
      • Marzo F.
      • Duran J.M.
      • Adler E.D.
      • Giannattasio C.
      • Basso C.
      • McDonagh T.
      • Kerneis M.
      • Combes A.
      • Camici P.G.
      • de Lemos J.A.
      • Metra M.
      Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.
      ]. Viral infections are a common cause of acute myocarditis, due to a combination of direct cellular injury and T-cell cytotoxicity pointed at the myocardium, which can be amplified by the cytokine storm syndrome, as described in SARS-CoV-2 infection [
      • Yajima T.
      • Knowlton K.U.
      Viral myocarditis.
      ,
      • Hu B.
      • Huang S.
      • Yin L.
      The cytokine storm and COVID-19.
      ,
      • McKinney J.
      • Connelly K.A.
      • Dorian P.
      • Fournier A.
      • Goodman J.M.
      • Grubic N.
      • Isserow S.
      • Moulson N.
      • Philippon F.
      • Pipe A.
      • Poirier P.
      • Taylor T.
      • Thornton J.
      • Wilkinson M.
      • Johri A.M.
      COVID-19-Myocarditis and Return to Play: Reflections and Recommendations From a Canadian Working Group.
      ]. Recent analyses have mainly focused on the potential pathophysiological mechanisms and occurrence of AM either as a complication of the infection during the acute phase of disease or after the administration of COVID-19 vaccines [
      • Haussner W.
      • DeRosa A.P.
      • Haussner D.
      • Tran J.
      • Torres-Lavoro J.
      • Kamler J.
      • Shah K.
      COVID-19 associated myocarditis: A systematic review.
      ,
      • Castiello T.
      • Georgiopoulos G.
      • Finocchiaro G.
      • Claudia M.
      • Gianatti A.
      • Delialis D.
      • Aimo A.
      • Prasad S.
      COVID-19 and myocarditis: a systematic review and overview of current challenges.
      ,
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • Lee M.S.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ]. Conversely, few studies have investigated the risk of myocarditis following the index SARS-CoV-2 infection and the estimation of potential post-acute COVID-19 myocarditis represents a major knowledge-gap to be addressed. Therefore, the aim of the present manuscript is to assess the risk of incident myocarditis in COVID-19 survivors within one year from the index infection by a systematic review and meta-analysis of the available data.

      Material and Methods

      Study design

      This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline (Supplemental Table S1) [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022 and reporting the long-term risk of incident myocarditis in COVID-19 survivors diagnosed between 4 months (minimum follow-up length of revised investigations) and a maximum of 12 months post discharge (maximum follow-up length of revised studies) after index infection. In the revised manuscripts, this group of patients were compared to contemporary cohorts, defined as subjects who did not experience the SARS-CoV-2 infection and developed an AM in the same follow-up period. The reviewed investigations identified the occurrence of AM by screening the medical records of enrolled patients using the International Classification of Diseases 10th Revision (ICD-10) codes I40 and I51.4.

      Data extraction and quality assessment

      The selection of studies to be included in our analysis was independently conducted by two authors (M.Z., C.B.) in a blinded fashion. Any discrepancies in study selection were resolved by consulting a third author (G.R.). The following MeSH terms were used for the search: “Myocarditis” AND “COVID-19 sequelae” OR “myocarditis” AND “COVID-19”. Moreover, we searched the bibliographies of the target studies for additional references. Specifically, inclusion criteria were: (i) studies enrolling subjects with previous confirmed COVID-19 infection (ii) providing the hazard ratio (HR) and relative 95% confidence interval (CI) for the risk of incident myocarditis in the long-term period after the index infection compared to contemporary control cohorts. Conversely, case reports, review articles, abstracts, editorials/letters, and case series with less than 10 participants were excluded. Data extraction was independently conducted by two authors (M.Z., G.R). For all investigations reviewed we extracted, when provided, the number of patients enrolled, the mean age, male gender, prevalence of cardiovascular comorbidities such as arterial hypertension (HT), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), obesity, pre-existing HF, cerebrovascular disease and length of follow-up. The quality of included studies was graded using the Newcastle-Ottawa quality assessment scale (NOS) [

      Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, 2012. http://wwwohrica/programs/clinical_epidemiology/oxfordasp, Accessed September 29, 2022

      ].

      Data synthesis and analysis

      Continues variables were expressed as mean while categorical variables were presented as numbers and relative percentages. Myocarditis risk data were pooled using the Mantel–Haenszel random effects models with Hazard ratio (HR) as the effect measure with 95% confidence interval (CI). Heterogeneity among studies was assessed using Higgins and Thomson I2 statistic. Specifically, the I2 values correspond to the following levels of heterogeneity: low (<25%), moderate (25%-75%) and high (>75%). The presence of potential publication bias was verified by visual inspection of the funnel plot. Due to the low number of the included studies (<10), small-study bias was not examined as our analysis was underpowered to detect such bias. However, a predefined sensitivity analysis (leave-one-out analysis) was performed removing 1 study at the time, to evaluate the stability of our results regarding the risk of myocarditis. All meta-analyses were conducted using Comprehensive Meta-Analysis software, version 3 (Biostat, USA).

      Results

      Search results and included studies

      A total of 5.235 articles were obtained using our search strategy. After excluding duplicates and preliminary screening, 372 full-text articles were assessed for eligibility. Among them, 368 studies were excluded for not meeting the inclusion criteria, leaving 4 investigations fulfilling the inclusion criteria (Figure 1) [
      • Cohen K.
      • Ren S.
      • Heath K.
      • Dasmariñas M.C.
      • Jubilo K.G.
      • Guo Y.
      • Lipsitch M.
      • Daugherty S.E.
      Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
      ,
      • Wang W.
      • Wang C.Y.
      • Wang S.I.
      • Wei J.C.
      Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks.
      ,
      • Xie Y.
      • Xu E.
      • Bowe B.
      • Al-Aly Z.
      Long-term cardiovascular outcomes of COVID-19.
      ,
      • Daugherty S.E.
      • Guo Y.
      • Heath K.
      • Dasmariñas M.C.
      • Jubilo K.G.
      • Samranvedhya J.
      • Lipsitch M.
      • Cohen K.
      Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study.
      ].
      Figure thumbnail gr1
      Figure 1Flow diagram of selected studies for the meta-analysis according to the Preferred reporting items for systematic reviews and meta-analyses (PRISMA).

      Characteristics of the population and quality assessment

      Overall, 20.875.843 patients (mean age 56.1 years, 59.1% males) were included in this analysis [
      • McKinney J.
      • Connelly K.A.
      • Dorian P.
      • Fournier A.
      • Goodman J.M.
      • Grubic N.
      • Isserow S.
      • Moulson N.
      • Philippon F.
      • Pipe A.
      • Poirier P.
      • Taylor T.
      • Thornton J.
      • Wilkinson M.
      • Johri A.M.
      COVID-19-Myocarditis and Return to Play: Reflections and Recommendations From a Canadian Working Group.
      ,
      • Haussner W.
      • DeRosa A.P.
      • Haussner D.
      • Tran J.
      • Torres-Lavoro J.
      • Kamler J.
      • Shah K.
      COVID-19 associated myocarditis: A systematic review.
      ,
      • Castiello T.
      • Georgiopoulos G.
      • Finocchiaro G.
      • Claudia M.
      • Gianatti A.
      • Delialis D.
      • Aimo A.
      • Prasad S.
      COVID-19 and myocarditis: a systematic review and overview of current challenges.
      ,
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ]. Among them 1,245,167 had confirmed COVID-19 infection. The general characteristics of the studies included are presented in Table 1. Although the demographic characteristics and concomitant comorbidities were not systematically recorded in all investigations, the cohorts mainly consisted of middle-aged patients. The mean length of follow-up was 9.5 months. Over the follow-up period, myocarditis occurred to 0.21 [95% CI: 0.13- 0.42] out of 1000 patients survived to COVID-19 infection. Conversely, AM occurred in 0.09 [95% CI: 0.07-0.12] out of 1000 control subjects. Quality assessment showed that all studies were of moderate-high quality according to the NOS scale (Table 1) [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].
      Table 1General characteristics of the population reviewed. HT: Arterial Hypertension; DM: Diabetes Mellitus; COPD: chronic obstructive pulmonary disease; CKD: Chronic Kidney disease; HF: Heart failure; FW: Follow-up; NOS: Newcastle-Ottawa quality assessment scale; NR: Not reported. *Defined as Chronic Pulmonary disease; **Only DM type 2
      Sample sizeAge (years)MalesHTDMCOPDCKDObesityHFCancerCerebrovascular diseaseFW-length (months)NOS
      Cohen et al. [

      Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, 2012. http://wwwohrica/programs/clinical_epidemiology/oxfordasp, Accessed September 29, 2022

      ]
      2.895.94375.71.227.545 (42.0%)2.081.772 (72.0%)938.043 (32.7%)578.650 (20%)*528.314 (14.0%)478.902 (17.0%)334654 (12%)418.700 (14.4%)364.782 (13.0%)48
      Wang et al. [
      • Cohen K.
      • Ren S.
      • Heath K.
      • Dasmariñas M.C.
      • Jubilo K.G.
      • Guo Y.
      • Lipsitch M.
      • Daugherty S.E.
      Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
      ]
      2.940.98843.81.241.483 (42.2%)440.998 (14.9%)188.488 (6.4%)**51592 (1.7%)59177 (2.0%)286338 (9.7%)**NRNRNR127
      Xie et al. [
      • Wang W.
      • Wang C.Y.
      • Wang S.I.
      • Wei J.C.
      Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks.
      ]
      5.791.40762.55.228.431 (90.2%)1.525.944 (26.3%)1.321.907 (22.8%)633.000 (10.9%)970.057 (16.7%)2.462.44 (42.5%)NR357.192 (6.1%)NR128
      Daugherty et al. [
      • Xie Y.
      • Xu E.
      • Bowe B.
      • Al-Aly Z.
      Long-term cardiovascular outcomes of COVID-19.
      ]
      9.247.50542.44.640.393 (50.2%)NR521.699 (5.6%)NRNRNRNRNRNR66

      One-year risk of incident myocarditis

      During the follow-up period, recovered COVID-19 patients presented an increased risk of incident myocarditis (HR: 5.16, 95% CI: 3.87-6.89, p<0.0001, I2=7.9%) compared to subjects who did not experience COVID-19 infection but developed an AM over the same period (Figure 2). The funnel plot disclosed the presence of potential publication bias (Supplemental Figure S1). The sensitivity analysis confirmed yielded results reporting an HR ranging between 4.97 (95% CI: 3.81-6.47, p<0.0001, I2:0%) and 5.67 (95% CI: 4.06-7.88, p<0.0001, I2:16.7%), indicating that the obtained results were not driven by any single study.
      Figure thumbnail gr2
      Figure 2Forest plots investigating the long-term risk of incident myocarditis after COVID-19 Infection

      Discussion

      Our findings, based on a large population of more than 20 million people, demonstrated that myocarditis occurred in about 0.2 out of 1000 patients survived to COVID-19 infection. Moreover, after COVID-19 recovery, subjects had a significantly higher risk of myocarditis within one year from the index infection. To the best of our knowledge, the present analysis represents the first attempt to comprehensively assess the risk of incident myocarditis in the post-acute phase of COVID-19 subjects. Currently, long COVID represents a world-wide epidemic, caused by long-lasting multi-organ involvement, including cardiovascular system, that endures for weeks or months after the index SARS-CoV-2 infection has already subsided [
      • Gyöngyösi M.
      • Alcaide P.
      • Asselbergs F.W.
      • Brundel B.J.J.M.
      • Camici G.G.
      • da Costa Martins P.
      • Ferdinandy P.
      • Fontana M.
      • Girao H.
      • Gnecchi M.
      • Gollmann-Tepeköylü C.
      • Kleinbongard P.
      • Krieg T.
      • Madonna R.
      • Paillard M.
      • Pantazis A.
      • Perrino C.
      • Pesce M.
      • Schiattarella G.G.
      • Sluijter J.P.G.
      • Steffens S.
      • Tschöpe C.
      • Van Linthout S.
      • Davidson S.M.
      Long COVID and the cardiovascular system - elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: A joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial & Pericardial Diseases.
      ]. Our results demonstrate that the incidence rate of myocarditis among survivors of COVID-19 is 2-fold higher than that observed in unvaccinated subjects with COVID-related myocarditis in a recent study by Barda et al (21 vs 11 cases per 100.000 individuals) [
      • Barda N.
      • Dagan N.
      • Ben-Shlomo Y.
      • Kepten E.
      • Waxman J.
      • Ohana R.
      • Hernán M.A.
      • Lipsitch M.
      • Kohane I.
      • Netzer D.
      • Reis B.Y.
      • Balicer R.D.
      Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.
      ]. Of note, in that analysis, two contemporary series of subjects (vaccinated and unvaccinated) were followed up for 42 days after the administration of the first dose of mRNA vaccine against SARS-CoV-2 infection.
      AM has been also recognized as a rare complication of COVID-19 mRNA vaccinations, especially in young adult and adolescent males, with an estimated incidence of about 12.6 cases per million doses of second-dose mRNA vaccine [
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ]. mRNA vaccines contain nucleoside-modified mRNA, encoding the viral spike glycoprotein of SARS-CoV-2. However, selected RNA molecules can be immunogenic and stimulate the innate immune system, destroying the mRNA before it reaches target cells, preventing the spike protein and neutralizing antibody production, promoting the activation of an aberrant innate and acquired immune response and which may lead to the activation of proinflammatory cascades and immunologic pathways triggering AM [
      • Karikó K.
      • Buckstein M.
      • Ni H.
      • Weissman D.
      Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA.
      ,
      • Caso F.
      • Costa L.
      • Ruscitti P.
      • Navarini L.
      • Del Puente A.
      • Giacomelli R.
      • Scarpa R.
      Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects?.
      ].However, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is currently recommended for everyone ≥12 years of age [
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ].
      Findings from the present study point towards a mild increase in the incidence of myocarditis in the first year compared to that observed in the first 1-2 months following the index SARS-CoV-2 infection. Moreover, the risk of AM resulted higher compared to other subjects who did not experience the infection in the same period. Available studies did not systematically report data regarding the risk of incident myocarditis according to age, gender, pre-existence of any cardiovascular conditions, and hospitalization for COVID-19 infection; therefore, dedicated sub analyses on this were not feasible. However, a higher risk of incident myocarditis after COVID-19 recovery has been reported in younger patients, aged < 44 years [
      • Haussner W.
      • DeRosa A.P.
      • Haussner D.
      • Tran J.
      • Torres-Lavoro J.
      • Kamler J.
      • Shah K.
      COVID-19 associated myocarditis: A systematic review.
      ,
      • Castiello T.
      • Georgiopoulos G.
      • Finocchiaro G.
      • Claudia M.
      • Gianatti A.
      • Delialis D.
      • Aimo A.
      • Prasad S.
      COVID-19 and myocarditis: a systematic review and overview of current challenges.
      ], as well as in subjects with previous cardiovascular disease prior to the SARS-CoV-2 exposure [
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis With COVID-19 mRNA Vaccines.
      ,
      • Simone A.
      • Herald J.
      • Chen A.
      • Gulati N.
      • Shen A.Y.
      • Lewin B.
      • Lee M.S.
      Acute Myocarditis Following COVID-19 mRNA Vaccination in Adults Aged 18 Years or Older.
      ]. Moreover, available data regarding the risk of AM during the follow-up period are controversial as Daugherty et al. [
      • Daugherty S.E.
      • Guo Y.
      • Heath K.
      • Dasmariñas M.C.
      • Jubilo K.G.
      • Samranvedhya J.
      • Lipsitch M.
      • Cohen K.
      Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study.
      ] observed a higher risk among subjects who were not hospitalized for the COVID-19 infection, while Xie et al [
      • Xie Y.
      • Xu E.
      • Bowe B.
      • Al-Aly Z.
      Long-term cardiovascular outcomes of COVID-19.
      ] reported an increased risk in patients managed in the intensive care unit at the time of the index infection. No significant gender differences were observed regarding AM.
      The different recovery setting, and therefore the illness severity may have influenced such results. Indeed, subjects with a mild/moderate COVID-19 infection, gene3rally treated at home, should have received a lower dosage or neither immunomodulatory treatment, as corticosteroids, while those admitted into intensive care unit, due to a more severe disease, may have received higher dose of immunomodulatory drugs. Therefore, the different systemic corticosteroid regimens, or more in general the administration of immunomodulatory drugs, related to the severity of the infection, may have influenced the patient’s immunosuppression and as consequence the cytocidal effect of the virus on cardiac muscle, which has a critical role in the genesis of myocarditis [
      • Karikó K.
      • Buckstein M.
      • Ni H.
      • Weissman D.
      Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA.
      ,
      • Caso F.
      • Costa L.
      • Ruscitti P.
      • Navarini L.
      • Del Puente A.
      • Giacomelli R.
      • Scarpa R.
      Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects?.
      ]. Several pathophysiological mechanisms have been suggested to explain the cardiac involvement including a direct damage to the myocardium by the virus, a micro-thrombotic damage to vessels or endothelium and a persistent systemic inflammation [
      • Siripanthong B.
      • Asatryan B.
      • Hanff T.C.
      • Chatha S.R.
      • Khanji M.Y.
      • Ricci F.
      • Muser D.
      • Ferrari V.A.
      • Nazarian S.
      • Santangeli P.
      • Deo R.
      • Cooper Jr., L.T.
      • Mohiddin S.A.
      • Chahal C.A.A.
      The Pathogenesis and Long-Term Consequences of COVID-19 Cardiac Injury.
      ]. Intriguingly, our results demonstrates that the incidence and risk of myocarditis after hospital discharge is much lower compared to the in-hospital incidence and relative risk observed during the acute phase of COVID-19 infection [
      • Priyadarshni S.
      • Westra J.
      • Kuo Y.F.
      • Baillargeon J.G.
      • Khalife W.
      • Raji M.
      COVID-19 Infection and Incidence of Myocarditis: A Multi-Site Population-Based Propensity Score-Matched Analysis.
      ]. Unfortunately, to date, specific markers, able to identify and guide managing physicians in the treatment of long COVID, and its cardiovascular sequelae have not yet been identified. Dedicated studies are urgently required in the future to identify the profiles of subjects at higher risk of post-acute COVID sequelae and strategies to minimize their cardiovascular risk. To this regard, future investigation assessing the risk of post-COVID-19 sequelae, will have to evaluate whether current criteria for vaccination against COVID-19 should be revised or enriched especially in subjects with previous cardiovascular disease or just having some cardiovascular risk factors [
      • Oster M.E.
      • Shay D.K.
      • Su J.R.
      • Gee J.
      • Creech C.B.
      • Broder K.R.
      • Edwards K.
      • Soslow J.H.
      • Dendy J.M.
      • Schlaudecker E.
      • Lang S.M.
      • Barnett E.D.
      • Ruberg F.L.
      • Smith M.J.
      • Campbell M.J.
      • Lopes R.D.
      • Sperling L.S.
      • Baumblatt J.A.
      • Thompson D.L.
      • Marquez P.L.
      • Strid P.
      • Woo J.
      • Pugsley R.
      • Reagan-Steiner S.
      • DeStefano F.
      • Shimabukuro T.T.
      Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021.
      ]

      Limitations

      Our study has several limitations related to the observational nature of the studies reviewed and their own limitations with all inherited bias. Potential underestimation could derive from detection bias considering that most of the articles reviewed identified the occurrence of an incident myocarditis from larger medical records dataset using the relative ICD-10 codes; therefore, the investigators did not perform a clinical follow-up; thus, we cannot exclude that miscoding may have biased our results. Moreover, we cannot exclude potential overestimation of our results due to the presence of competing risks. Nevertheless, the sample size analyzed, the sensitivity analysis and the very low heterogeneity level observed confirmed the robustness of our results. Unfortunately, the revised studies did not systematically report data regarding potential risk factors for AM as well as no data related to the characteristics of observed events. Moreover, sampling bias by the competing risk of death could be another potential source of biases. Furthermore, available data from included study did not allow us to provide information on the diagnostic criteria adopted (non-invasive or invasive) and the type of AM, the type and number of vaccinations against SARS-CoV-2 as well as the proportion of patients having a COVID-related myocarditis during the index infection. Finally, the reviewed data may have underestimated the real impact of myocarditis after COVID-19 recovery especially during the early phase of the pandemic, for the presence of undiagnosed cases and for patients lost during the follow-up period. Unfortunately, no data were provided regarding the demographical and clinical characteristics of subjects experiencing an acute myocarditis after the COVID-19 infection, limiting potential sub-analyses.

      Conclusions

      Myocarditis represents a relatively rare post-acute COVID-19 sequelae within one year after the index infection. Physicians must be aware of this potential sequalae allowing its prompt recognition and treatment.

      Acknowledgements

      None
      Funding Sources: None
      Disclosures: None of the authors have conflicts of interest to declare

      Supplementary Material

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      Linked Article

      • Incident myocarditis in COVID-19 recovered patients- Is there a cause for concern?
        Canadian Journal of Cardiology
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          In this issue of the Canadian Journal of Cardiology, Zuin et al. completed a systematic review and meta-analysis to assess the risk of incident acute myocarditis (AM) in novel Coronavirus disease 2019 (COVID-19) survivors within 1 year following their index infection.1 Data from 4 studies reporting cases of AM in the post-acute phase of infection (4-12 months) were identified searching MEDLINE and Scopus (up to September 1, 2022). Mean age, sex, pre-existing co-morbid conditions including presence of hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and stroke, as well as length of follow-up were recorded.
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