Skip to main content

Our take —

A rare and serious adverse event involving abnormal blood clotting (vaccine-induced thrombosis and thrombocytopenia, or VITT) has been associated with the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. This study reported on the clinical features and laboratory features of 23 patients who had received the AstraZeneca vaccine and who subsequently developed thrombosis and thrombocytopenia 6-24 days later, despite being mostly young and healthy. As seen in other studies, the clinical presentation of patients strongly resembled heparin-induced thrombocytopenia (HIT), even though patients had not been treated with heparin before symptom onset. All but two of the patients tested positive for anti-platelet factor 4 (anti-PF4) antibodies, which strongly supports the hypothesis that platelet activation induced by anti-PF4 antibodies leads to VITT. The results have implications for clinical guidance; the authors recommend avoidance of platelet transfusions, and suggest intravenous immunoglobulin and direct thrombin inhibitors as the first line of treatment. The study is limited by a relatively small sample size, which is a consequence of the rarity of this serious adverse event. It is still unknown how the vaccine might induce production of anti-PF4 antibodies, and what might predispose individuals to this reaction.

Study design

Case Series

Study population and setting

This study from the UK evaluated blood samples of 22 patients with venous thrombosis and thrombocytopenia and one patient with isolated thrombocytopenia and markedly elevated D-dimer after vaccination with the ChAdOx1 nCoV-19 vaccine (AstraZeneca). Because the clinical presentation in 22 patients highly resembled heparin induced thrombocytopenia (HIT), the investigators used enzyme-linked immunosorbent assays (ELISA) to test for antibodies against platelet factor 4 (PF4), which are the primary cause of HIT. A functional assay that tests platelet activation was used to confirm ELISA results for 7 of the 23 patients. The authors also described clinical characteristics and outcomes of the patients who provided samples.

Summary of Main Findings

All patients presented 6-24 days after receiving the first dose of ChAdOx1 nCoV-19, with a median time of 12 days. The median age was 46 years (range 21-77 years). Sixteen patients (70%) were younger than 50 years, and 14 (61%) were female. One patient had a history of deep vein thrombosis, and one patient was taking oral contraceptive pills at the time she sought medical attention. Clinically, 13 patients (56%) presented with cerebral venous thrombosis (one had deep vein thrombosis and pulmonary embolism along with cerebral venous thrombosis). One patient had deep vein thrombosis and bilateral adrenal hemorrhage, two patients had acute stroke due to thrombosis at the middle cerebral artery, and two patients had portal vein thrombosis: one with concurrent myocardial infarction and the other one had concurrent aortic thrombosis. Seven patients (30%) died. One patient had available data on post-mortem evaluation, which showed thrombosis at small arteries in the intestine, brain, lung, venous sinuses and intracerebral hemorrhage. Of note, additional thrombotic events occurred among patients who received platelet transfusion for thrombocytopenia and/or heparin for thrombosis. Only 10 patients (34%) had their sera available for antibody testing against coronavirus. All of these patients had negative antibodies against SARS-CoV-2 nucleocapsid protein, which ruled out recent COVID-19 infection. The levels of anti-SARS-CoV-2 receptor binding domain (RBD) and anti-spike antibodies were consistent with the level expected after ChAdOx1 nCoV-19 vaccination. The level of antibodies against non-SARS-CoV-2 coronavirus antibodies were similar to those in the general population. Thirteen patients (56%) had low fibrinogen levels, and all patients had markedly elevated D-dimer levels. Twenty-one patients (91%) had positive anti-PF4 antibodies via ELISA. One patient whose sample was collected five days after clinical presentation (and who had multiple platelet transfusions) tested  negative for anti-PF4 antibodies, and another had equivocal results. Of the 7 patients tested with the functional HIT assay, 5 had significant platelet activation in the absence of heparin. Adding heparin in excess of physiological doses fully suppressed platelet activation.

Study Strengths

In addition to ELISA, the authors used a functional platelet assay in a subset of patients to identify the presence of platelet activation. The clinical presentation of patients was reported in detail.

Limitations

The study had a small sample size (n=23). Only 10 patients were investigated for the possibility of previous SARS-CoV-2 infection, and only one-third of patients with detectable anti-PF4 antibodies were tested with the functional HIT assay. The course of treatments provided to the patients was not reported in detail, limiting inference about the benefits or harms associated with VITT treatment. Patient characteristics were also not reported in detail, and key demographic details were not available (e.g., ethnicity, country of origin, comorbidities); since it is not yet known what characteristics might predispose individuals to VITT, these data would have been particularly useful.

Value added

The study adds significant data pertaining to the mechanism of a rare adverse event known as vaccine-induced thrombosis and thrombocytopenia (VITT), which appears to be causally related to ChAdOx1 nCoV-19 (AstraZeneca) vaccine.

Our take —

A bar reopening event in rural Illinois led to a COVID-19 outbreak event with 46 cases identified, both among attendees and close contacts of attendees. At this indoor event, adherence to mask-wearing and physical distancing was poor. Though there may be limitations in measurement of cases (e.g. total number of attendees unknown, underreporting of close contacts, not all contacts were tested), this study provides further evidence that good public health prevention measures are needed to prevent the spread of SARS-CoV-2 in high-risk transmission settings like a bar.

Study design

Case Series

Study population and setting

In February 2021, the Illinois Department of Public Health and local health department conducted an investigation of an outbreak associated with an opening event at a rural Illinois bar. The event was held indoors in a 2800 square foot bar with limited ventilation. Cases associated with the outbreak were defined as COVID-19-like symptoms or a positive SARS-CoV-2 nucleic acid amplification test (NAAT) or antigen test within 14 days of the event. Cases could have been among attendees or employees who were at the event and reported no other known COVID-19 contacts. Secondary cases tied to the outbreak were defined as close contacts of the cases with a positive SARS-CoV-2 NAAT or antigen test. Interviews were conducted among all cases, both primary and secondary.

Summary of Main Findings

The total number of people who attended the event is unknown (the venue accommodated approximately 100 people), but there were six employees present. There was a total of 46 cases identified as linked to the event, including 26 attendees, three employees, and 17 secondary cases. At the event, there was one asymptomatic individual who had had a previous COVID-19 diagnosis from the day before, along with four people who had COVID-19 symptoms. Among attendees, it was reported that mask use was inconsistent and physical distancing of more than 6 feet apart was not adhered to during the event. There were 71 close contacts identified, of which 37 received testing (37/71, 52.1%). Among those who were tested, 46% received a positive result (17/37). Transmission associated with the event resulted in one school closure and one hospitalization of a long-term care facility resident.

Study Strengths

The use of contact tracing data allows us to understand the real-world implications of limited mask use and lack of consistent physical distancing.

Limitations

Because it is unknown how many people actually attended the event and because all close contacts were not tested, these numbers could be an underestimate of the total number of cases associated with the event. The cases identified are likely related to the bar opening event, but sequencing was not conducted and it is possible that the source of infection originated elsewhere or that there were multiple sources of infection.

Value added

This study builds on the evidence that when community transmission is relatively high, indoor events with poor mask use and limited physical distancing can lead to outbreaks.

Our take —

Reports of rare severe thrombotic events (blood clotting), associated with the Oxford-AstraZeneca vaccine have led to temporary suspensions of its use in several countries. This study reported on 11 patients (9 of whom were female, with a median age of 36 years) in Germany and Austria who had thrombotic events and low platelet counts. Antibodies against platelet factor 4 (PF4) were present in these patients, and platelet activation was enhanced by the presence of PF4. The clinical presentation of these cases resembled heparin-induced thrombocytopenia; however, none of the patients had been exposed to heparin before symptom onset. The following inhibited platelet activation in vitro: immune globulin, antibodies against platelet receptor factor IIA, and heparin. These results provide some detail on vaccine-induced thrombosis and thrombocytopenia, reports of which remain quite rare, though many questions about pathogenesis, risk factors, and treatment remain unanswered.

Study design

Case Series

Study population and setting

This study reported on clinical and laboratory characteristics of 11 patients who received the Oxford-AstraZeneca (ChAdOx1 nCov-19) vaccine in Germany and Austria and who developed thrombosis or thrombocytopenia. Laboratory testing was conducted on blood samples from 9 of the 11 patients, with ELISA used to test for the presence of platelet factor 4 (PF4)-heparin antibodies, and a modified (PF4-enhanced) platelet activation assay used for detection of platelet-activating antibodies under a range of conditions. Samples from 24 additional patients with suspected thrombocytopenia related to vaccination were also tested for validation purposes.

Summary of Main Findings

Nine of the 11 patients were women, with a median age of 36 years. Thrombotic complications began 5 to 16 days after vaccination, and all patients presented with moderate-to-severe thrombocytopenia (median platelet count nadir: 20,000 per cubic millimeter). Five patients had more than one thrombotic event; events included cerebral venous thrombosis (n=9), splanchnic-vein thrombosis (splenic, mesenteric, portal and hepatic veins; n=3), pulmonary embolism (n=3), and other types (n=4). One patient presented with fatal cerebral hemorrhage. Six patients died, and one had an unknown clinical outcome. None of the patients had received heparin before symptom onset, and only one patient was known to have prothrombotic blood disorder before symptom onset. There was evidence of disseminated intravascular coagulation in five patients, who all had d-dimer levels above 10mg/L and one or more of the following abnormalities: fibrinogen levels below 200ng/mL, elevation of the international normalized ratio (INR), and elevation of partial thromboplastin time(PTT). All samples that tested positive for PF4-heparin antibodies (n=24) showed strong reactivity; PF4-dependent platelet activation occurred in the absence of heparin. Platelet activation was enhanced by PF4 and inhibited by heparin, monoclonal antibody against platelet receptor FC gamma IIA, and immune globulin (10 mg/mL).

Study Strengths

Platelet activation patterns were assessed for additional samples from 24 patients suspected of thrombosis and/or thrombocytopenia, which allowed for comparison with the case series. The authors used two assays to measure antibodies against PF4.

Limitations

The sample of patients was small and detailed information on risk factors was not available. As this was a case series, data are needed on the prevalence of PF4-heparin antibodies among all individuals receiving the ChAdOx1 vaccine. More attention may have been paid to unusual thrombotic events, and so these may have been overrepresented (i.e., it is possible that the profile of thrombotic events associated with the ChAdOx1 vaccine is different from that observed in this study due to under-ascertainment). Detailed laboratory results are reported for only a subsample (n=4) of the 11 patients.

Value added

This study provides more detail about the mechanism of thrombotic adverse events that have led to pauses in the global rollout of the Oxford-AstraZeneca vaccine.

Our take —

This large case series from more than 200 US hospitals provides additional evidence that obesity is associated with increased risk of COVID-19 severity and death, and that risk goes up with increasing obesity severity, with a 2-fold higher risk of death among adults with BMI ≥ 45 kg/m^2 relative to those with healthy weight. Notably, this study demonstrated that the risk persisted among adults aged 65 years and older, a finding in contrast to some previous studies. These findings reinforce the use of BMI as a factor in vaccine prioritization, and also suggest that clinicians may need to manage COVID-19 more intensively among patients with obesity.

Study design

Case Series

Study population and setting

This large case series included patients aged 18 and older who were diagnosed with COVID-19 in 238 hospitals across the United States from March 1 to December 31, 2020. The data were drawn from the Premier Healthcare Database Special COVID-19 Release, a hospital-based electronic database that includes patients from all health insurance/payer groups; data from the subset of hospitals (238/~800) that recorded height and weight were used. The primary analytic sample included adults with ICD-10 code confirmed COVID-19 diagnosis in either the emergency department (ED) or inpatient setting, and with non-missing height and weight. Multivariable logit regression analyses evaluated the association between body mass index (BMI; weight in kg/height in m^2) and four outcomes: 1) inpatient hospitalization (reference group: those seen in ED only), 2) intensive care unit (ICU) admission, 3) invasive mechanical ventilation, and 4) death. The analysis for inpatient hospitalization included all adults diagnosed in the ED or inpatient, while the remaining 3 outcomes were assessed among hospitalized patients. BMI was assessed as both a continuous and categorical variable; the latter grouped by underweight (<18.5 kg/m^2), healthy weight (18.5-24.9 kg/m^2), overweight (25-29.9 kg/m^2), and four classes of obesity (30-34.9; 35-39.9; 40-44.9; ≥45 kg/m^2).

Summary of Main Findings

Among the 148,494 patients with COVID-19 in the hospital/ED setting (median age 55 years; 46% male; 51% non-Hispanic white), 51% were obese, 28% were overweight, 9% were healthy weight, and 2% were underweight. Approximately half—71,491—of these COVID-19 patients were hospitalized (median age 65 years; 51% male; 56% non-Hispanic white), with similar BMI category distributions. Hospitalization was elevated for adults with obesity and underweight relative to those of normal weight, and risk increased with category of obesity, independent of age, sex, race/ethnicity, payer type, geospatial characteristics of the hospital (urbanicity and US Census region), and admission month. Similarly, when assessed as a non-linear continuous variable, BMI demonstrated a J-shaped association with hospitalization, ICU admission, and death. Among hospitalized patients, the risk of ICU admission was significantly elevated only in the two highest obesity classes relative to healthy weight, while the risk of mechanical ventilation increased in a graded relationship across all BMI categories. The risk of death among hospitalized patients increased with obesity severity; patients with the highest obesity class had a 2-fold greater risk of mortality relative to those with healthy weight. Most of the inferences were observed both among those younger than aged 65 years and those aged 65 years and older, although the effect sizes and uncertainty around them were larger in the younger age group. The magnitude of the risks attenuated after accounting for comorbidities (hypertension, diabetes, chronic kidney disease, asthma, coronary atherosclerosis or other heart disease, chronic obstructive pulmonary disease, and cancer), but the ordering of risk was retained.

Study Strengths

The large sample size provided sufficient power to assess BMI across seven categories (including four obesity classes) and to stratify the analyses above and below aged 65 years to assess potential differences in the risks of BMI by age group. The authors performed rigorous multivariable analysis, including sensitivity analyses to assess robustness to adjustment for comorbidities and to address missing BMI with a multiple imputation approach.

Limitations

The hospitalization outcome in this study, assessed only among patients in the hospital or ED, is not comparable to hospitalization in studies with population-based cases of COVID-19, because those seeking care in the ED are likely to differ in significant ways from the overall population with COVID-19 (i.e. more likely to have severe symptoms; less likely to have a primary healthcare provider; more likely to be underweight or obese). The authors justified not adjusting for known risk factors for COVID-19 severity–such as heart disease, lung disease, and diabetes–because these conditions may be partially caused by obesity, but it might be more balanced to consider the effect of BMI as falling between the primary results and the more modest results from the sensitivity analyses that adjusted for these comorbidities.

Value added

This study assessed the relationship between BMI and four COVID-19 severity outcomes in more granularity than has been possible in previous smaller studies, demonstrating the relative effects of seven mutually exclusive BMI categories, and showing graded increases in risk with increasing obesity severity for most outcomes. The study also evaluated BMI as a non-linear continuous variable, identifying specific BMI values in the healthy to overweight range as inflection points with the lowest risk of severe COVID-19 events using polynomial spline models. The large sample size supported age-stratified analyses, and demonstrated that obesity remained a strong risk factor for mortality and invasive mechanical ventilation among patients aged 65 and older as well as the younger population.

Our take —

This study investigated a cluster of COVID-19 cases linked to two instructors reported to the Hawaii Department of Health. They found that the attack rate in these classes varied based on proximity to symptom onset, and classes held <1 day from symptom onset had attack rates of 100% for Instructor A, and 95% for Instructor B, but classes held >=2 days from onset had no reported cases. The primary limitation of this study is that class participants may not seek out testing and underreport asymptomatic infections. However, this study showed that COVID-19 remains a major risk in exercise settings despite other infection control protocols being followed, including social distancing, sanitization, plexiglass installments, and intermittent mask use. Policies of six feet of physical distancing in indoor areas with limited ventilation are likely to be insufficient, particularly when individuals are breathing heavily due to physical exertion.

Study design

Case Series

Study population and setting

This study investigated a suspected COVID-19 outbreak first identified on July 2, 2020 by the Hawaii Department of Health. Fitness Instructor A tested positive by RT-PCR, and displayed signs and symptoms. Instructor A taught at two facilities (X and Y), and was linked to 21 cases. Another instructor, B, came into contact with Instructor A and later tested positive. Instructor A taught a class on June 27 at Facility X (60 hours before symptom onset), and another class on June 28, 38 hours before symptom onset at Facility Y. While Instructor A followed social distancing and sanitization protocols, they shouted instructions at students without a mask at a distance >6 ft. They taught another class on June 29 at Facility Y, 4 hours before symptom onset. A number of students had exposure to Instructor A during multiple classes. Instructor B worked at a third facility, Z, and was exposed via the June 28 class at Facility Y. Instructor B taught five personal training sessions and small-group classes at Facility Z 2 days after their first exposure, and more than 2 days before their symptom onset. They taught another person on July 1, and another 10 participants and 3 small classes on July 2, before developing symptoms 12 hours later.

Summary of Main Findings

The study calculated the attack rate for each class, ranging from 0% to 100%. The highest attack rate (10/10, 100%) was seen at Facility Y during a stationary cycling class with Instructor A where no one was masked on June 29. All participants tested positive by RT-PCR. For Instructor B at Facility Z, the highest attack rate was seen at the kickboxing small group class on July 2, 12 hours before symptom onset, where only 2 participants of 9 who attended were masked, and all (9/9, 100%) later tested positive by RT-PCR. There was a notable gradient of attack rates based on proximity to symptom onset for both instructors. Instructor A had an attack rate of 0% for classes taught >1 day from symptom onset, but 100% attack rate for <1 day. For Instructor B, more than 2 days from onset had an attack rate of 0% for 33 participants in the classes, and 13% attack rate for <2 and >1 day from symptom onset. Finally, <1 day from symptoms, Instructor B had a 95% attack rate in classes.

Study Strengths

The study strength was the depth of data collected for the type of classes, whether individuals were masked, and the timing of classes taught. This investigation allowed them to calculate attack rates for each class, as well as based on symptom onset. They also investigated the COVID-19 distancing and sanitation protocols in place, and whether they were being adhered to.

Limitations

The study notes that participants may have multiple dates of exposure, and so it may be challenging to uncover exactly when transmission could have occurred for some. Additionally, they did not require all contacts be tested, and so some individuals who did not experience symptoms or who refused testing were assumed to not have COVID-19 when calculating the attack rate. Thus, these estimates may underestimate the level of transmission among these classes.

Value added

This study shows the high risk of transmissibility of COVID-19 in exercise settings despite other COVID-19 mitigation protocols being followed and demonstrated that transmission in this setting was likely highest in the day of or before symptom onset of the infectious case.

Our take —

This large case-series found a low prevalence of myocardial injury through return to play cardiac screening after resolution of symptomatic or asymptomatic SARS-CoV-2 infection among professional league athletes in the US and Canada. Cardiac screening identified 30/789 (3.8%) athletes with abnormalities in one or more of the initial parameters. Subsequent evaluation among those with abnormalities confirmed just five athletes (0.6% of the total cohort) with evidence of myocardial (n=3) or pericardial inflammation (n=2) on cardiac MRI, all of whom had moderate symptoms while ill with COVID-19; these individuals were not cleared to return to play. There were no adverse cardiovascular outcomes in short term follow-up among those athletes who cleared cardiac screening and returned to play. The prevalence of myocardial injury after SARS-CoV-2 infection found in this population of healthy recovered young, predominantly male professional athletes, many who had asymptomatic infection, is likely to be lower than that among the general population, but highlighted the importance of disease severity/symptoms as a prognostic factor for myocardial injury. The low yield among athletes with prior asymptomatic infection supports the American College of Cardiology expert consensus panel recommendation that screening is limited to athletes who had symptomatic infection. Furthermore, the study findings substantiate the judicious use of advanced imaging such as cardiac MRI as a downstream test option rather than for broad, first line screening.

Study design

Case Series

Study population and setting

This study examined the prevalence of myocardial injury after the resolution of symptoms of laboratory-confirmed SARS-CoV-2 infection among 789 professional athletes in six major North American sports leagues (Major League Soccer, Major League Baseball, National Hockey League, the National Football League, and the men’s and women’s National Basketball Associations). Prior to resuming activity, athletes who tested positive for SARS-CoV-2, irrespective of symptoms, underwent downstream cardiac evaluation after the resolution of symptoms following the American College of Cardiology (ACC) return to play (RTP) screening algorithm. This study included data from all athletes who underwent RTP cardiac assessment between May and October 2020. Cardiac screening included cardiac enzymes (troponin), electrocardiogram (ECG) and transthoracic echocardiogram; those with abnormal results underwent further cardiac testing with cardiac magnetic resonance imaging (CMR) and/or stress echocardiography, at the discretion of the team physicians, and events were reported through December 2020. The case data were deidentified and pooled by Columbia University.

Summary of Main Findings

Of the 789 athletes with SARS-CoV-2 infection (98.5% male; mean age 25 years; 74% tested by PCR), 42% had been asymptomatic for the duration of their infection while 58% had mild to moderate or pauci-symptomatic COVID-19 illness. Only one athlete was monitored overnight in a healthcare facility with COVID-19; none were hospitalized for or had cardiopulmonary symptoms. The median time between SARS-CoV-2 test and cardiac screening was 17 days (3-156 days). There were 30/789 (3.8%) athletes with abnormalities on RTP screening tests; 6 (0.8%) had elevated troponin levels, 10 (1.3%) had ECG abnormalities concerning for myocardial injury and 20 (2.5%) had abnormalities in their echocardiograms. Those athletes underwent further downstream cardiac evaluation; 27 had CMR and 15 had stress echocardiograms (12 had both tests). There were no abnormalities in the stress echocardiograms that were performed. On CMR, three athletes met criteria for myocarditis (myocardial inflammation) and two had imaging evidence of pericarditis (pericardial inflammation) (0.6% of the total cohort). All 5 athletes with CMR abnormalities previously had mild to moderately symptomatic SARS-CoV-2 infection (loss of smell or taste, cough and/or fatigue). On the other hand, 15 athletes who had echocardiographic abnormalities and four out of six who had troponin elevation had normal CMR and returned to play. Resting ECGs had particularly low specificity as a screening test. All athletes with normal cardiac screening RTP testing and those with normal CMR returned to their normal sports activities without reporting any cardiac symptoms up to December 2020.

Study Strengths

The health care staff associated with each team followed the RTP cardiac screening algorithm recommended by an American College of Cardiology (ACC) expert consensus panel. However, they departed from the ACC guidelines by applying the same screening algorithm to all athletes who tested positive for SARS-CoV-2, including asymptomatic cases, which provides a broader and more systematic view of the prevalence of cardiovascular sequelae of SARS-CoV-2.

Limitations

Predominantly male athletes were included. The screening algorithm was performed after the resolution of symptoms and therefore represents a healthy recovered population, excluding athletes with unresolved symptoms who may have a higher likelihood of persisting myocardial abnormalities. There was no centralization of the cardiac testing protocol, which was individually directed by each team’s medical staff nor was cardiac testing interpretation centrally performed. Study athletes had wide variation in the time interval between their cardiac evaluation and diagnosis of COVID-19 infection (3-156 days). Some cardiac abnormalities due to COVID-19 may have been underestimated but missed due to delayed cardiac evaluation. There were no significant adverse outcomes observed after return to play, though follow-up duration was short.

Value added

The study adds valuable knowledge on the prevalence of myocardial injury among healthy professional athletes recovering from COVID-19 and supports the safe return to play with a judicious cardiac testing protocol.

Our take —

Much is still unknown about the extent and duration of immunity amongst individuals previously infected with SARS-CoV-2, and the rate and outcomes associated with reinfection, both in the general population and among vulnerable groups. This study described suspected reinfection among five permanent residents of a Kentucky skilled nursing facility during two separate outbreaks in July 2020 and October 2020. Although all five individuals were either asymptomatic or experienced mild symptoms during the first outbreak, illness was more severe during the second outbreak, including one death. Unfortunately, samples were not retained, so it was not possible to identify the phylogenetic strains that played a role in the outbreaks. Infection prevention and control measures remain important, even among populations with previous infection.

Study design

Case Series; Prospective Cohort

Study population and setting

This was a descriptive study carried out by the Kentucky Department of Public Health at a skilled nursing facility which had two COVID-19 outbreaks (in July 2020 and October 2020). In the first outbreak, which lasted from July 16 to August 11, 2020, 20 of 115 (17.4%) residents and five of the 143 health care professionals (3.5%) tested positive for SARS-CoV-2. Initially, testing was based on symptoms and contact, but was expanded to all residents and staff. Overall, eight residents with COVID-19 were hospitalized, of whom five died. Following the first outbreak, the facility monitored staff and residents for symptoms and tested symptomatic individuals, while health care personnel were tested at least every two weeks. Tests conducted in September and from October 1 to October 29 on facility residents and staff were all negative. On October 30, 2020, two symptomatic residents received positive test results, and all residents and staff were tested twice weekly. Subsequently, 85 of 114 (74.6%) residents and 43 of 146 (29.5%) personnel received positive results, of whom 15 residents died between October 30 and December 7, 2020. No health care professionals died during either outbreak.

Summary of Main Findings

Five permanent residents of the facility had positive reverse-transcription PCR SARS-CoV-2 tests at both outbreaks, even though all had at least four consecutive negative RT-PCR SARS-CoV-2 tests after the first outbreak. The five individuals ranged in age from 67 to 99 years; four were women, and all had more than three chronic underlying health conditions, although none had an immunosuppressive condition or were taking immunosuppressive medication. During the first outbreak, three of these individuals were asymptomatic, while two had mild symptoms. During the second outbreak, three of the five individuals had a roommate who tested positive to SARS-CoV-2, but no direct route of exposure was identified for the other two. All five experienced more severe disease in the second outbreak and one died. Investigators speculated that the findings could be due to true re-infection resulting from waning immunity in this aging population, or as a result of mild/asymptomatic cases not triggering a robust immune response to prevent reinfection. Alternatively, investigators noted the potential of false positive results during the first outbreak. However, they noted that the cycle threshold for all five of these residents met the cutoff for limit of detection during the first outbreak, supporting infection.

Study Strengths

Reverse-transcription PCR testing was used to confirm diagnoses during both outbreaks. Testing of all residents, including those who were asymptomatic, also strengthens our understanding of reinfection among residents overall.

Limitations

The investigators provided solid evidence to support their claim that residents were reinfected (versus experiencing prolonged disease). This evidence could have been bolstered even further by ruling out false positives during the first outbreak — with either repeat RT-PCR, antibody tests, or both — and using phylogenetic analyses to detect differences in the infecting virus. However, investigators were unable to ascertain phylogenetic strains between outbreaks because test samples had not been preserved and no further testing was performed on the residents until 10 or more days after the first RT-PCR positive test.

Value added

This study highlights the importance of continued infection prevention and control strategies, even among persons with previous COVID-19 diagnosis.

Our take —

This case series of 1117 children and adolescents (<21 years) hospitalized with MIS-C (N=539) and severe acute COVID-19 (N=577) at 66 hospitals across 31 US states between March 15 and October 31, 2020 compared the clinical characteristics and outcomes of each condition. Compared to those with severe acute COVID-19, individuals with MIS-C were less likely to have an underlying condition, were more often aged 6-12 years than 0-5 or 13-20 years, were much more likely to have severe cardiovascular involvement, and more often admitted to the ICU, though risk of death was similar. Results should be interpreted with caution given reliance on electronic medical record data and possible detection bias, though they provide important insight about differentiating the presentation of MIS-C and COVID-19 in children.

Study design

Case Series

Study population and setting

This case series included 1116 children and adolescents (<21 years) who were hospitalized with COVID-19-related illnesses between March 15 and October 31, 2020 (with follow-up through January 5, 2021) from 66 hospitals across 31 states in the US. Patients were classified as being hospitalized due to multisystem inflammatory syndrome in children (MIS-C; N=539, median age 8.9 years, 58% male) or severe acute COVID-19 (N=577, median age 11.7 years, 53% male) based on adjudication by site and coordinating principal investigators. MIS-C was defined based on fever lasting more than 24 hours, laboratory evidence of inflammation, multisystem (≥2) organ involvement, no alternative plausible diagnosis, and a positive SARS-CoV-2 test based on RT-PCR, antibody, or antigen test (indicating recent or current infection). Before May 31, prior/recent SARS-CoV-2 infection criteria could also be met by exposure to a suspected or confirmed COVID-19 case in the previous 4 weeks. The case-definition for severe acute COVID-19 included: positive RT-PCR test during current illness, severe involvement of at least one organ system, and not meeting the definition for MIS-C. Demographic, clinical, and laboratory findings were abstracted from hospital medical records. Analyses compared sociodemographics, clinical presentation and outcomes (respiratory support, length of hospitalization, ICU admission, death) between patients with MIS-C and COVID-19 and evaluated cardiac dysfunction resolution over time for patients with MIS-C.

Summary of Main Findings

Overall, patients with MIS-C were younger (median age 8.9 vs. 11.7 years), more likely to be non-Hispanic Black (35% vs. 23%), and had fewer underlying medical conditions (presence of at least one underlying condition: 31% vs. 62%) than severe acute COVID-19 cases; these differences were significant in multivariable Poisson models adjusting for age, sex, race/ethnicity, presence of underlying medical conditions, and US Census region. Approximately 80% of both groups had respiratory involvement, but MIS-C cases more often had cardiovascular involvement (67% vs. 12%), asthma exacerbation (56% vs. 23%), hematologic involvement (48% vs. 22%), pleural effusion (32% vs. 15%), pericardial effusion (25% vs. 4%), coronary artery aneurysm (13% vs. 1%), or arrhythmia (8% vs. 1%). Comparing mutually-exclusive categories of severe organ impairment, most severe acute COVID-19 cases had severe respiratory involvement without cardiovascular involvement (71%), whereas MIS-C cases most often had severe cardiorespiratory involvement (56%), followed by severe respiratory without cardiovascular involvement (24%) and severe cardiovascular without respiratory involvement (11%). MIS-C cases were more likely to require vasopressor use (45% vs. 9%), ICU admission (74% vs. 44%), and had longer length of hospital stays (median 7 days vs. 3 days), but both groups had similar risk of death (1.9% vs. 1.4%). Among patients with MIS-C, 503 (93%) had left ventricular ejection fraction (LVEF) evaluated on at least one echocardiogram, and of those, 34% had depressed LVEF (majority of which were mildly depressed, 55%); almost all had returned to normal by 30 days (91%) and among the subset followed through 90 days, all but patient had normalized. Of 424 patients with coronary artery evaluation, 57 (13%) had coronary aneurysm (93% mild), but which had returned to normal in 79% by 30 days and 100% in the subset with follow-up through 90 days.

Study Strengths

The study was a relatively large, multi-site, case series differentiating MIS-C and severe acute COVID-19 in children and adolescents in the United States. Data included several important clinical and laboratory assessments, and applied standardized criteria for case, demographic, clinical, laboratory and outcome criteria.

Limitations

Data originated from electronic medical records, which are subject to incomplete documentation and reporting, and missing data were excluded from analyses. Diagnostic or detection bias dependent on individual diagnosis is possible, resulting in potential over- or under-ascertainment of clinical phenotypes and laboratory testing. For example, few children with severe acute COVID-19 received cardiac assessment, whereas almost all patients with MIS-C did; this may have underestimated cardiac involvement in the latter group and overestimated the differences in cardiac manifestations between the two conditions. Diagnostic criteria for MIS-C and severe acute COVID-19 changed throughout the study period and may have resulted in some misclassification; of the patients with MIS-C, 31% were RT-PCR and antibody positive, 45% were only antibody positive, 5% were RT-PCR positive and antibody negative, and 19% did not have antibody testing performed.

Value added

The largest case series of MIS-C and severe acute COVID-19 to date, and first to directly compare the conditions.

Our take —

This case series and case-control study set in Brazil examined risk factors for COVID-19 recurrence among 33 cases and 62 controls who were diagnosed and treated at the study hospital. The study found that the vast majority (>90%) of recurrent cases were healthcare workers. While symptom rates did not differ between first and second episode, cases were more likely to be hospitalized during their second episode; other studies have observed mixed results related to infection severity among reinfected cases, though often reinfections have been milder in other reports. The interval range between first and second episodes was 8 to 130 days (mean: 41 days). The major limitation was the challenge in determining if recurrence was actually a second new infection, or just symptoms of the same first infection. The study partially addressed this using next generation sequencing, providing evidence of new infection. It remains to be seen whether these secondary infections reflect new variants and potentially increased severity of disease associated with them.

Study design

Case Series, Case-Control

Study population and setting

The study objective was to determine risk factors for recurrent COVID-19. At the Federal University of Sergipe in Brazil, daily phone monitoring of confirmed COVID-19 cases from the Centro de Doencas Respiratorias (Center for Respiratory Diseases) was conducted. From this patient population, the study recruited 33 cases of recurrent, symptomatic, reverse transcription polymerase chain reaction (RT-PCR) positive infection with SARS-CoV-2. They defined recurrence as symptom recurrence in an individual having developed symptomatic COVID-19, medically isolated for 14 days, and then clinically recovering with at least 7 days without symptoms. They required cases to test positive by RT-PCR in both the first and second episode of COVID-19. They collected sociodemographic and clinical variables from the original 33 cases, and then randomly selected a control group of 62 people with only a single episode of the database. SARS-CoV-2 antibody testing was performed for a subset (51.5%, N=17) of recurrent cases, and the controls (50%, N=31). Next generation sequencing of viral genomes from 2 recurrent cases were also conducted.

Summary of Main Findings

The study found 33 recurrent COVID-19 cases, the majority of whom were female (78.8%, N=26) and were more likely to be healthcare workers (OR: 36.4, 95% CI: 9.7 – 137.2). Healthcare workers in the recurrent group were likely exposed in their work environment (97% reported possible work exposure), 48.5% of whom worked specifically in COVID-19 units. The average interval between recovery and second onset of symptoms was 41 days, with a range of 8 to 130 days. Blood type A+ had the highest prevalence (42%, N=14 cases), followed by O+ (30%, N=10). 45.5% (N=15) had comorbidities which placed them at higher risk for severe COVID-19, with obesity (N=10, 30.3%) being the most prevalent. For clinical symptoms, patients did not have any significant differences between number of symptoms in the first and later episode. Hospitalization was not required for any individuals in the first episode, but 12.1% of patients were hospitalized in the second episode, 2 required ICU admission, and 1 died from COVID-19 in their second episode. Genomic sequencing provided further evidence that these were true reinfections of different viral variants.

Study Strengths

The study had significant case data available for the recurrent cases, which are often understudied. Using next-generation sequencing, they were able to show that a likely second infection did in fact occur among the two participants tested. They also used a case definition that required clinically confirmed recovery before being eligible to be considered a recurrent case, which further added to the robust case definition and likely avoided some misclassification from cases who had a single, long infection as having recurrent infection.

Limitations

The major limitation was that they were not able to sequence all of the study participants to determine if each had a new infection. There may have been some misclassification of cases who had a single, long infection where symptoms may have abated for a short period, before returning. These individuals would therefore not reflect an actual second infection. Additionally, the study found that individuals were less likely to be hospitalized in the first episode compared to the second episode, however there may have been some survivorship bias due to individuals who were hospitalized and passed from COVID-19 no longer being at risk of second infection, and had they not died they may have gone on to become reinfected. This different survivorship biases their study towards more mild symptoms in the first episode. Finally, there were constraints on the power for the study, given the number of recurrent cases was only 33 and the confidence intervals were very large; adjusting for key confounders thus is difficult and controls were not matched to cases based on underlying characteristics.

Value added

This study has one of the largest sample sizes of recurrent infections included in research. Prior reinfection studies have suffered from very low sample sizes, given that reinfection is unlikely in the majority of COVID-19 patients.

Our take —

This multinational study found that 13% (n=356/2,760) of hospitalized COVID-19 patients also developed cardiac arrhythmia, the most common being atrial arrhythmia (81.8%). Only data from four institutions, of the 29 across Asia, Europe, and the Americas, were used to calculate the aforementioned proportion; nearly 90% of those patients were from two New York City hospitals. However, this study also assessed outcomes in the full global sample of 827 patients with cardiac arrhythmias that developed during COVID-19. About one half died. Pre-existing cardiac comorbidities (e.g., hypertension, diabetes mellitus) were common and were likely a significant contributor to cardiac arrhythmia. Ventricular fibrillation and ventricular tachycardia (monomorphic or polymorphic) were associated with higher mortality, more comorbid conditions, reduced left ventricular ejection fraction upon presentation, and more severe concurrent hemodynamic and metabolic compromise. Lastly, the study reported a >50% decline in cardiac device implantations and electrophysiological procedures during the COVID pandemic. This furthers concerns that people are not seeking or able to access specialized electrophysiology care.

Study design

Case Series

Study population and setting

This was an international case series that evaluated the characteristics of cardiac arrhythmias among patients aged 18 years and older with confirmed SARS-CoV-2 infection who were admitted to 29 institutions in 12 countries across 4 continents (Asia, Europe, North America, South America), from January 4 to August 7, 2020. Cardiac electrophysiologists from participating institutions contributed deidentified data from hospitalized COVID-19 patients, including demographics, comorbidities, electrocardiography (ECG) and echocardiogram, treatment with oseltamivir or remdesivir, hydroxychloroquine (HCQ) or azithromycin medications, presence and type of cardiac arrhythmias (atrial fibrillation [AF], atrial flutter [AFL], supraventricular tachycardia [SVT], non-sustained ventricular tachycardia [NSVT], monomorphic or polymorphic ventricular tachycardia [VT], atrioventricular block [AVB], sinus bradycardia below 40bpm [bradyarrhythmia]). Standardized data elements were uploaded through research electronic data capture from each center and analyzed by the Columbia University Medical Center, which served as the coordinating center. Chi-square tests and analysis of variance (ANOVA) were used to compare proportions and means respectively between different groups of COVID-19 subjects.

Summary of Main Findings

A total of 4526 adults hospitalized with COVID-19 were included in the study database (mean age 62.8 years old, 57% male), among whom 827 had cardiac arrhythmias during their hospitalization. The prevalence of cardiac arrhythmia was 12.9% among 2762 COVID-19 patients from the four institutions who included data from all hospitalized COVID-19 patients over the study period. Among the study sample of 827 patients with cardiac arrhythmia, the mean age was 71.1 years old, 64.7% were male, and 43.7% were white. A significant proportion had hypertension (68.6%), diabetes (41.6%), congestive heart failure (30.8%), coronary artery disease (24.3%), lung disease (18.3%), and chronic kidney disease (21%). Compared to the overall sample of 4526 patients with COVID-19, the sample who developed cardiac arrhythmia were older, had more comorbidities including hypertension, diabetes, coronary artery disease, chronic kidney and lung disease, and reduced left ventricular ejection fraction. There was considerable heterogeneity in the treatment of SARS-CoV-2 across the continents. Antiviral treatments were commonly given to subjects with COVID-19 and arrhythmia in Asia and Europe (93.2% and 50.9% respectively). On the other hand, HCQ and azithromycin were commonly given as an anti-SARS-CoV-2 treatment in Europe, North and South America. About 14% of the subjects had received anti-IL-6 treatment, while 61.3% received anticoagulation therapy. The majority of HCQ (87%) and azithromycin was given early in the pandemic (January to May 2020), while there was no difference in the prescription of antiviral treatment across the study period. Data pertaining to dexamethasone treatment was not captured. The prevalence of death among COVID-19 patients with arrhythmias was consistently high across the study period; 51% early in the pandemic (January to April 2020) and 48% from April to August, 2020 The most common cardiac arrhythmia was atrial arrhythmia (SVT, AF, AFL), observed in 81.8% of those with arrhythmia. In addition, 21% and 22.6% developed ventricular arrhythmia (NSVT, VT, VF) and bradyarrhythmia, respectively. Ventricular arrhythmia was associated with worse survival compared to atrial arrhythmia and bradyarrhythmia (37.8% vs. 50.9%). Patients with ventricular arrhythmia tended to have slightly higher baseline corrected QT interval compared to others (overall sample mean QTc 446.5±43.2 ms) and the majority of those who developed monomorphic (n=30) or polymorphic VT (n=33) had reduced baseline left ventricular ejection fraction, LVEF, by echocardiography (mean 36.1% and 46.4% respectively). Overall, the mean LVEF was normal among subjects with any type of cardiac arrhythmia who underwent echocardiography (267/827, 32%). Treatment with HCQ or antiviral medications and regional locations did not affect baseline QT interval. 50% of subjects with ventricular arrhythmia were either hypoxic or hypotensive and 1/3 had renal failure or acidosis at the time of the arrhythmia. Pulseless electrical activity (PEA) and asystole were the most common cardiac rhythm among COVID-19 subjects who died. A secondary aim to document the effect of the COVID-19 pandemic on the volume of electrophysiologic procedures noted a significant decline across the institutions, with more than a 50% decrease in both elective and urgent device implantations and cardiac ablation procedures during the study period (January 1 to August 7, 2020) compared to the

Study Strengths

The study was able to collect data on hospitalized COVID-19 patients from 29 institutions across the globe, which enhances generalizability of the results. Data were collected by electrophysiologists at each institution, which decreases the chance of misclassification of cardiac arrhythmia types. Also, the study included data across an 8-month period during the pandemic to capture any changes in cardiac arrhythmia types that could be attributed to changes in medical care and treatment for COVID-19 patients.

Limitations

The sample was not inclusive of all patients admitted for COVID-19 at each institution (except for four sites); it is possible that patients who were monitored for cardiac arrhythmia were sicker with a higher likelihood of arrhythmia compared to all hospitalized COVID-19 patients. 60% of those with cardiac arrhythmia were from North American institutions, with the majority from two New York City hospitals, further limiting generalizability of the findings on arrhythmia types and correlates measured among the 827 patients with arrhythmia. Though the authors estimated arrhythmia prevalence only among the subset of institutions who submitted data for all hospitalized COVID-19 patients rather than the full sample from all sites, unfortunately, the characteristics of this denominator were not described, making it difficult to evaluate the representativeness of the sample or to directly compare those with and without arrhythmia. Echocardiogram results were available for just a third of the COVID-19 patients with arrhythmia, and those results should be interpreted with caution given the smaller sample which may not be representative of hospitalized COVID-19 patients. Lastly, the study could not differentiate whether the cardiac arrhythmia observed among COVID-19 patients is specific to the pathological effects of SARS-CoV-2 virus or more likely, a marker of critical illness.

Value added

The study added significant incremental new information on the characteristics of patients with COVID-19 who develop cardiac arrhythmia, and the relative types of arrhythmia and their associations with patient morbidity and mortality.