Abstract
Cardiovascular adverse conditions are caused by coronavirus disease 2019 (COVID-19) infections and reported as side-effects of the COVID-19 vaccines. Enriching current vaccine safety surveillance systems with additional data sources may improve the understanding of COVID-19 vaccine safety.
Using a unique dataset from Israel National Emergency Medical Services (EMS) from 2019 to 2021, the study aims to evaluate the association between the volume of cardiac arrest and acute coronary syndrome EMS calls in the 16–39-year-old population with potential factors including COVID-19 infection and vaccination rates.
An increase of over 25% was detected in both call types during January–May 2021, compared with the years 2019–2020. Using Negative Binomial regression models, the weekly emergency call counts were significantly associated with the rates of 1st and 2nd vaccine doses administered to this age group but were not with COVID-19 infection rates.
While not establishing causal relationships, the findings raise concerns regarding vaccine-induced undetected severe cardiovascular side-effects and underscore the already established causal relationship between vaccines and myocarditis, a frequent cause of unexpected cardiac arrest in young individuals.
Surveillance of potential vaccine side-effects and COVID-19 outcomes should incorporate EMS and other health data to identify public health trends (e.g., increased in EMS calls), and promptly investigate potential underlying causes.
Introduction
Cardiovascular adverse outcomes such as blood clotting (e.g., coronary artery thrombosis), acute coronary syndrome, cardiac arrest and myocarditis have been identified as consequences of coronavirus disease 2019 (COVID-19) infection1,2,3,4,5. Similarly, data from regulatory surveillance and self-reporting systems, including the Vaccine Adverse events Reporting System (VAERS) in the United States (US)6, the Yellow Card System in the United Kingdom7 and the EudraVigilance system in Europe8, associate similar cardiovascular side-effects9,10,11,12,13 with a number of COVID-19 vaccines currently in use.
More recently, several studies established probable causal relationship between the messenger RNA (mRNA) vaccines of BNT162b2 and mRNA-127311,14,15,16 as well as adenovirus (ChAdOx1) vaccines17 with myocarditis, primarily in children, young and middle-age adults. The study by the Ministry of Health in Israel, a country with one of the highest vaccination rates in the world, assesses the risk of myocarditis after receiving the 2nd vaccine dose to be between 1 in 3000 to 1 in 6000 in men of age 16–24 and 1 in 120,000 in men under 3011,12,13. A follow up study by the US Center of Disease Control (CDC) based on the VAERS and V-Safe self-reporting systems18 further confirms these findings19. The CDC has recently posted a warning regarding a vaccine-related risk of myocarditis, but still maintained their recommendation to vaccinate young individuals and children over 127. Similar concerns are reflected in the recent Food and Drug Administration approval to the Pfizer vaccine that requires several follow studies on the short and long terms effects of myocarditis in young individuals20.
While the benefits of COVID-19 vaccination are clear, especially for populations at great risk of developing serious and potentially life-threatening illness15,21, it is important to better understand the potential risks to minimize potential harm. However, assessing the connection between myocarditis and other potential cardiovascular conditions, and the COVID-19 vaccines is challenging. First, self-reporting systems22 of adverse events are known to have self-reporting bias and both under and over-reporting problems23,24,25. Even the study from Israel that is based on more proactive data collection mentions that some of the potentially relevant cases were not fully investigated.
Second, myocarditis is a particularly insidious disease with multiple reported manifestations. There is vast literature that highlights asymptomatic cases of myocarditis, which are often underdiagnosed26,27, as well as cases in which myocarditis can possibly be misdiagnosed as acute coronary syndrome (ACS)28,29,30. Moreover, several comprehensive studies demonstrate that myocarditis is a major cause of sudden, unexpected deaths in adults less than 40 years of age, and assess that it is responsible for 12–20% of these deaths26,31,32,33. Thus, it is a plausible concern that increased rates of myocarditis among young people could lead to an increase in other severe cardiovascular adverse events, such as cardiac arrest (CA) and ACS. Anecdotal evidence suggests that this might not be only a theoretical concern16.
Third, myocardial injury and myocarditis is prevalent among patients with COVID-19 infection26,34. As COVID-19 vaccine rollouts often take place with background community COVID-19 infections, it could be challenging to identify whether increased incidence of myocarditis and related cardiovascular conditions, such as CA and ACS, is driven by COVID-19 infections or induced by COVID-19 vaccines. Moreover, such increases may even be caused by other underlying causal mechanisms indirectly related to COVID-19, for example, patients delaying seeking emergent care because of fear of the pandemic and lockdowns35.
This study aims to explore how additional data sources, such as those from emergency medical services (EMS), can complement self-reporting vaccine surveillance systems in identifying COVID-19 related public health trends. More specially, the study examines the association between CA and ACS incidents in the 16–39-year-old population and two potential causal factors: COVID-19 infection rates and COVID-19 vaccine rollout. The study leverages the Israel National EMS (IEMS) data system and analyzes all calls related to CA and ACS events over two and a half years, from January 1st, 2019, throughout June 20th, 2021.
Discussion
This study leverages a unique dataset of all EMS CA and ACS calls in Israel over two and half years that span 14 months prior to the start of the COVID-19 pandemic, 10 months that include two waves of the COVID-19 pandemic, and 6 months with a third wave of the pandemic parallel to the vaccination rollout among the 16-year-old and over population. Thus, it provides a unique perspective to explore the association between trends in CA and ACS call volume over the study period and different factors, such as COVID-19 infection rates and vaccination rates.
Moreover, because the IEMS is a national organization the data provide a more comprehensive access to the respective incidence of the conditions being studied. This stands in contrast to the known very partial and biased access provided by adverse event self-reporting surveillance systems23,24,25, and highlights the importance of incorporating additional data sources into these systems48. However, it is important to highlight several significant differences between the CA and ACS EMS calls. For CA events, it is reasonable to assume that the IEMS data includes almost all of the relevant events, since CA events almost always involve calling EMS services. Moreover, the diagnosis of CA is relatively more straightforward. In contrast, for ACS events, while EMS calls capture a significant fraction of the respective incidents, direct hospital walk-in will not be accounted for in the EMS data. In Israel this is estimated to be 50% of all events. Additionally, the diagnosis of ACS events is more involved, and while EMS protocols during the study period did not change, it is reasonable to assume a higher rate of diagnosis error.
The main finding of this study concerns with increases of over 25% in both the number of CA calls and ACS calls of people in the 16–39 age group during the COVID-19 vaccination rollout in Israel (January–May, 2021), compared with the same period of time in prior years (2019 and 2020), as shown in Table 1. Moreover, there is a robust and statistically significant association between the weekly CA and ACS call counts, and the rates of 1st and 2nd vaccine doses administered to this age group. At the same time there is no observed statistically significant association between COVID-19 infection rates and the CA and ACS call counts. This result is aligned with previous findings which show increases in overall CA incidence were not always associated with higher COVID-19 infections rates at a population level35,49,50, as well as the stability of hospitalization rates related to myocardial infarction throughout the initial COVID-19 wave compared to pre-pandemic baselines in Israel51. These results also are mirrored by a report of increased emergency department visits with cardiovascular complaints during the vaccination rollout in Germany52 as well as increased EMS calls for cardiac incidents in Scotland53.
The visuals in Figs. 1 and 2 support and reinforce these findings. The increase in CA and ACS calls starting early January 2021 seems to track closely the administration of 2nd dose vaccines. This observation is consistent with prior findings that associated more significant adverse events, including myocarditis to the 2nd dose of the vaccine19. A second increase in the CA and ACS call counts is observed starting April 18th, 2021, which seems to track an increase of single-dose vaccination to individuals who recovered from COVID-19 infections. This is consistent with prior findings that suggest that the immune response generated by a single dose on recovered individuals is generally stronger than the response to the 2nd vaccine dose in individuals, who were not exposed to COVID-19 infection54. Additionally, the graphs emphasize the absence of correlation between the call counts and COVID-19 infection counts, which is most clearly seen during the two major pandemic waves in 2020.
While increased CA incidence was not observed among the 16–39 age group in 2020, there was a significant increase in the proportion of CA patients that died on scene during 2020, relative to 2019 (Supplemental Table 1), emphasizing the potential direct and indirect harmful effects of the pandemic35,49,55 on out-of-hospital CA patient outcomes. The percent of patients that died on scene remained elevated in 2021.
The large increase in the incidence of CA and ACS events in the population of age 16–39 parallel to the vaccination rollout and its association with the vaccination rates could be consistent with the known causal relationship between the mRNA vaccines and incidents of myocarditis in young people14,17,19,56, as well as the fact that myocarditis is often misdiagnosed as ACS28,29,30, and that asymptomatic myocarditis is a frequent cause for unexplained sudden death among young adults from CA26,31,32,33. This is further supported by more anecdotal reports describing sudden cardiac death following COVID-19 vaccination16,57. While vaccine-induced myocarditis was predominantly reported in males14,19it is interesting to note that the relative increases of CA and ACS events (Table 1) was larger in females. This may suggest the potential underdiagnosis or under-self-reporting of myocarditis in females, or other unique patterns, which is consistent with the ongoing challenge of gender-related differences related to cardiovascular disease diagnosis and care15,58.
The paper suggests several important policy implications. First, it is important that surveillance programs of potential vaccine side-effects and COVID-19 infection outcomes incorporate EMS and other health data to identify public health trends and promptly investigate potential underlying causes. Specifically, prompt investigation is needed to better understand the potential underlying causes of the observed increase in cardiac-related EMS calls, including vaccine and COVID-19 infection related factors, as well as additional factors, such as reduced willingness to seek hospital or EMS care, reduced access to care, and increased public awareness to post-vaccination adverse events. Second, it is essential to raise awareness among patients and clinicians with respect to related symptoms (e.g., chest discomfort and shortness of breath) following vaccination or COVID-19 infection to ensure that potential harm is minimized. This is especially important among the younger population and particularly young females, who often receive less diagnostic evaluation for adverse cardiac events compared to males15. These implications are further underscored by the continued administration of additional vaccine booster doses to the public because of the waning vaccine immunity against COVID-19 variants (e.g., delta variant) after the 2nd vaccine dose59. Moreover, recent studies have also demonstrated the association of increased risk of myocarditis with the administration of adenovirus-based vaccines (i.e., ChAdOx1)17, in addition to mRNA vaccinations, increasing the number of individuals that could be susceptible potential vaccine side-effects as well that can benefit from enhanced vaccine surveillance programs.
It is important to note the main limitation of this study, which is that it relies on aggregated data that do not include specific information regarding the affected patients, including hospital outcomes, underlying comorbidities as well as vaccination and COVID-19 positive status. Such related data are critical to determine the exact nature of the observed increase in CA and ACS calls in young people, and what the underlying causal factors are. Notably, recent studies have found vaccination induced myocardial injury has differentiating features, such as histopathology60, compared to typical myocarditis, which can further support identification of possible drivers of these cardiac events. The Israel Ministry of Health and the large HMOs have access to such data, which should be investigated in detail. Additionally, the CA examined in the study included those of both cardiac and medical etiology as data discerning these differences were not available, increasing the importance of further investigation of these patients. However, previous literature has estimated that the vast majority, approximately 84–92%, of non-traumatic cardiac arrest cases stem from cardiac origins61. For example, among other potential causes of CA, approximately 2–9% and 2% of cardiac arrests stem from pulmonary embolism62,63 and acute cerebrovascular events (e.g. subarachnoid hemorrhage)64, respectively. Therefore, it is likely that the observed changes in incidence can primarily be attributed to CAs of cardiac etiology.
The significant increases in CA calls and ACS calls among the 16–39 age population during the COVID-19 vaccination rollout highlights the value of additional data sources, such as those from EMS systems, that can supplement self-reporting surveillance systems in identifying concerning public health trends. Moreover, it underscores the need for the thorough investigation of the apparent association between COVID-19 vaccine administration and adverse cardiovascular outcomes among young adults. Israel and other countries should immediately collect the data necessary to determine whether such association indeed exists, including thorough investigation of individual CA and ACS cases in young adults, and their potential connection to the vaccine or other factors. This would be critical to better understanding the risk-benefits of the vaccine and to inform related public policy and prevent potentially avoidable patient harm. In the interim, it is vital that following vaccination, patients should be instructed to seek appropriate emergency care if they are experiencing symptoms potentially associated with myocarditis, such as chest discomfort and shortness of breath, as well as consider avoiding strenuous physical activity following the vaccination that may induce severe adverse cardiac events.