a Attribute is significant ( P <.05).
b Not available.
c The corresponding coefficients and P values are not provided.
In total, 2 of the 5 multicountry studies did not report preferences for each country and were therefore excluded from the synthesis of the most important attribute. A total of 53 data points on COVID-19 vaccine preferences were collected from the study population of the corresponding country. In the outcome category, among the 30 attributes examined, effectiveness emerged as the most prominent, accounting for 40% (21/53) of the studies [ 31 , 35 , 36 , 38 - 42 , 48 , 50 - 52 , 57 , 58 , 60 - 62 , 64 - 67 ]. Safety was addressed in 13% (7/53) of the studies [ 33 , 43 , 47 , 56 , 59 , 68 , 69 ], while protection duration was mentioned in 4% (2/53) [ 11 , 50 ]. In the process category, 13 attributes were identified. Brand (1/53, 2%) [ 32 ], region of vaccine manufacturer (1/53, 2%) [ 34 ], and halal content (1/53, 2%) [ 53 ] were associated with vaccine production. In addition, waiting time for COVID-19 vaccination (1/53, 2%) [ 70 ] and vaccine frequency (1/53, 2%) [ 71 ] were considered. Furthermore, 3 (6%) studies on vaccine distribution prioritized vaccination for the medical risk group (1/53, 2%) [ 72 ], those who had a higher COVID-19 mortality risk (6/53, 11%) [ 63 ], and those who had the potential capacity to spread the virus (1/53, 2%) [ 72 ]. In the cost category, personal vaccination cost accounted for 6% (3/53) [ 31 , 37 , 41 ]. Among the other attributes (7/53, 13%), disease risk threat was of particular importance, including possible trends of the epidemic (1/53, 2%) [ 30 ] and COVID-19 mortality rate (1/53, 2%) [ 55 ]. In addition, incentives and penalties for vaccination were identified, including quarantine-free travel (1/53, 2%) [ 33 ] and mandatory testing at own expense if not vaccinated (1/53, 2%) [ 44 ]. Vaccine advice or support included vaccination invitation sender (1/53, 2%) [ 73 ] and recommenders (1/53, 2%) [ 46 ]. The proportion of friends and family members who had received the vaccine (1/53, 2%) [ 26 ] was also among the other attributes influencing decision-making ( Table 2 ).
Although effectiveness remained the most important attribute, it is worth noting that variations in preferences were also observed among different subgroups. A higher proportion of studies conducted in LMICs (4/24, 17%) than in HICs (3/29, 10%) prioritized on safety ( Multimedia Appendix 5 ). In addition, COVID-19 mortality risk was the second most important attribute (6/29, 21%) after effectiveness in HICs. Cost was considered to be another most important attribute (3/24, 13%) in LMICs. Interestingly, many other attributes also became more important as the pandemic progressed. Protection duration (2/24, 8%) emerged as one of the most important attributes during the pandemic wave. COVID-19 mortality risk (5/25, 20%) and cost (3/25, 12%) were considered as the most important attributes after the pandemic wave ( Multimedia Appendix 6 ).
The overall reporting quality was deemed acceptable but there is room for improvement. The PREFS scores of the 47 studies ranged from 2 to 4, with a mean of 3.23 (SD 0.52). No study scored 5. Most studies scored 3 (32/47, 68%) or 4 (13/47, 28%), while 2 studies (2/47, 4%) scored 2 ( Multimedia Appendix 7 [ 11 , 26 , 30 - 74 ]).
This systematic review synthesizes existing data on preference for COVID-19 vaccine using DCE, with the aim of informing improvements in vaccine coverage and vaccine policy development. We identified 47 studies conducted in 29 countries, including 21 HICs and 8 LMICs. HICs had an adequate supply of vaccine since the early emergency availability of COVID-19 vaccine, and HICs had 1.5 times more doses of COVID-19 vaccinations than LMICs by September 2023 [ 85 ]. In total, 19 (40%) studies were conducted in China and 9 (19%) in the United States, demonstrating their significant contribution to the research and their leadership in vaccine research and development. Vaccine effectiveness and safety were the most important attributes in DCEs, although preferences differed among subgroups.
Recent years have seen new trends in the design, implementation, and validation of the DCE. For example, most studies (40/47, 85%) reported that the DCE was administered through web-based surveys, which have become a quick and cost-effective way to collect DCE data [ 66 ]. Almost half of the studies (25/47, 53%) did not report a pilot test. However, piloting in multiple stages throughout the development of a DCE is conducive to identifying appropriate and understandable attributes, considering whether participants can effectively evaluate the full profiles, and producing an efficient design [ 21 , 86 , 87 ].
Overall, vaccine effectiveness and safety have emerged as the most commonly investigated attributes in the outcome category. Despite heterogeneity in preferences across subpopulations, effectiveness remains the primary driver for COVID-19 vaccination across the studies [ 31 , 35 , 36 , 38 - 42 , 48 , 50 , 51 , 57 , 58 , 60 - 62 , 64 - 67 ], similar to the previous findings [ 18 ]. A study conducted in India and Europe found that respondents’ preference for the COVID-19 vaccine increased with effectiveness and peaked at 95% effectiveness [ 45 ]. Another study conducted among university staff and students in South Africa found that vaccine effectiveness not only was a concern but also significantly influenced vaccine choice behavior [ 64 ]. Interestingly, a nationwide stated choice survey in the United States found a strong interaction between effectiveness and other attributes [ 58 ]. These findings support the ongoing efforts to maximize vaccine effectiveness while emphasizing the importance of communicating information on vaccine effectiveness to the target population for promotion [ 62 ].
Safety has also been identified as a crucial factor influencing the acceptance of COVID-19 vaccine [ 33 , 43 , 47 , 56 , 59 , 68 , 69 ]. One study indicated that the likelihood of the general public choosing vaccines with low or moderate side effects increased by 75% and 63%, respectively, compared with vaccines with high side effects. While the likelihood changed within a 30% range when most attributes other than effectiveness and safety were changed [ 69 ]. In addition, respondents in Australia expressed a willingness to wait an additional 0.04 and 1.2 months to reduce the incidence of mild and severe adverse events by 1/10,000, respectively [ 56 ].
Similar to the results of previous systematic reviews of DCEs for various vaccines [ 18 , 19 ], the most common predictors of COVID-19 vaccine acceptance are effectiveness and safety, particularly during the rapid development and rollout of COVID-19 vaccines, which essentially boils down to trust in the vaccine [ 31 ]. Respondents expressed the importance of having a safe and effective COVID-19 vaccine available as soon as possible, but the majority preferred to wait a few months to observe the experience of others rather than be the first in line [ 43 ]. Therefore, collaborating to enhance vaccine effectiveness while reducing the risk of severe side effects could be a highly effective strategy to address vaccine hesitancy and augment vaccine desirability. Dissemination of this important vaccine-related information by governments and health care institutions, along with effective communication by health care professionals, can help build public trust and ultimately increase vaccination rates [ 69 ]. However, these inherent vaccine attributes are typically beyond the control of a vaccination program, and given the ongoing mutations of SARS-CoV-2, it is challenging to predict the effectiveness of the vaccines currently in development [ 66 ]. Global collaboration between scientists and pharmaceutical companies is therefore essential to improve vaccine effectiveness and minimize side effects [ 41 ].
Vaccine production, including its origin, brand, vaccine frequency, and content, are key considerations in the process category. Vaccine brand also has a significant impact on vaccine choice [ 32 ], independent of effectiveness and safety, due to factors such as reputation, country of origin, technological advances, and reported side effects associated with the brands [ 35 ]. For vaccine origin, some studies found that participants preferred domestic vaccines to imported vaccines, which may depend on the availability or the approval of vaccines in different countries [ 31 , 41 , 50 ] or the incidence of side effects among different types of COVID-19 vaccines [ 37 ]. However, some studies found that imported vaccines were more likely to be accepted than domestically produced vaccines, which may be attributed to less trust in domestically produced vaccines [ 57 , 66 ]. A study on vaccine preferences among the Malaysian population found that the composition and production process of the COVID-19 vaccine, which complied with Islamic dietary requirements (ie, halal content) was an important factor for many Malaysians when deciding whether to be vaccinated. This underscores the substantial influence of religion on vaccine choice [ 53 ].
Vaccine frequency was emphasized to play an important role in the choice of COVID-19 vaccine among the US public, while the 90% efficacy with low side effect rate of the COVID-19 vaccine was set. The prospect of vaccinating once to get lifelong immunity was very attractive, reflecting the fact that people were effort minimizers [ 71 ]. This is similar to the nature of the 2 studies referenced in the outcome attribute, where the protection duration is prioritized. Given the threat of COVID-19, people expect the protection duration to be as long as possible [ 11 , 50 ].
When vaccine supply is limited, people tend to prioritize vaccination for those who are more susceptible to the disease, have higher mortality rates from infectious diseases, or have greater potential to spread the virus. A study in Iran found that individuals tend to prioritize vaccination for those in the community with higher potential for virus transmission [ 57 ]. In addition, results from a study in 6 European countries revealed unanimous agreement among respondents that candidates with higher mortality and infection risks should be prioritized for vaccination [ 63 ]. While another study conducted among Belgians also found that respondents would prioritize populations at higher medical risk [ 72 ].
Cost was another important factor influencing COVID-19 vaccine preferences, mostly related to out-of-pocket costs [ 31 , 37 , 41 ]. In 2 studies comparing public preferences for COVID-19 vaccines in China and the United States, vaccine efficacy emerged as the most important driver for the American public, whereas the cost of vaccination had the greatest impact on the Chinese public. This difference was likely due to the relatively stable pandemic situation in China at the time and the lower perceived risk of COVID-19. As a result, the Chinese population was more price sensitive and reluctant to pay for vaccination [ 31 , 37 , 41 ].
For the other category, several different attributes were highlighted, depending on the specific population or situation. When people perceive the threat of a disease, their desire to be vaccinated becomes more urgent. In a study among health care workers in China, participants’ expectations about the future development of COVID-19 had a greater impact on their decision to be vaccinated than their perceived risk of infection or actual case rates, which may have been influenced by their previous experience with seasonal influenza vaccination [ 30 ]. The mortality rate of COVID-19 was considered the most influential factor in the uptake of COVID-19 booster shots in Vietnam. This study was conducted during a pandemic wave in Vietnam, which may have led to an increased perception of public health risks and a greater inclination toward COVID-19 vaccination [ 55 ]. To achieve herd immunity, government authorities can implement policies of incentives and penalties for vaccination to encourage population-wide uptake. A study conducted in the Netherlands revealed that respondents particularly disliked policies that penalized those who were not vaccinated, such as mandatory testing at their own expense if they were not vaccinated [ 44 ]. Instead, they favored policies that rewarded vaccination, such as giving vaccinated individuals additional privileges through a vaccination passport. This finding is consistent with a study in Hong Kong, which found that quarantine-free travel was considered the most important motivator among university students and staff, given their frequent engagement in international travel [ 33 ].
The source of vaccine information also influences vaccine decision-making [ 30 ]. Variation in the sender of vaccination appointment invitation via SMS text messaging and recommenders may potentially influence the public’s willingness to vaccinate against a disease [ 30 , 46 , 73 ]. Furthermore, the acceptance of vaccines was observed to change as the firsthand information about vaccine side effects and effectiveness was provided by friends and family in India [ 26 ].
In HICs, COVID-19 mortality risk was the second most important attribute after effectiveness, as respondents in all 6 high-income European countries from a study of public preferences for COVID-19 vaccine distribution prioritized candidates with higher mortality risks [ 63 ]. However, individuals from LMICs appeared to be more concerned about vaccine safety than those from HICs. This may be related to greater confidence in vaccine safety in HICs due to the earlier initiation and higher rates of COVID-19 vaccination [ 85 ]. In contrast, in some LMICs, vaccine safety was reported as the main reason influencing the willingness to vaccinate due to the rapid development of the COVID-19 vaccines [ 26 , 43 , 47 , 59 , 68 , 69 , 74 , 88 ].
Interestingly, the preference for COVID-19 vaccines may also have changed as the pandemic progressed [ 63 ]. Similarly, effectiveness remained the most important attribute in all periods, possibly due to the continuing severity of the pandemic and the fear of the possible emergence of new coronavirus strains [ 43 ]. Before the pandemic wave, the information on vaccine effectiveness was limited [ 26 ], but people still considered vaccine effectiveness to be the most important driver of vaccination. However, during the pandemic, the public’s perception of the health risk increased. As vaccines were introduced and used, people seemed to become more concerned about the duration of vaccine protection and preferred a longer vaccine protection [ 11 , 50 ]. After the pandemic wave, as the pandemic situation gradually stabilized, cost, combined with their perception of the risk of susceptibility, became more important in their preferences. However, despite this shift, most of the public still believed that people who are at higher risk of infection or death should be vaccinated first [ 63 ].
Our study had several limitations. First, not all studies used the same attributes and levels, which limited our ability to perform a quantitative synthesis and directly compare the estimates of model parameters. Instead, we qualitatively synthesized and summarized the range of attributes that may be useful in the formative stage of attribute selection in future DCE surveys investigating the preference for COVID-19 vaccine. Second, although DCEs have been shown to be a valid method for eliciting preferences, the experiment may not represent real market choices but rather hypothetical scenarios with plausible and realistic attributes. However, it offers opportunities to evaluate vaccines that are not yet available in the market or to specific population [ 68 ]. Third, the commonly used classification of outcome, cost, and process was used in order to better explain the public’s preference for vaccine attributes. However, several attributes could not be properly classified, and a fourth category (ie, other attributes) had to be added [ 19 ]. Meanwhile, the variety of attributes included may make it difficult to appropriately name and interpret this category as a whole. Fifth, the PREFS checklist is limited to 5 questions and fails to elicit several criteria that should be reported in DCE studies. Also, it does not provide sufficient tools to assess the biases in a DCE, such as selection bias and nonresponse bias [ 79 , 89 ]. Finally, although there was no specific theoretical framework to structure our qualitative analysis from the 4 identified categories, our classification was based on previous studies [ 18 , 19 , 82 , 90 , 91 ] and our own findings. This synthesis led us to categorize attributes into 4 main classes, providing a clear structure for analyzing and presenting participants’ vaccine preferences and making it easier to compare their preferences across different studies.
In conclusion, this systematic review synthesized the global evidence on preferences for COVID-19 vaccines using the DCE methodology. Vaccine effectiveness and safety were found to be the main drivers for COVID-19 vaccination, highlighting the importance of global collaboration to improve vaccine effectiveness and minimize side effects, as well as the importance of communicating this vaccine-related information to the public to maximize the uptake of COVID-19 vaccines. The subgroup analyses emphasized the importance of differences in vaccine preference of specific populations and time periods in optimizing the acceptance of COVID-19 vaccines. These findings may serve as valuable insights for government agencies involved in the social mobilization process for COVID-19 vaccination. However, the response to the pandemic is a continuous learning process [ 92 ]. It is crucial for policy makers to consider preference evidence when designing policies to promote vaccination.
The authors have not received a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
All data relevant to the study are included in the article or uploaded as supplemental information. Data sets of this study are available upon reasonable request to the corresponding author.
YH, SF, and YZ are joint first authors. HJ conceived the study and its methodology. YH, SF, and YZ designed, refined, and implemented the search strategy; screened articles for inclusion; and extracted and curated the data. All authors contributed to the interpretation of the results. YH, SF, and YZ wrote the initial draft of the manuscript. HJ and HW critically reviewed the manuscript. HJ supervised the study design and provided overall guidance. All authors approved the final draft of the manuscript. HJ had full access to all the data used in this study, and all authors had final responsibility for the decision to submit for publication.
None declared.
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 checklist.
Search strategies.
Attributes included in each category.
The detailed distribution of the study period across countries.
Preference for COVID-19 vaccines among high-income countries and low- and middle-income countries (n=53).
Preference for COVID-19 vaccines in the different study periods (n=53).
Assessment of 47 included studies quality using the Purpose, Respondents, Explanation, Findings, and Significance checklist.
discrete choice experiment |
high-income country |
low- and middle-income country |
Purpose, Respondents, Explanation, Findings, and Significance |
Preferred Reporting Items for Systematic Reviews and Meta-Analyses |
Edited by A Mavragani; submitted 19.01.24; peer-reviewed by T Ricks, I Saha; comments to author 11.04.24; revised version received 01.05.24; accepted 26.05.24; published 29.07.24.
©Yiting Huang, Shuaixin Feng, Yuyan Zhao, Haode Wang, Hongbo Jiang. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 29.07.2024.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Public Health and Surveillance, is properly cited. The complete bibliographic information, a link to the original publication on https://publichealth.jmir.org, as well as this copyright and license information must be included.
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Evidence-based interventions for frontline health care workers—a literature review.
Delassalle, Nancy BSN, RN, CCRN; Cavaciuti, Mary MPH, BSN, RN, CCRN
Nancy Delassalle, BSN, RN, CCRN , has more than 35 years of experience as a critical care nurse at Long Island Jewish Medical Center, New Hyde Park, New York. She has been on the Rapid Response/Code Blue team for the past 8 years.
Mary Cavaciuti, MPH, BSN, RN, CCRN , has more than 31 years of experience in critical care at Long Island Jewish Medical Center, New Hyde Park, New York.
Nancy Delassalle and Mary Cavaciuti are cochairs of the Research and Evidence-Based council.
Nancy Delassalle and Mary Cavaciuti are co–primary authors.
The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Address correspondence and reprint requests to: Nancy Delassalle BSN, RN, CCRN ( [email protected] ).
The COVID-19 pandemic has had a serious impact on the psychological well-being of frontline health care workers. A variety of interventions have been offered to health care workers in their workplace that has them questioning which intervention would be most beneficial. The purpose of this review is to determine what evidence-based interventions would have an impact on alleviating COVID-19-related psychological distress.
A search was conducted from multiple databases, including Pubmed, CINAHL, Joanna Briggs, and Cochrane, using the PRISMA framework. The search included COVID-19 as well as previous pandemics. Critical appraisal and synthesis of the 16 relevant sources of evidence were completed.
Based on the current evidence, one cannot conclude that any specific intervention is effective for pandemic-relate distress.
The development, implementation, and scientific evaluation of evidence-based interventions to address the immediate, as well as the long-term, psychological effects of COVID-19 on the mental well-being of health care workers, are needed.
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A culture of respect: champions and models, the gifts of summer, auricular acupuncture to relieve health care workers’ stress and anxiety:..., dccn</em>', 'gould kathleen ahern phd rn', 'dimensions of critical care nursing', 'september/october 2013', '32', '5' , 'p 272');" onmouseout="javascript:tooltip_mouseout()" class="ejp-uc__article-title-link">submitting a manuscript to dccn, should prayer be used in medicine.
The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among individuals older than 40 years of age, there were no more than 8 reports of myocarditis for any individual age after receiving either vaccine. For the BNT162b2 vaccine, there were 114 246 837 first vaccination doses and 95 532 396 second vaccination doses; and for the mRNA-1273 vaccine, there were 78 158 611 and 66 163 001, respectively. The y-axis range differs between panels A and B.
The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among recipients of either vaccine, there were only 13 reports or less of myocarditis beyond 10 days for any individual time from vaccination to symptom onset. The y-axis range differs between panels A and B.
A, For the BNT162b2 vaccine, there were 138 reported cases of myocarditis with known date for symptom onset and dose after 114 246 837 first vaccination doses and 888 reported cases after 95 532 396 second vaccination doses.
B, For the mRNA-1273 vaccine, there were 116 reported cases of myocarditis with known date for symptom onset and dose after 78 158 611 first vaccination doses and 311 reported cases after 66 163 001 second vaccination doses.
eMethods. Medical Dictionary for Regulatory Activities Preferred Terms, Definitions of Myocarditis and Pericarditis, Myocarditis medical review form
eFigure. Flow diagram of cases of myocarditis and pericarditis reported to Vaccine Adverse Event Reporting System (VAERS) after receiving mRNA-based COVID-19 vaccine, United States, December 14, 2020-August 31, 2021.
eTable 1. Characteristics of all myocarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.
eTable 2. Characteristics of all pericarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.
eTable 3. Characteristics of myocarditis cases reported to Vaccine Adverse Event Reporting System after mRNA-based COVID-19 vaccination by case definition status.
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Oster ME , Shay DK , Su JR, et al. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021. JAMA. 2022;327(4):331–340. doi:10.1001/jama.2021.24110
© 2024
Question What is the risk of myocarditis after mRNA-based COVID-19 vaccination in the US?
Findings In this descriptive study of 1626 cases of myocarditis in a national passive reporting system, the crude reporting rates within 7 days after vaccination exceeded the expected rates across multiple age and sex strata. The rates of myocarditis cases were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively).
Meaning Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men.
Importance Vaccination against COVID-19 provides clear public health benefits, but vaccination also carries potential risks. The risks and outcomes of myocarditis after COVID-19 vaccination are unclear.
Objective To describe reports of myocarditis and the reporting rates after mRNA-based COVID-19 vaccination in the US.
Design, Setting, and Participants Descriptive study of reports of myocarditis to the Vaccine Adverse Event Reporting System (VAERS) that occurred after mRNA-based COVID-19 vaccine administration between December 2020 and August 2021 in 192 405 448 individuals older than 12 years of age in the US; data were processed by VAERS as of September 30, 2021.
Exposures Vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna).
Main Outcomes and Measures Reports of myocarditis to VAERS were adjudicated and summarized for all age groups. Crude reporting rates were calculated across age and sex strata. Expected rates of myocarditis by age and sex were calculated using 2017-2019 claims data. For persons younger than 30 years of age, medical record reviews and clinician interviews were conducted to describe clinical presentation, diagnostic test results, treatment, and early outcomes.
Results Among 192 405 448 persons receiving a total of 354 100 845 mRNA-based COVID-19 vaccines during the study period, there were 1991 reports of myocarditis to VAERS and 1626 of these reports met the case definition of myocarditis. Of those with myocarditis, the median age was 21 years (IQR, 16-31 years) and the median time to symptom onset was 2 days (IQR, 1-3 days). Males comprised 82% of the myocarditis cases for whom sex was reported. The crude reporting rates for cases of myocarditis within 7 days after COVID-19 vaccination exceeded the expected rates of myocarditis across multiple age and sex strata. The rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively). There were 826 cases of myocarditis among those younger than 30 years of age who had detailed clinical information available; of these cases, 792 of 809 (98%) had elevated troponin levels, 569 of 794 (72%) had abnormal electrocardiogram results, and 223 of 312 (72%) had abnormal cardiac magnetic resonance imaging results. Approximately 96% of persons (784/813) were hospitalized and 87% (577/661) of these had resolution of presenting symptoms by hospital discharge. The most common treatment was nonsteroidal anti-inflammatory drugs (589/676; 87%).
Conclusions and Relevance Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.
Myocarditis is an inflammatory condition of the heart muscle that has a bimodal peak incidence during infancy and adolescence or young adulthood. 1 - 4 The clinical presentation and course of myocarditis is variable, with some patients not requiring treatment and others experiencing severe heart failure that requires subsequent heart transplantation or leads to death. 5 Onset of myocarditis typically follows an inciting process, often a viral illness; however, no antecedent cause is identified in many cases. 6 It has been hypothesized that vaccination can serve as a trigger for myocarditis; however, only the smallpox vaccine has previously been causally associated with myocarditis based on reports among US military personnel, with cases typically occurring 7 to 12 days after vaccination. 7
With the implementation of a large-scale, national COVID-19 vaccination program starting in December 2020, the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration began monitoring for a number of adverse events of special interest, including myocarditis and pericarditis, in the Vaccine Adverse Event Reporting System (VAERS), a long-standing national spontaneous reporting (passive surveillance) system. 8 As the reports of myocarditis after COVID-19 vaccination were reported to VAERS, the Clinical Immunization Safety Assessment Project, 9 a collaboration between the CDC and medical research centers, which includes physicians treating infectious diseases and other specialists (eg, cardiologists), consulted on several of the cases. In addition, reports from several countries raised concerns that mRNA-based COVID-19 vaccines may be associated with acute myocarditis. 10 - 15
Given this concern, the aims were to describe reports and confirmed cases of myocarditis initially reported to VAERS after mRNA-based COVID-19 vaccination and to provide estimates of the risk of myocarditis after mRNA-based COVID-19 vaccination based on age, sex, and vaccine type.
VAERS is a US spontaneous reporting (passive surveillance) system that functions as an early warning system for potential vaccine adverse events. 8 Co-administered by the CDC and the US Food and Drug Administration, VAERS accepts reports of all adverse events after vaccination from patients, parents, clinicians, vaccine manufacturers, and others regardless of whether the events could plausibly be associated with receipt of the vaccine. Reports to VAERS include information about the vaccinated person, the vaccine or vaccines administered, and the adverse events experienced by the vaccinated person. The reports to VAERS are then reviewed by third-party professional coders who have been trained in the assignment of Medical Dictionary for Regulatory Activities preferred terms. 16 The coders then assign appropriate terms based on the information available in the reports.
This activity was reviewed by the CDC and was conducted to be consistent with applicable federal law and CDC policy. The activities herein were confirmed to be nonresearch under the Common Rule in accordance with institutional procedures and therefore were not subject to institutional review board requirements. Informed consent was not obtained for this secondary use of existing information; see 45 CFR part 46.102(l)(2), 21 CFR part 56, 42 USC §241(d), 5 USC §552a, and 44 USC §3501 et seq.
The exposure of concern was vaccination with one of the mRNA-based COVID-19 vaccines: the BNT162b2 vaccine (Pfizer-BioNTech) or the mRNA-1273 vaccine (Moderna). During the analytic period, persons aged 12 years or older were eligible for the BNT162b2 vaccine and persons aged 18 years or older were eligible for the mRNA-1273 vaccine. The number of COVID-19 vaccine doses administered during the analytic period was obtained through the CDC’s COVID-19 Data Tracker. 17
The primary outcome was the occurrence of myocarditis and the secondary outcome was pericarditis. Reports to VAERS with these outcomes were initially characterized using the Medical Dictionary for Regulatory Activities preferred terms of myocarditis or pericarditis (specific terms are listed in the eMethods in the Supplement ). After initial review of reports of myocarditis to VAERS and review of the patient’s medical records (when available), the reports were further reviewed by CDC physicians and public health professionals to verify that they met the CDC’s case definition for probable or confirmed myocarditis (descriptions previously published and included in the eMethods in the Supplement ). 18 The CDC’s case definition of probable myocarditis requires the presence of new concerning symptoms, abnormal cardiac test results, and no other identifiable cause of the symptoms and findings. Confirmed cases of myocarditis further require histopathological confirmation of myocarditis or cardiac magnetic resonance imaging (MRI) findings consistent with myocarditis.
Deaths were included only if the individual had met the case definition for confirmed myocarditis and there was no other identifiable cause of death. Individual cases not involving death were included only if the person had met the case definition for probable myocarditis or confirmed myocarditis.
We characterized reports of myocarditis or pericarditis after COVID-19 vaccination that met the CDC’s case definition and were received by VAERS between December 14, 2020 (when COVID-19 vaccines were first publicly available in the US), and August 31, 2021, by age, sex, race, ethnicity, and vaccine type; data were processed by VAERS as of September 30, 2021. Race and ethnicity were optional fixed categories available by self-identification at the time of vaccination or by the individual filing a VAERS report. Race and ethnicity were included to provide the most complete baseline description possible for individual reports; however, further analyses were not stratified by race and ethnicity due to the high percentage of missing data. Reports of pericarditis with evidence of potential myocardial involvement were included in the review of reports of myocarditis. The eFigure in the Supplement outlines the categorization of the reports of myocarditis and pericarditis reviewed.
Further analyses were conducted only for myocarditis because of the preponderance of those reports to VAERS, in Clinical Immunization Safety Assessment Project consultations, and in published articles. 10 - 12 , 19 - 21 Crude reporting rates for myocarditis during a 7-day risk interval were calculated using the number of reports of myocarditis to VAERS per million doses of COVID-19 vaccine administered during the analytic period and stratified by age, sex, vaccination dose (first, second, or unknown), and vaccine type. Expected rates of myocarditis by age and sex were calculated using 2017-2019 data from the IBM MarketScan Commercial Research Database. This database contains individual-level, deidentified, inpatient and outpatient medical and prescription drug claims, and enrollment information submitted to IBM Watson Health by large employers and health plans. The data were accessed using version 4.0 of the IBM MarketScan Treatment Pathways analytic platform. Age- and sex-specific rates were calculated by determining the number of individuals with myocarditis ( International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes B33.20, B33.22, B33.24, I40.0, I40.1, I40.8, I40.9, or I51.4) 22 identified during an inpatient encounter in 2017-2019 relative to the number of individuals of similar age and sex who were continually enrolled during the year in which the myocarditis-related hospitalization occurred; individuals with any diagnosis of myocarditis prior to that year were excluded. Given the limitations of the IBM MarketScan Commercial Research Database to capture enrollees aged 65 years or older, an expected rate for myocarditis was not calculated for this population. A 95% CI was calculated using Poisson distribution in SAS version 9.4 (SAS Institute Inc) for each expected rate of myocarditis and for each observed rate in a strata with at least 1 case.
In cases of probable or confirmed myocarditis among those younger than 30 years of age, their clinical course was then summarized to the extent possible based on medical review and clinician interviews. This clinical course included presenting symptoms, diagnostic test results, treatment, and early outcomes (abstraction form appears in the eMethods in the Supplement ). 23
When applicable, missing data were delineated in the results or the numbers with complete data were listed. No assumptions or imputations were made regarding missing data. Any percentages that were calculated included only those cases of myocarditis with adequate data to calculate the percentages.
Between December 14, 2020, and August 31, 2021, 192 405 448 individuals older than 12 years of age received a total of 354 100 845 mRNA-based COVID-19 vaccines. VAERS received 1991 reports of myocarditis (391 of which also included pericarditis) after receipt of at least 1 dose of mRNA-based COVID-19 vaccine (eTable 1 in the Supplement ) and 684 reports of pericarditis without the presence of myocarditis (eTable 2 in the Supplement ).
Of the 1991 reports of myocarditis, 1626 met the CDC’s case definition for probable or confirmed myocarditis ( Table 1 ). There were 208 reports that did not meet the CDC’s case definition for myocarditis and 157 reports that required more information to perform adjudication (eTable 3 in the Supplement ). Of the 1626 reports that met the CDC’s case definition for myocarditis, 1195 (73%) were younger than 30 years of age, 543 (33%) were younger than 18 years of age, and the median age was 21 years (IQR, 16-31 years) ( Figure 1 ). Of the reports of myocarditis with dose information, 82% (1265/1538) occurred after the second vaccination dose. Of those with a reported dose and time to symptom onset, the median time from vaccination to symptom onset was 3 days (IQR, 1-8 days) after the first vaccination dose and 74% (187/254) of myocarditis events occurred within 7 days. After the second vaccination dose, the median time to symptom onset was 2 days (IQR, 1-3 days) and 90% (1081/1199) of myocarditis events occurred within 7 days ( Figure 2 ).
Males comprised 82% (1334/1625) of the cases of myocarditis for whom sex was reported. The largest proportions of cases of myocarditis were among White persons (non-Hispanic or ethnicity not reported; 69% [914/1330]) and Hispanic persons (of all races; 17% [228/1330]). Among persons younger than 30 years of age, there were no confirmed cases of myocarditis in those who died after mRNA-based COVID-19 vaccination without another identifiable cause and there was 1 probable case of myocarditis but there was insufficient information available for a thorough investigation. At the time of data review, there were 2 reports of death in persons younger than 30 years of age with potential myocarditis that remain under investigation and are not included in the case counts.
Symptom onset of myocarditis was within 7 days after vaccination for 947 reports of individuals who received the BNT162b2 vaccine and for 382 reports of individuals who received the mRNA-1273 vaccine. The rates of myocarditis varied by vaccine type, sex, age, and first or second vaccination dose ( Table 2 ). The reporting rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.73 [95% CI, 61.68-81.11] per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.86 [95% CI, 91.65-122.27] per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.43 [95% CI, 45.56-60.33] per million doses of the BNT162b2 vaccine and 56.31 [95% CI, 47.08-67.34] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in adolescent males and young men exceeded the upper bound of the expected rates after the first vaccination dose with the BNT162b2 vaccine in those aged 12 to 24 years, after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 49 years, after the first vaccination dose with the mRNA-1273 vaccine in those aged 18 to 39 years, and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 49 years.
The reporting rates of myocarditis in females were lower than those in males across all age strata younger than 50 years of age. The reporting rates of myocarditis were highest after the second vaccination dose in adolescent females aged 12 to 15 years (6.35 [95% CI, 4.05-9.96] per million doses of the BNT162b2 vaccine), in adolescent females aged 16 to 17 years (10.98 [95% CI, 7.16-16.84] per million doses of the BNT162b2 vaccine), in young women aged 18 to 24 years (6.87 [95% CI, 4.27-11.05] per million doses of the mRNA-1273 vaccine), and in women aged 25 to 29 years (8.22 [95% CI, 5.03-13.41] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in females exceeded the upper bound of the expected rates after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 29 years and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 29 years.
Among the 1372 reports of myocarditis in persons younger than 30 years of age, 1305 were able to be adjudicated, with 92% (1195/1305) meeting the CDC’s case definition. Of these, chart abstractions or medical interviews were completed for 69% (826/1195) ( Table 3 ). The symptoms commonly reported in the verified cases of myocarditis in persons younger than 30 years of age included chest pain, pressure, or discomfort (727/817; 89%) and dyspnea or shortness of breath (242/817; 30%). Troponin levels were elevated in 98% (792/809) of the cases of myocarditis. The electrocardiogram result was abnormal in 72% (569/794) of cases of myocarditis. Of the patients who had received a cardiac MRI, 72% (223/312) had abnormal findings consistent with myocarditis. The echocardiogram results were available for 721 cases of myocarditis; of these, 84 (12%) demonstrated a notable decreased left ventricular ejection fraction (<50%). Among the 676 cases for whom treatment data were available, 589 (87%) received nonsteroidal anti-inflammatory drugs. Intravenous immunoglobulin and glucocorticoids were each used in 12% of the cases of myocarditis (78/676 and 81/676, respectively). Intensive therapies such as vasoactive medications (12 cases of myocarditis) and intubation or mechanical ventilation (2 cases) were rare. There were no verified cases of myocarditis requiring a heart transplant, extracorporeal membrane oxygenation, or a ventricular assist device. Of the 96% (784/813) of cases of myocarditis who were hospitalized, 98% (747/762) were discharged from the hospital at time of review. In 87% (577/661) of discharged cases of myocarditis, there was resolution of the presenting symptoms by hospital discharge.
In this review of reports to VAERS between December 2020 and August 2021, myocarditis was identified as a rare but serious adverse event that can occur after mRNA-based COVID-19 vaccination, particularly in adolescent males and young men. However, this increased risk must be weighed against the benefits of COVID-19 vaccination. 18
Compared with cases of non–vaccine-associated myocarditis, the reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination were similar in demographic characteristics but different in their acute clinical course. First, the greater frequency noted among vaccine recipients aged 12 to 29 years vs those aged 30 years or older was similar to the age distribution seen in typical cases of myocarditis. 2 , 4 This pattern may explain why cases of myocarditis were not discovered until months after initial Emergency Use Authorization of the vaccines in the US (ie, until the vaccines were widely available to younger persons). Second, the sex distribution in cases of myocarditis after COVID-19 vaccination was similar to that seen in typical cases of myocarditis; there is a strong male predominance for both conditions. 2 , 4
However, the onset of myocarditis symptoms after exposure to a potential immunological trigger was shorter for COVID-19 vaccine–associated cases of myocarditis than is typical for myocarditis cases diagnosed after a viral illness. 24 - 26 Cases of myocarditis reported after COVID-19 vaccination were typically diagnosed within days of vaccination, whereas cases of typical viral myocarditis can often have indolent courses with symptoms sometimes present for weeks to months after a trigger if the cause is ever identified. 1 The major presenting symptoms appeared to resolve faster in cases of myocarditis after COVID-19 vaccination than in typical viral cases of myocarditis. Even though almost all individuals with cases of myocarditis were hospitalized and clinically monitored, they typically experienced symptomatic recovery after receiving only pain management. In contrast, typical viral cases of myocarditis can have a more variable clinical course. For example, up to 6% of typical viral myocarditis cases in adolescents require a heart transplant or result in mortality. 27
In the current study, the initial evaluation and treatment of COVID-19 vaccine–associated myocarditis cases was similar to that of typical myocarditis cases. 28 - 31 Initial evaluation usually included measurement of troponin level, electrocardiography, and echocardiography. 1 Cardiac MRI was often used for diagnostic purposes and also for possible prognostic purposes. 32 , 33 Supportive care was a mainstay of treatment, with specific cardiac or intensive care therapies as indicated by the patient’s clinical status.
Long-term outcome data are not yet available for COVID-19 vaccine–associated myocarditis cases. The CDC has started active follow-up surveillance in adolescents and young adults to assess the health and functional status and cardiac outcomes at 3 to 6 months in probable and confirmed cases of myocarditis reported to VAERS after COVID-19 vaccination. 34 For patients with myocarditis, the American Heart Association and the American College of Cardiology guidelines advise that patients should be instructed to refrain from competitive sports for 3 to 6 months, and that documentation of a normal electrocardiogram result, ambulatory rhythm monitoring, and an exercise test should be obtained prior to resumption of sports. 35 The use of cardiac MRI is unclear, but it may be useful in evaluating the progression or resolution of myocarditis in those with abnormalities on the baseline cardiac MRI. 36 Further doses of mRNA-based COVID-19 vaccines should be deferred, but may be considered in select circumstances. 37
This study has several limitations. First, although clinicians are required to report serious adverse events after COVID-19 vaccination, including all events leading to hospitalization, VAERS is a passive reporting system. As such, the reports of myocarditis to VAERS may be incomplete, and the quality of the information reported is variable. Missing data for sex, vaccination dose number, and race and ethnicity were not uncommon in the reports received; history of prior SARS-CoV-2 infection also was not known. Furthermore, as a passive system, VAERS data are subject to reporting biases in that both underreporting and overreporting are possible. 38 Given the high verification rate of reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination, underreporting is more likely. Therefore, the actual rates of myocarditis per million doses of vaccine are likely higher than estimated.
Second, efforts by CDC investigators to obtain medical records or interview physicians were not always successful despite the special allowance for sharing information with the CDC under the Health Insurance Portability and Accountability Act of 1996. 39 This challenge limited the ability to perform case adjudication and complete investigations for some reports of myocarditis, although efforts are still ongoing when feasible.
Third, the data from vaccination administration were limited to what is reported to the CDC and thus may be incomplete, particularly with regard to demographics.
Fourth, calculation of expected rates from the IBM MarketScan Commercial Research Database relied on administrative data via the use of ICD-10 codes and there was no opportunity for clinical review. Furthermore, these data had limited information regarding the Medicare population; thus expected rates for those older than 65 years of age were not calculated. However, it is expected that the rates in those older than 65 years of age would not be higher than the rates in those aged 50 to 64 years. 4
Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.
Corresponding Author: Matthew E. Oster, MD, MPH, US Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333 ( [email protected] ).
Correction: This article was corrected March 21, 2022, to change “pericarditis” to “myocarditis” in the first row, first column of eTable 1 in the Supplement.
Accepted for Publication: December 16, 2021.
Author Contributions: Drs Oster and Su had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Oster, Shay, Su, Creech, Edwards, Dendy, Schlaudecker, Woo, Shimabukuro.
Acquisition, analysis, or interpretation of data: Oster, Shay, Su, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Marquez, Strid, Woo, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.
Drafting of the manuscript: Oster, Shay, Su, Gee, Creech, Marquez, Strid, Woo, Shimabukuro.
Critical revision of the manuscript for important intellectual content: Oster, Shay, Su, Creech, Broder, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.
Statistical analysis: Oster, Su, Marquez, Strid, Woo, Shimabukuro.
Obtained funding: Edwards, DeStefano.
Administrative, technical, or material support: Oster, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Smith, Baumblatt, Thompson, Reagan-Steiner, DeStefano.
Supervision: Su, Edwards, Soslow, Dendy, Schlaudecker, Campbell, Sperling, DeStefano, Shimabukuro.
Conflict of Interest Disclosures: Dr Creech reported receiving grants from the National Institutes of Health for the Moderna and Janssen clinical trials and receiving personal fees from Astellas and Horizon. Dr Edwards reported receiving grants from the National Institutes of Health; receiving personal fees from BioNet, IBM, X-4 Pharma, Seqirus, Roche, Pfizer, Merck, Moderna, and Sanofi; and receiving compensation for being the associate editor of Clinical Infectious Diseases . Dr Soslow reported receiving personal fees from Esperare. Dr Schlaudecker reported receiving grants from Pfizer and receiving personal fees from Sanofi Pasteur. Drs Barnett, Ruberg, and Smith reported receiving grants from Pfizer. Dr Lopes reported receiving personal fees from Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and receiving grants from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. No other disclosures were reported.
Funding/Support: This work was supported by contracts 200-2012-53709 (Boston Medical Center), 200-2012-53661 (Cincinnati Children’s Hospital Medical Center), 200-2012-53663 (Duke University), and 200-2012-50430 (Vanderbilt University Medical Center) with the US Centers for Disease Control and Prevention (CDC) Clinical Immunization Safety Assessment Project.
Role of the Funder/Sponsor: The CDC provided funding via the Clinical Immunization Safety Assessment Project to Drs Creech, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, and Lopes. The authors affiliated with the CDC along with the other coauthors conducted the investigations; performed collection, management, analysis, and interpretation of the data; were involved in the preparation, review, and approval of the manuscript; and made the decision to submit the manuscript for publication.
Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the CDC or the US Food and Drug Administration. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC or the US Food and Drug Administration.
Additional Contributions: We thank the following CDC staff who contributed to this article without compensation outside their normal salaries (in alphabetical order and contribution specified in parenthesis at end of each list of names): Nickolas Agathis, MD, MPH, Stephen R. Benoit, MD, MPH, Beau B. Bruce, MD, PhD, Abigail L. Carlson, MD, MPH, Meredith G. Dixon, MD, Jonathan Duffy, MD, MPH, Charles Duke, MD, MPH, Charles Edge, MSN, MS, Robyn Neblett Fanfair, MD, MPH, Nathan W. Furukawa, MD, MPH, Gavin Grant, MD, MPH, Grace Marx, MD, MPH, Maureen J. Miller, MD, MPH, Pedro Moro, MD, MPH, Meredith Oakley, DVM, MPH, Kia Padgett, MPH, BSN, RN, Janice Perez-Padilla, MPH, BSN, RN, Robert Perry, MD, MPH, Nimia Reyes, MD, MPH, Ernest E. Smith, MD, MPH&TM, David Sniadack, MD, MPH, Pamela Tucker, MD, Edward C. Weiss, MD, MPH, Erin Whitehouse, PhD, MPH, RN, Pascale M. Wortley, MD, MPH, and Rachael Zacks, MD (for clinical investigations and interviews); Amelia Jazwa, MSPH, Tara Johnson, MPH, MS, and Jamila Shields, MPH (for project coordination); Charles Licata, PhD, and Bicheng Zhang, MS (for data acquisition and organization); Charles E. Rose, PhD (for statistical consultation); and Scott D. Grosse, PhD (for calculation of expected rates of myocarditis). We also thank the clinical staff who cared for these patients and reported the adverse events to the Vaccine Adverse Event Reporting System.
Objective : In this paper we report how the United Kingdom's National Institute for Health and Care Excellence (NICE) search filters for treating and managing COVID-19 were validated for use in MEDLINE (Ovid) and Embase (Ovid). The objective was to achieve at least 98.9% for recall and 64% for precision.
Methods : We did two tests of recall to finalize the draft search filters. We updated the data from an earlier peer-reviewed publication for the first recall test. For the second test, we collated a set of systematic reviews from Epistemonikos COVID-19 L.OVE and extracted their primary studies. We calculated precision by screening all the results retrieved by the draft search filters from a targeted sample covering 2020-23. We developed a gold-standard set to validate the search filter by using all articles available from the "Treatment and Management" subject filter in the Cochrane COVID-19 Study Register.
Results : In the first recall test, both filters had 99.5% recall. In the second test, recall was 99.7% and 99.8% in MEDLINE and Embase respectively. Precision was 91.1% in a deduplicated sample of records. In validation, we found the MEDLINE filter had recall of 99.86% of the 14,625 records in the gold-standard set. The Embase filter had 99.88% recall of 19,371 records.
Conclusion : We have validated search filters to identify records on treating and managing COVID-19. The filters may require subsequent updates, if new SARS-CoV-2 variants of concern or interest are discussed in future literature.
Paul levay, national institute for health and care excellence.
Senior Information Specialist, National Institute for Health and Care Excellence, Manchester, United Kingdom
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Copyright (c) 2023 Paul Levay, Amy Finnegan
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Bulletin of the National Research Centre volume 48 , Article number: 74 ( 2024 ) Cite this article
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COVID-19 vaccines have been a game changer in the pandemic, their extensive use was favorable compared to the burden of COVID-19 complications. Despite the low incidence of complications, it was important to analyze them carefully to understand the underlying mechanisms and predisposing factors. For instance, myopericarditis especially from mRNA vaccines, and its relatively higher prevalence in young adults and adolescents has raised a public concern about the use of this vaccine in this group. We aimed through this review to compare the age likelihood of ADEM from COVID-19 vaccines, with that reported in myopericarditis cases; secondary outcome parameters included the gender and number of doses needed to induce COVID-19 vaccines related to ADEM.
A literature search has been conducted on relevant databases to retrieve all case reports/series and systematic reviews describing ADEM with possible linkage to COVID-19. Exclusion criteria included any report not including the desired outcome parameters. Our results were then qualitatively compared with a similar systematic review reporting myopericarditis from COVID-19 vaccines.
In 38 cases with ADEM, mean age was 49 ± 16 compared to 25 ± 14 in myopericarditis, females were more likely to be affected, and while most of myopericarditis cases develop after the second dose, most of ADEM cases develop after the first dose (76%). Moreover, age > 56 years was more predictive of negative outcome after ADEM in the form of death or permanent vegetative state.
The discrepancy in age, gender and number of doses needed to induce complications between ADEM and myopericarditis, signify that the tissue affected is the major orchestrator of the age, gender, and dose characteristics, and not the type of vaccines. A leakier blood brain barrier with aging, might allow easier passage of autoantibodies and cytokines into the brain while lack of inhibitory immune checkpoints in the myocardium in young age might explain the higher prevalence of those cases in young adults and adolescents.
There has been a dilemma in the diversified sequelae of post-COVID-19 (coronavirus disease 2019) mRNA (messenger Ribonucleic acid) vaccinations. Although most of the outcomes are satisfactory, and vaccination benefits outweighs the risk, there have been some case reports that intrigued further analysis. A study conducted by Minghui Li et al. assessed the incidence rate of myocarditis and pericarditis following COVID-19 vaccination in the USA in perspective to age group and vaccine type (Li et al. 2021 ). It was found that the rates of myocardial affection are more prevalent in adolescents and young adults than in older age groups while using the mRNA vaccines. As the reporting odds ratio (ROR) of BNT162b2 (Pfizer-Biontech) and mRNA-1273 (Moderna) vaccine subtypes were higher than the ROR of viral vector vaccines of Ad26.COV2. S (Janssen), 5.3, 2.91 and 1.39, respectively. Another study supports the outcomes of mRNA vaccination post-COVID-19 in youths. A retrospective study was implemented by Dongngan T. Truong et al., and the results of the collected data on patients < 21 years old following mRNA vaccination were significant.(Truong et al. 2022 ) The incidence of suspected myocarditis in younger patients was noticeable.
The affection of young age by postvaccine myocarditis has not only be observed with mRNA vaccines; as myocardial and pericardial complications can also occur in young age groups following the smallpox vaccine, not only after the COVID-19 mRNA vaccine. This can be supported by an observational cohort study conducted by Engler et al., where the outcomes of smallpox vaccines were elaborated (Engler et al. 2015 ). Three hundred and forty-eight individuals out of over 5000 case reports that showed side effects post smallpox vaccination, manifested with cardiological adversities such as myocarditis and pericarditis: 276 and 72 cases, respectively. The median age of the myopericarditis cases was 24 years old, emphasizing the prevalence of myocarditis post-vaccination in the younger segment of the age spectrum, irrespective to vaccination subtype.
This young age trend for postvaccine myocarditis, regardless of the type of vaccine, is poorly understood.
In contrast, postvaccine acute disseminated encephalomyelitis (ADEM), tend to occur in a relatively older age. A report by Huynh and colleagues illustrated a case of 61-year-old male with ADEM following influenza vaccine, while Nakamura et al. documented two adult cases aged 62 and 70 with post-influenza vaccine ADEM (Huynh et al. 2008 ; NAKAMURA et al. 2003 ). The rest of systematic reviews were mainly focused on postvaccine neurologic sequelae overall and not specifically targeting the specific age of ADEM following different types of vaccines. In addition most of the studies assessing postvaccine ADEM, cannot be reliably cited as the involved vaccines are exclusive childhood compulsory vaccines, thus they cannot reflect the true age trend of postvaccine ADEM. (Sejvar 2005 ; Williams et al. 2011 ).
It seems, from the above that age likelihood of postvaccine tissue affection, might be related to the tissue characteristics rather than to the vaccine type. For this purpose, we dedicate this systematic review, to study the age likelihood of acute disseminated encephalomyelitis (ADEM), post-COVID-19 vaccination specifically post-mRNA COVID-19 vaccines. We hypothesize that we might find a discrepancy between the mean age of ADEM cases reported after COVID-19 vaccines compared to myocarditis seen after the same vaccines. The latter finding might consolidate our initial impression that tissue characteristics might be closely tied to the age predilection of post-vaccination immune sequelae in the respective tissue.
A literature search was implemented on PubMed, Scopus, Google scholar and Web of science to identify studies using the following key words ADEM and COVID-19 vaccination. The bibliography of any identified study was clearly inspected to find any report that could have been missed during the initial computer run.
Inclusion criteria included any age, developing ADEM after COVID-19 vaccination, accepted type of studies were systematic reviews, case reports, and case series.
Studies not fulfilling the outcome parameters targeted by the study were excluded.
Three of the authors examined each study for the following outcome parameters: age, gender, type, and dose of the vaccine incriminated, the time interval between the vaccination and the development of ADEM, the main neurologic presentation, the treatment lines used, and the outcome of the case.
Data collected were analyzed using Excel and MedCalc statistical software. Numerical data were represented using mean and standard deviation when normally distributed and using median, minimum, and maximum when non-normally distributed. Non-recovery was defined as persistence of neurologic abnormalities, vegetative state or death in our collected cases, this categorical division was essential to perform a Receiver Operating Characteristic analysis (ROC) to determine the cut-off age predicting non-recovery from ADEM developing from COVID-19 vaccines. The latter was represented using an interactive dot diagram.
A systematic review has been identified (Nabizadeh et al. 2023 ) including 20 studies, out of which 19 were eligible to be included in our review: (Ahmad, Timmermans, and Dakakni 2022 ; Al-Quliti et al. 2022 ; Ancau et al. 2022 ; Ballout et al. 2022 ; Cao and Ren 2022 ; Kania et al. 2021 ; Lazaro et al. 2022 ; Maramattom et al. 2022 ; Miyamoto et al. 2022 ; Mumoli et al. 2022 ; Nagaratnam et al. 2022 ; Netravathi et al. 2022 ; Ozgen Kenangil et al. 2021 ; Permezel et al. 2022 ; Rinaldi et al. 2022 ; Shimizu et al. 2021 ; Simone et al. 2021 ; Vogrig et al. 2021 ; Yazdanpanah et al. 2022 ) (Fig. 1 ).
PRISMA flow chart
In addition to the 19 studies included, our literature search has identified nine other studies:
(Bastide et al. 2022 ; Garg et al. 2023 ; Gustavsen et al. 2023 ; Lohmann et al. 2022 ; Mousa et al. 2022 ; Nimkar et al. 2022 ; Raknuzzaman 2021 ; Sazgarnejad and Kordipour 2022 ). Thus, a total of 28 studies were analyzed comprising a total of 38 cases. (Table 1 ).
Most of the cases were attributed to the adenoviral vector vaccines (63%) ADEM occurred following the first dose of vaccination (76%), with a median interval of 14 after vaccination. (Table 2 ).
The oldest age seen in ADEM cases following vaccination was seen in patients receiving mRNA vaccines (57 ± 19) compared to a mean of 48 ± 14 following adenoviral vector vaccines.
Complete recovery was observed in 37% of patients, while non-recovery (defined as residual motor deficit or the development of vegetative state) or death was observed in a total of 45% of cases. (Table 2 ).
Receiver operating characteristic analysis illustrated as an interactive dot diagram showed that an age > 56, predicts non-recovery in ADEM cases following post-COVID-19 vaccines. (Fig. 2 ).
The diagnostic accuracy of age in predicting non-recovery after ADEM post COVID-19 Vaccines. ADEM acute disseminated encephalomyelitis, COVID-19 Coronavirus Disease 2019
Treatment received was mainly steroids (oral and pulse intravenous), intravenous immunoglobulins, and plasma exchange. While only three cases received rituximab (8%), and one received eculizumab and another one received cyclophosphamide (3%) (Table 1 ). Table 1 illustrates the details of each case in the included cases and case reports.
Our review describes the demographic, and clinical characteristics of a rare complication of COVID-19 vaccines. It is the second systematic review of reported cases in this context, after Nabizadeh et al. study(Nabizadeh et al. 2023 ), however with a different aim. The aim of our systematic review was mainly to study the differences of age predisposition, type of vaccine and number of doses between myocarditis and ADEM following COVID-19 vaccines. Several major differences were observed, notably the number of literature reports, which points to a relatively higher incidence of myocarditis as our group could only find 28 reports with a total of 38 cases compared to thousands of cases of myopericarditis in the literature; this can make the comparison between the two complications flawful, as the scarcity of ADEM reports is not very helpful to draw solid conclusions.
However, we still decided to compare the aforementioned outcome parameters across the two complications. We took Goyal et al. study as a reference for myopericarditis cases as it shares the different outcome parameters intended in our study, and it is not a VAERS based study; thus, its results can be qualitatively compared to the results of our research. (Goyal et al. 2023 ).
Age of clustered ADEM cases was 49 ± 16 compared to 25 ± 14 in myopericarditis cases. The young age of myopericarditis especially from mRNA vaccines, lead to fears among parents, planning to vaccinate their children using these vaccines, and led to an overall impression that mRNA vaccines might be associated with increased complications’ rate at the young age. Our study contradicts this false belief, as it clearly shows that ADEM occurring from mRNA vaccines is likely to occur in older age groups compared to myocarditis and to ADEM cases from other COVID-19 vaccines. Nevertheless, older age was also predictive of worst outcomes in our collected cases (Fig. 2 ), patients older than 56 were more prone to develop residual neurologic deficit, vegetative state, or death. This might also mean that age likelihood and other demographic characteristics of any vaccine complication are related to the type of the complication and tissue involved rather than the vaccine type.
One of the theories that can explain the young age of myocarditis from COVID-19 and other vaccines (such as vaccinia virus vaccine used for smallpox) is the mechanism of immune inhibition inside the myocardium. The heart muscle harbors a strict system for immune surveillance, that can prevent any immune-mediated damage, this immune surveillance is particularly important in the heart as the regenerative capacity of myocardial cells is absent.
Two main mechanisms of peripheral tolerance protect myocytes from T cell damage namely cytotoxic T-lymphocyte-associated protein-4 (CTLA4), and Programmed cell protein death-1 (PD1). CTLA4 and PD1 block T cell activation by binding to CD-28 receptors on the surface of T cells, thereby preventing any viral antigen from its activation. (Grabie et al. 2019 ) The myocardial protection from autoimmunity, offered by inhibitory immune checkpoints, such as PD1, is upregulated by aging, which might mean that the susceptibility of myocardium to immune-mediated inflammation, should decrease with aging. (Platt et al. 2017 ) On another note, antibodies implicated in CNS autoimmune inflammation, must gain access to the CNS via the blood brain barrier, olfactory route, or blood-cerebrospinal fluid barrier, or sometimes produced locally witing the CNS itself. The latter mechanism has been particularly of focus in multiple sclerosis, as Quintana and colleagues proved the present of myelin reactive antibodies that are locally produced in the brain. There also hypotheses that post-infectious ADEM, which is intriguingly common in the pediatric age group, involves the local production of antibodies in the CNS against viral antigen entering the CNS through the olfactory route. But, for antibodies, to gain access to the CNS, this implies a leakier BBB Blood brain barrier) or BCSFB (Blood cerebrospinal fluid barrier), this can be understandable in post-infectious ADEM, where implicated micro-organisms weaken the tight junctions of the BBB, and this allows access of cross-reactive antibodies to the brain (Spindler and Hsu 2012 ); but this cannot be the case in post-vaccination ADEM, as no offending organism is present to play this synergistic getaway role. An explanation for antibody access to the CNS in post-vaccination ADEM, is aging. If aging protects the myocardium against autoimmunity, it plays an inverse role in the CNS by rendering the BBB and BCSFB more permeable to antibodies and to external antigens. (Adesse et al. 2022 ).
Back to the findings, of our study, which also showed that ADEM mainly occurs after the first dose of vaccination, this is different than the immune-priming pattern seen in myocarditis from COVID-19 vaccines, as they need two doses usually to produce this complication.
This pattern might be consistent with a cytokine rather than immune-mediated damage. Wu et al. described a subtype of ADEM known as acute necrotizing encephalitis which involves a personal susceptibility to CNS damage due to hypercytokinemia. (Wu et al. 2015 ).
Finally, yet importantly female patients were more likely to develop ADEM following COVID-19 vaccination compared to male patients. A study by Falahi et al., examined COVID-19 outcomes across both genders, and showed that female patients have a higher susceptibility to cytokine storm, and suggested that estrogen upregulates pro-inflammatory molecules, leading to an augmented inflammatory response in females. This might consolidate the impression taken from dose pattern of post-COVID-19 vaccination ADEM, that it is mainly mediated via hypercytokinemia rather than auto-antibodies. (Falahi and Kenarkoohi 2021 ).
It is worth highlighting again as mentioned in the first paragraph of the discussion, that one of the most important limitations of this study that can hinder the solidity of our results; is the discrepancy in the number of cases across the two complications (ADEM and myopericarditis); with only 38 ADEM cases compared to hundreds of myopericarditis patients.
Figure 3 summarizes the differences outlined above between ADEM and myopericarditis developing following COVID-19 vaccines in view of our findings compared to the findings of Goyal et study ( 2023 ).
Summary figure for comparison of age, sex, and dose characteristics of post COVID-19 myopericarditis vs. ADEM. ADEM: acute disseminated encephalomyelitis, COVID-19: Coronavirus Disease 2019
This review compares the demographic, vaccine types and dose characteristics of post-COVID-19 vaccines ADEM and Post-COVID-19 vaccines myopericarditis. Older age, predominance of female gender, and first dose implication all characterize ADEM compared to myopericarditis. And despite the rarity of these complications, they open new horizons in understanding post-vaccination complications and their underlying mechanisms. They might signify that aging can be protective against autoimmunity in the myocardium, but the same aging can jeopardize the BBB, rendering it more susceptible to delivery of antibodies and cytokines to the CNS. More studies at the molecular level, should be implemented to confirm these findings and to prove that vaccine complications are not only determined by the vaccine type but also by the type of the target tissue. The findings highlighted by our study, can wipe out the public-based impression that mRNA vaccines are linked to higher complications in younger individuals, and can help in combating vaccine hesitancy especially toward a vaccine mechanism that might be very promising in the future for other infectious and non-infectious disorders. Risk of Bias assessment has been performed and illustrated in Fig. 4 :
Risk of bias assessment for our systematic review
Not applicable.
Janssen vaccine
Acute Disseminated Encephalomyelitis
Blood brain Barrier
Blood cerebrospinal fluid barrier
Pfizer Biontech vaccine
Cluster of differentiation
Is a chimpanzee (Ch) adenovirus-vectored vaccine (Ad), whose development was led by the University of Oxford (Ox).
Central nervous system
Coronavirus vaccine initiative
Coronavirus Disease 2019
Cytotoxic T-lymphocyte-associated protein-4
Disturbed Conscious level
Gam: Gamaleya, COVID-Sputnik Vaccine
Glasgow Coma Scale
Intravenous
Intravenous immunoglobulins
Methylprednisolone
Messenger Ribonucleic acid
Moderna Spikevax vaccine
Not reported
Programmed Death ligand 1
Plasmapheresis
Vaccine adverse events Reporting system
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AbdelMassih, A., Kamel, A., Barakat, A. et al. The heart versus the brain, are they also different when it comes to post-vaccination complications, insights from a systematic review of post-COVID-19 vaccines ADEM cases. Bull Natl Res Cent 48 , 74 (2024). https://doi.org/10.1186/s42269-024-01230-1
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Purpose SARS-CoV-2 is an RNA virus responsible for COVID-19 pandemic. Some authors described the set of persistent symptoms COVID-related as “Long-COVID Syndrome.” Several cases of post-COVID-19 osteonecrosis (ON) are described. Our primary aim was to study the hypothetical correlation between SARS-CoV-2 infection and ON; our secondary aim was to understand if ON can be considered part of Long-COVID. Materials and methods We performed a systematic review following the Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) guidelines. Because COVID-19 is a recently described disease, we included all levels of evidence studies. We excluded studies lacking specification regarding the use of corticosteroids (CCS) and studies not related to COVID-19. The variables extracted were age, sex, risk factors, affected joints, signs and symptoms, magnetic resonance imaging (MRI) and X-ray features, histology, treatment of COVID-19, dose and duration of treatment with CCS, treatment of ON, follow-up, and treatment outcome. Results A total of 13 studies were included, involving 95 patients and 159 joints. Time between the diagnosis of COVID-19 and the onset of symptoms related to ON was 16 weeks on average. Time between the onset of symptoms and the MRI was 6 weeks. An average of 926.4 mg of prednisolone equivalent per patient were administered. On average, CCS were administered for 20.6 days. Conclusions Patients with a history of COVID-19 infection developed osteonecrosis prematurely and with a lower dose of CCS than usually reported in the literature. Symptoms of osteonecrosis occur within the interval of the period described as Long-COVID. Surgeons should not underestimate the persistence of arthralgia when a history of SARS-CoV-2 infection and use of CCS is reported.
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Za, P., Papalia, G.F., Gregori, P. et al. Osteonecrosis as a manifestation of Long-COVID Syndrome: a systematic review. Musculoskelet Surg (2024). https://doi.org/10.1007/s12306-024-00854-w
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Background: The year 2020 has been marked by the emergence of coronavirus disease 2019 (COVID-19). This virus has reached many countries and has paralyzed the lives of many people who have been forced to stay at home in confinement. There have been many studies that have sought to analyze the impact of this pandemic from different perspectives; however, this study will pay attention to how it has affected and how it may affect children between 0 and 12 years in the future after the closure of schools for months.
Objective: The objective of this article is to learn about the research carried out on the child population in times of confinement, especially those dealing with the psychological and motor aspects of minors.
Methods: To carry out this systematic review, the PRISMA statement has been followed to achieve an adequate and organized structure of the manuscript. The bibliography has been searched in the Web of Science (WOS), Scopus, and Dialnet databases, using as keywords: “COVID-19” and “Children.” The criteria that were established for the selection of the articles were (1) articles focusing on an age of up to 12 years, (2) papers relating COVID-19 to children, and (3) studies analyzing the psychological and motor characteristics of children during confinement.
Results: A total of nine manuscripts related to the psychological and motor factors in children under 12 have been found. The table presenting the results includes the authors, title, place of publication, and key ideas of the selected manuscripts.
Conclusion: After concluding the systematic review, it has been detected that there are few studies that have focused their attention on the psychological, motor, or academic problems that can occur to minors after a situation of these characteristics. Similarly, a small number of studies have been found that promote actions at the family and school level to reverse this situation when life returns to normal. These results may be useful for future studies that seek to expand the information according to the evolution of the pandemic.
When news of an epidemic began to spread in a Chinese city in early 2020, no one anticipated the scope of the epidemic for the entire world in a very short period. From Wuhan (China) to New York (USA) through Africa, South America, Asia, and Europe, the new coronavirus, coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has paralyzed, to a greater or lesser extent, the life in many countries, causing thousands of deaths and about 6 million infections. For these reasons, the scientific community is on the alert by conducting studies on the virus, the disease it produces, the situation it creates, and the population it attacks, from different perspectives, including systematic reviews of the literature, such as the one presented in this paper.
However, researchers on this topic are not only biologists or physicians. It is worth noting the contribution of Maestre Maestre ( 2020 ), President of the Society for Latin Studies, in an article on the virus that has caused the pandemic, in which, playing with different related terms, he explains that the neutral noun “virus” means “poison” in Latin, so most current research is trying to find a medicine that will kill the virus. Likewise, the Greek term ϕάρμακoν (in Latin pharmacum) also means poison. The relationship between the two terms is that pharmacies are looking for poisons that will kill the “poisons” that undermine people's health or their desire to be safe. Remember the symbol of the pharmacies, the “Bowl of Hygieia” with the snake that pours a “poison” into it that stops being a poison to become an antidote. The name “coronavirus” is given to it because, through the microscope, the “virus-poison” is shaped like a “crown” that makes it king of poisons.
However, in addition to scientists who study the pandemic, biologists, doctors, and humanists, educators are obliged to care for the psychological and emotional health, as well as cultivate the minds, of children. The consequences of the containment measures of COVID-19 are being detrimental to the mental health of people around the world. It is logical that the most vulnerable are children who do not understand what is happening and who, along with the concern and frustration of their elders, may present risk factors, such as anxiety and affective and post-traumatic stress disorders (Giallonardo et al., 2020 ). However, not only minors are affected. According to Roy et al. ( 2020 ), more than 80% of people over 18 have shown the need for attention to their mental health as a result of the anxiety and stress experienced during the pandemic. Forte et al. ( 2020 ) agree with this idea, stating that the pandemic has caused stress, psychological discomfort, sleep disorders, and instability, among others, in a large part of the population.
In this sense, many questionnaires have been applied to obtain information in the educational context or related to it from research groups at different universities, including the one from the IDIBAPS research group at the Hospital Universitario de Barcelona, concerning behaviors to reduce emotional distress during the pandemic and confinement by COVID-19, https://enquesta.clinic.cat/index.php/268395?lang=es ; Universidad de las Palmas de Gran Canaria on family relationships during confinement: Study of the effect of COVID-19 in the family context, https://forms.gle/2xpmqRtQ8mtBMAz77 ; Universidad de Oviedo, as a longitudinal study on how isolation and the practice of physical activity (PA) during confinement is affecting to offer effective strategies that it called “pills”: EDAFIDES Questionnaire COVID-19, https://docs.google.com/forms/d/e/1FAIpQLSfyID6X7YgUejwXNv2YyOQ1YU2LrFsPkkvHzux_TD_BjPIGNw/viewform?usp=sf_link ; Euskal Herriko Unibertsitatea, to find out about the situation of university students in confinement and to propose improvements: https://forms.gle/jDkFgW7xeKfSFNHB6 ; Universidad da Coruña y Universidad de Jaén, on the activities of children in Spanish homes in times of confinement. This last questionnaire was applied in Spain and in South America: https://docs.google.com/forms/d/e/1FAIpQLSeyBBkMEmPxj-AoPQG98QorsaLyNex9wlI2FJ2Ku2q8nbsdNQ/viewform .
Based on the above-mentioned questionnaires, there is a concern to analyze how confinement has affected children under 12 at the motor and psychological levels. This literature review is carried out and explained in detail in the procedure and search strategy of the methodology. The impact of the pandemic is such that many national and international journals are offering special issues on COVID-19, including Frontiers, which, being digital, contains 229 articles signed by many authors from various countries, which look at the subject from different perspectives: there are eight that refer to age and especially to children in some way, including: who cares about the elderly (Fischer et al., 2020 ), physical inactivity (Ricci et al., 2020 ), age distribution (Cortis, 2020 ), and newborns (Ovali, 2020 ), but none discusses parents' views on the period of confinement from the psychological, educational, academic, physical, and emotional points of view of their children. Neither do they inquire into the opinion of the children themselves, understanding by these those who are in infant and primary education, that is, up to the age of 12.
Education must seek to provide the child with a comprehensive education, trying to help his or her physical, emotional, intellectual, family, social, and moral development. Active methods are crucial for early childhood education, and teachers are needed to apply them in schools (Salvador, 2008 ), now in the homes of their students, which they access through the Internet. The role of parents is also to educate, but from different perspectives, complementing those of teachers in the acquisition of children's learning. For these reasons, many families say that they do not know how to undertake these activities with their children for so long.
Likewise, the lack of other family members, such as grandparents, who had been playing a role in accompanying, especially with children in preschool, complicates the state of confinement and the lack of school attendance that is taking place, initially planned for 6 months in a row. The study by Clemente-González ( 2016 ) of the University of Murcia highlights the relevance of grandparent–grandchild relationships and the role of the former in the social and emotional development of the child, which gives great significance to their grandparents for the appreciation observed in them, recognizing their importance in the family structure. At this point, it is also necessary to point out the lack of relationships between equals, which is so important for the correct emotional development of children.
Another important aspect that has been affected by the coronavirus pandemic is the practice of PA. Many schoolchildren practice physical exercise based solely on the subject of Physical Education. This subject is not only based on motor skills but is a practice that affects schoolchildren in a global way, influences many aspects of their daily lives, and helps teachers to better understand students in their different dimensions (Founaud and González-Audicana, 2020 ). Lack of PA is associated with obesity, as indicated by different studies that relate the regular practice of physical exercise with the reduction of health problems (Castañeda-Vázquez et al., 2020 ).
The opinion article written by the Spanish secondary school teacher, Fandino-Pérez ( 2020 ), is significant in which he reflects on the virtuality of education and his position regarding personalized education, so demanded in times of normality, where teachers and students know each other, interact, and socialize, precisely the attitude that has taken away the virus. Fandino-Pérez says that the pandemic has put us in front of the mirror to see a distorted and absurd image of the work of teachers as producers of programming and good results, which turns them and their students into a kind of machine. We have forgotten the main thing: to be human beings capable of creating a better world and of overcoming ignorance, fear, and demagogy.
As a background to this study, we refer to March 11, 2020 when the World Health Organization (World Health Organization, 2020a ) declared this disease produced by the coronavirus (COVID-19) to be a pandemic. It was first reported in Wuhan (China) on December 31, 2019. According to World Health Organization ( 2009 ), the global public health community recognized the need for standardized research and data collection after the 2009 flu epidemics, so the WHO Expert Working Group on Special Research and Studies has developed several standard protocols for pandemic flu. This has led World Health Organization ( 2019a , 2020b ) to develop similar protocols for the Middle East respiratory syndrome coronavirus (MERS-CoV) and, with the support of expert advisors, has adapted the protocols for influenza and MERS-CoV to help better understand the clinical, epidemiological, and virological characteristics of COVID-19.
Some months have passed, and most of the inhabitants of planet Earth, more or less surprised, have been confined to their homes for about 60 days, where they have carried out their work online and have had to attend to their younger children, also confined without attending school and without being able to go out into the street or use the recreational facilities that some residential areas have.
When we find ourselves at the moment of reincorporation into the daily life known before the appearance of the pandemic (May 2020), other illnesses arise as a consequence of the involuntary confinement to which the population has been subjected; this is the cave syndrome or agoraphobia (fear of open spaces), and it is possible that with the passage of time, other psychological and affective disorders will arise in the adults who will be those who have suffered this confinement and this disaster as children.
The disease mainly attacks people over 70 years old and only 0.3% of children in countries where there have been more deaths (for example, Spain). According to the Instituto de Salud Carlos, this may be the reason why medical research does not deal with children, but these subjects have special psychological, academic, and emotional characteristics at a stage of their lives when they are in full development, so from the educational point of view, it is necessary to find out how children have developed in their homes, what their parents think, and what future expectations experts, teachers, and psychologists have for them.
For all these reasons, the aim of this work is to find out about the research carried out on the child population in times of confinement, especially those that deal with the psychological and motor aspects of minors.
Considering this objective and following the Population, Intervention, Comparison, and Outcome (PICO) strategy, the following research question arises: what do the studies already published determine about how confinement has affected children under the age of 12 on a psychological and motor level?
For the elaboration of this systematic review, we have followed the items to publish systematic reviews and meta-analyses of the PRISMA statement (Sotos-Prieto et al., 2014 ; Hutton et al., 2015 ), in order to achieve an adequate and organized structure of the manuscript. The guidelines of Cochrane Training (Higgins and Green, 2011 ) have also been used.
The literature review took place during the last weeks of May 2020 and focused mainly on the Web of Science (WOS) database, using Scopus and Dialnet as support. The topic considered for the selection of articles was the one related to the global pandemic caused by COVID-19 and how it has affected psychologically and motorically children up to 12 years old. The following keywords were used: “COVID-19” and “children” and the Boolean operator “and.” After this first search and taking into account only the works published in 2020 (since that is when the pandemic occurred), 837 scientific documents were obtained. By restricting the search to only journal articles, the documents were reduced to 576 articles, after which the language filter was applied, selecting only those papers published in English and Spanish, leaving a total of 537. Since the pandemic started in China, the initial search was also done in that language, not finding any related articles. The articles signed by researchers of Chinese nationality are written in English. Finally, the following areas of research were chosen: “Psychology,” “Sociology,” and “Education Educational Research,” finally limiting the search to 48 scientific articles, which make up the sample of this study.
The criteria that were established for the selection of the articles were (1) articles focusing on an age of up to 12 years, (2) papers relating COVID-19 to children, and (3) studies analyzing the psychological and motor characteristics of children during confinement.
In order to apply these criteria, a first preliminary reading of the title and summary of each article was carried out, which made it possible to rule out papers that did not meet the above-mentioned criteria. A more exhaustive reading of the selected articles was then carried out, leaving a final sample of nine scientific papers ( Figure 1 ).
PRISMA flowchart.
To extract the data from the articles, the following coding process was followed: (1) author/authors and year of publication, (2) title of the research, (3) place/country of publication, and (4) key ideas of the research.
The research included in this systematic review was coded by four of the authors, in order to check the reliability of the coding and the degree of agreement among the researchers in relation to the selection and extraction of the data (González-Valero et al., 2019 ). The degree of agreement on the rating of the articles was 93%. This was obtained by dividing the number of coincidences by the total number of categories defined for each study and multiplying it by 100.
In order to establish the methodological quality of the present study, reliability was determined according to the detection and selection of the Fleiss' Kappa (Fk) statistical index for more than two evaluators (Fleiss, 1971 ). A value of Fk = 0.780 was obtained for data extraction and selection, which indicates that there is substantial agreement (0.61–0.80).
Table 1 presents the main results of different studies following the codification indicated in the previous section: (1) author/authors and year of publication, (2) title of the research, (3) place/country of publication, and (4) key ideas of the research.
Basis of the study.
Szabo et al. ( ) | From helpless to hero: promoting values-based behavior and positive family interaction in the midst of COVID-19 | USA | - Importance of the role of parents in the confinement of their children. - It is necessary for parents to establish schedules and routines to achieve psychological stability for their children. - Tips are proposed to make confinement easier for children |
Dalton et al. ( ) | Protecting the psychological health of children through effective communication about COVID-19 | UK | - Psychological consequences that confinement can have on children. - Children are exposed to large amounts of information and may not know how to handle it. Parents have to explain the situation to them, taking into account their age, making them see that they are not to blame for the situation. - Children may show distress, guilt, feel threatened, worry…. - They miss their other caregivers (e.g., grandparents) |
Yarimkaya and Esentürk ( ) | Promoting physical activity for children with autism spectrum disorders during coronavirus outbreak: benefits, strategies, and examples | Turkey | - It focuses on children with autism spectrum disorder (ASD). - It deals with the importance of PA during confinement. - It proposes exercises that these children with ASD can do during the time they are locked up in the house |
Liu et al. ( ) | Mental health considerations for children quarantined because of COVID-19 | China | - It focuses on children who are separated from their families or caregivers because one or the other is infected with coronavirus. - These children are at risk for acute stress, adjustment disorder, and grief. - Children who are isolated because they are infected with the coronavirus may suffer from post-traumatic stress. - Children who have lost their parents to this infection may commit suicide as adults as a result. - As for “normal” home confinement with parents, they mention that it can cause stress in children, although being with their parents can relieve it |
Ricci et al. ( ) | Recommendations for physical inactivity and sedentary behavior during the coronavirus disease (COVID-19) pandemic | Italy | - It focuses on the inactivity and sedentariness that the coronavirus has brought to the world population and its consequences on the health of individuals. - It presents PA recommendations for the entire population, also specifically mentioning exercise for children |
Guan et al. ( ) | Promoting healthy movement behaviors among children during the COVID-19 pandemic | China | - Reminder of the worldwide recommendations on daily PA time in children. - Child sedentarism as an effect of confinement. - Increased use of digital technologies. - Recommendations to parents and caregivers for the promotion of daily healthy behaviors |
Zhang et al. ( ) | Acute stress, behavioral symptoms and mood states among school-age children with attention-deficit/hyperactive disorder during the COVID-19 outbreak | China | - Worsening behavior in children with attention-deficit/hyperactive disorder during confinement. - Stress levels experienced by family members and children with this disorder |
Álvarez-Zarzuelo ( ) | El confinamiento de niñas y niños En España en 2020 por la Crisis del COVID-19: Propuestas desde la Educación Social Escolar para la vuelta al centro escolar | Spain | - Personal opinion article. Social educator concerned with how confinement will affect children psychologically. - Digitally illiterate or financially unsound families will create an academic gap among children. - Compilation of 12 needs of confined minors and responses at the socio-educational level to address them on their return to the classroom |
Gómez-Gerdel ( ) | El cerebro pleno del niño/a: la labor de un/a maestro/a de educación inclusiva con las familias en tiempos de confinamiento. Una reflexión educativa | Spain | - Crisis in the Spanish educational system originated by the COVID-19 pandemic, consequence: virtual education. - Benefits of confinement: possibility for minors to acquire greater autonomy in daily household tasks and improvement in family relations by living together with parents and children for longer periods of time. - Inclusive education in confinement and its difficulty in alleviating inequalities. - Self-knowledge and understanding of emotions and actions. - Promotion of correct coexistence with children in confinement and techniques for the integration of the upper and lower brain |
Of the nine articles analyzed because they met the characteristics of the search, three have been published in The Lancet , which began as an independent international weekly medical journal, founded in 1823 by Thomas Wakley. Since its first issue, it has strived to make science widely available so that medicine can serve, transform society, and positively impact people's lives. It has evolved into a family of journals including The Lancet Child & Adolescent Health , in which one of the three articles cited appears. These three articles, and most of those analyzed, relate to the classical medicine that should serve society to help improve life.
Most of the references in this article (84.22%) are from the year 2020, a sign of the interest in the subject and the dedication of scientists and teachers. Only three are earlier, the one by Hutton et al. ( 2015 ) that deals with a more technical content, the extension of PRISMA for network meta-analysis, and the ones by Salvador ( 2008 ) and Clemente-González ( 2016 ) that highlight the role of grandparents in children's lives.
Of the two articles by Spanish teachers, the one by Álvarez-Zarzuelo ( 2020 ) is a personal opinion of a social educator who is ahead of other research. It only provides the experts' ideas on the possible repercussions of confinement. For his part, Gómez-Gerdel ( 2020 ) writes an opinion article that, exceptionally, is being published by the International Journal of Education for Social Justice in its special issue 9(e) on “Consequences of the Closure of Schools by COVID-19 on Educational Inequalities.” The author, from the perspective of the departments of Educational Guidance that deal with inclusive education, raises the chaos that it has meant for the Spanish Educational System to apply teaching only on line, which means for the most vulnerable families: difficulties in accessing technologies and delays in education. On the other hand, it raises what could be a return to the family whose members had been living together for a long time, something absolutely necessary for the correct development of the minors who spend too much time away from home.
The teaching–learning system, which should seek the comprehensive training of the child, in which parents and teachers should participate, has been drastically modified, trying not to abandon the active methods used in schools (Salvador, 2008 ), with the difficulties that this entails for families, which in many cases have no training in this area.
Of the three articles by Chinese authors, Liu et al. ( 2020 ) analyze the situation of children whose parents have been infected with the virus or have died; Zhang et al. ( 2020 ) observe the behavior of children with attention-deficit/hyperactive disorder (ADHD) during this period; and finally, Guan et al. ( 2020 ) deal with the practice of childhood PA during confinement. Therefore, only one of them studies a type of activity in this period, the one dealing with PA coinciding with what is written by the Italians Ricci et al. ( 2020 ); in the same line, we find the Turks Yarimkaya and Esentürk ( 2020 ) who deal with the importance of PA in confinement for children with autism spectrum disorder (ASD). It is important to remember that World Health Organization ( 2010 , 2019b ) recommends a minimum of 1 h/day of moderate–vigorous PA in children, but that only one-third of children exceed these recommendations (Salas-Sánchez et al., 2020 ).
The American and British authors analyze the role of parents in the confinement of their children and provide some advice on this subject. They also look at the future psychological problems that may arise as a result of over-information, change of routines, and manifestation of feelings of distress and guilt, as well as the need to see peers and other carers (teachers, grandparents). They coincide with Clemente-González ( 2016 ) project based on the grandparent–grandchild relationship and the promotion of identity, which seemed to be a premonition of what would happen with the arrival of the COVID-19 pandemic that would force the disappearance of these relationships for a long time.
It is important to note that, according to the review carried out, there are authors who analyze the pandemic from different perspectives with which we agree: cultural aspects (Maestre Maestre, 2020 ); actions of biologists and doctors, more distant from our intentions; humanists (Fandino-Pérez, 2020 ), and especially for this study, of educators who are aware that the essence of being in the classroom and the immediate feedback that students offer in this situation has been lost. To this must be added the role of the WHO, overwhelmed by the health events that have occurred so quickly, as described in these lines.
We believe that the application of many questionnaires during the confinement and currently post-COVID-19 pandemic has saturated the patience of the respondents, although most have helped scientists and educators to obtain information that will facilitate a smooth exit from this disaster.
The above leads us to the general conclusion that there are very few studies on how confinement has affected children under 12 years old psychologically and motorly. These articles agree on the consequences that confinement can have on minors and on the importance of psychological support from the family, and the establishment of routines can be effective. The manuscripts that deal with PA remind us of the importance of it and indicate that the rates of sedentarism have increased during these months.
It is necessary to insist on the search for and analysis of other activities, as well as the behavior of parents and children in these circumstances, in order to prevent possible psychological and academic problems and because if the online teaching situation is prolonged, it is very important to know how to act from the educational and family environment.
The main limitation the authors have faced has been the small number of scientific articles related to the area of study. This scarcity of published works makes it necessary to continue researching this. This is the reason why our study can serve as a starting point or theoretical foundation for further studies.
JC-Z, MS-Z, DS-M, GG-V, AL-S, and MZ-S contributed to the conception and design of the revision. All authors wrote some part of the manuscript and all reviewed the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
* References marked with an asterisk are those articles analyzed in the systematic review.
Funding. This article has been financed by the Ministry of Science, Innovation and Universities through two grants for university teacher training (FPU) with references FPU17/00803 and FPU18/02567. This article has counted with the collaboration of the group HUM-653 of the University of Jaén.
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