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Our take —

An outbreak of 26 laboratory-confirmed Delta-variant SARS-CoV-2 cases took place at an elementary school in Marin County, California in May 2021 following exposure to an unvaccinated infected teacher. Despite school guidelines requiring mask wearing at all times, the teacher removed her mask to read aloud at times. While it is not possible to confirm that some/all of the subsequent infections were a result of exposure to this index patient, the attack rate in the homeroom classroom among students was high (54%), and even higher for the students sitting in the first few rows of the classroom closest to the teacher (80%). The total number of secondary cases outside of students in direct contact was relatively low and no cases were hospitalized, which may be partially explained by the high levels of community vaccination among eligible adults including parents and other teachers. These results, however, highlight the potential risk of infection to children who are ineligible for vaccination and their families (including vaccinated members) when COVID-19 prevention measures are not fully adopted by schools.

Study design

Case Series

Study population and setting

An outbreak investigation at an elementary school (pre-K to 8th grade) in Marin County, California was conducted by the Marin County Department of Health following a notification that an unvaccinated teacher had tested positive for SARS-CoV-2. The outbreak investigation involved contact tracing and whole genome sequencing of available specimens. The teacher (index patient) first started experiencing symptoms on May 19, continued working through May 21, and reported receiving a positive test to the school on May 23 (performed on May 21). School regulations required desks to be separated by 6 feet at all times; classrooms were equipped with particulate air filters; windows and doors were kept open as much as possible. Students and teachers during this period were required to be masked; it was reported that the index patient removed her mask at times to read aloud.  

Summary of Main Findings

During the outbreak investigation, 27 cases (including the index) were identified. Out of the teacher’s 24 students, 22 (ineligible for the vaccine) received testing and 12 tested positive (12/22; 54%). The attack rate among students was higher in the two rows closest to the teacher (8/10; 80%) compared with the back three rows (4/14; 28%), (Fisher’s exact test: p 0.036). Students in an additional classroom, separated from the original classroom by a courtyard, reported experiencing symptoms and 14/18 received testing; 6 of the 14 tested in this additional class tested positive (43%). Additional cases were identified among students in other grades (n=4) and among parents (n=4). The additional 8 cases were siblings and parents of students in the index patient’s class. Of those eligible for vaccination (index patient and parents), the teacher and one parent were unvaccinated. No one was hospitalized. All sequenced samples (n=18) were identified as the B.1.617.2 (Delta) variant.

Study Strengths

Given that most of the students who were exposed received testing, this outbreak investigation provides an important data estimate of secondary attack rate during the early days of the surge of the Delta variant within a school-setting in which precautions were taken, but teachers were not fully vaccinated.

Limitations

It is not possible to say with absolute certainty that the unvaccinated teacher was the source of any of the subsequent infections (the teacher’s sample was not available for genetic sequencing and so phylogenetic tracing was not possible). Additionally, the ascertainment of cases outside of the students may be limited as parents and siblings had to opt-in. 

Value added

This investigation adds evidence on the importance of 1) vaccination, 2) staying home when symptomatic, 3) masking, and 4) timely contact tracing all within a school setting.  

Our take —

There was an outbreak of SARS-CoV-2 in Barnstable County, Massachusetts in which 469 cases were detected following a series of public events. A majority of the cases identified were among those who were vaccinated, and many of those experiencing breakthrough infections were symptomatic. The Delta variant made up 89% of the samples sequenced and cycle threshold (Ct) values were similar between those who were vaccinated and unvaccinated, suggesting similar viral loads. The results do not represent the overall rate of infection amongst all vaccinated and unvaccinated individuals attending events, but do speak to risks of breakthrough infection and potential transmission associated with the Delta variant even amongst fully vaccinated and suggest that additional non-pharmaceutical interventions including masks may be necessary for outbreak prevention.

Study design

Case Series

Study population and setting

In July 2021, an outbreak of COVID-19 was detected in Barnstable County, Massachusetts associated with multiple public events including gatherings drawing several individuals from out-of-state. A total of 469 cases were identified among Massachusetts residents, with further cases identified among residents of 22 other states not detailed in this report. Genomic sequencing was conducted (n=133) and cycle threshold (Ct) values were measured (n=211) in a subset of cases. Genomic sequencing can tell us about the specific variant of SARS-CoV-2 an individual was infected with, and Ct values can tell us how much virus an individual harbors in their nasopharynx (higher Ct values generally represent lower levels of virus). Breakthrough infections were defined as infections among those who were fully vaccinated (at least 14 days before exposure with 2 doses of either Pfizer BioNTech or Moderna or 1 dose of Janssen). For context, vaccination coverage among Massachusetts residents at the time was 69%.

Summary of Main Findings

Among the 469 cases identified, 346 or 74% were among those fully vaccinated (breakthrough cases). Of those 346 breakthrough cases, 274 or 79% experienced symptoms of COVID-19. Genomic sequencing conducted in 133 cases revealed that 89% (119/133) had the Delta variant (B.1.617). Median Ct values were similar among vaccinated (n=127) and unvaccinated, partially vaccinated, or vaccination status unknown (n=84) (22.77 vs. 21.54, respectively). Four out of the five hospitalized cases were among vaccinated individuals; no deaths were recorded.

Study Strengths

Inclusion of testing data, genomic sequencing, and Ct values helps provide a more complete picture of this outbreak among vaccinated and unvaccinated individuals.

Limitations

This study is a case-series; vaccine coverage among all individuals attending public events during this time period is unknown. Thus, the high percentage of all cases among those vaccinated may have been influenced by: 1) the underlying level of vaccination coverage in an area (higher levels of vaccination coverage means more individuals are going to be vaccinated); and 2) detection bias (the sample is contingent on individuals seeking out testing). Comparisons of Ct values between those who were vaccinated and unvaccinated, in particular, should be interpreted in the context of this non-representative sampling approach; furthermore, the extent to which Ct values correspond to viral loads and viable replicable virus is not known in this setting. 

Value added

This report provides further information about SARS-CoV-2 among vaccinated individuals in a real-world setting. 

Our take —

This case series, available as a preprint and thus not yet peer-reviewed, attributed 167 SARS-CoV-2 Delta variant cases to one index case between May 21 and June 18, 2021 in Guangdong, China. Although selection criteria for SARS-CoV-2 cases from early 2020 for comparison are not specified, the authors found that among transmission events outside of the same family, there was a median of 4 days from Delta variant exposure to PCR test positivity vs. 6 days in 2020 (pre-Delta) suggesting the potential for rapid and pre-symptomatic transmission with the Delta variant.

Study design

Case Series

Study population and setting

This case series follows SARS-CoV-2 infections in Guangdong, China directly attributed to the first local Delta variant SARS-CoV-2 infection in the region on May 21, 2021. From May 21 to June 18, 2021, researchers performed contact tracing to determine exposure information for positive cases and their close contacts, which included frequent PCR testing following exposure. Transmission pairs included a recipient that was a close contact and had a clear and direct epidemiologic link with the donor and did not have any contacts with other cases. Viral genomes were sequenced to further ascribe linkage between cases and outbreak parameters in a subset of cases, such as the time between exposure and first detectable viral load and viral load measurements on the day of SARS-CoV-2 detection, which were compared to the SARS-CoV-2 outbreak in the same region in early 2020.

Summary of Main Findings

The study found 167 cases epidemiologically or genetically attributed to the index case from May 21 to June 18, 2021. After removing cases that occurred within family-transmission pairs, they found that the time from the exposure to the first positive PCR test for Delta variant cases (n = 34, median 4 days, interquartile range [IQR] 3-5 days) was shorter than during the 2020 pandemic (n = 29, median 6 days, IQR 5-8 days). Among a subset of individuals (n = 62 for the Delta variant, n = 63 for early 2020), they also found higher relative viral loads as measured by PCR cycle threshold (Ct) on the first day of a positive SARS-CoV-2 test (24 with an IQR of 19-29 for Delta cases versus 34 with and IQR of 31-36 for early 2020 cases).

Study Strengths

Through extensive contact tracing and viral genetic analysis, this study presents essential information on how quickly the SARS-CoV-2 Delta variant can spread in a community.

Limitations

The authors do not describe how they selected early 2020 SARS-CoV-2 comparison cases, which makes them difficult to interpret. They also report extensive population PCR testing, but do not elaborate on how frequently close contacts were tested for SARS-CoV-2 or how similar those protocols were during the comparison period. If, for example, they did more frequent testing during their study period, they may find a shorter interval between exposure and PCR-positivity due to more frequent testing. Furthermore, they do not clarify whether or not PCR Ct values were run on the same or different machines, or whether they normalized Ct values to positive controls to account for variability that occurs across PCR runs, further limiting comparisons both within and across SARS-CoV-2 transmission periods.

Value added

This study provides evidence of how rapidly the SARS-CoV-2 Delta variant can spread through a community.

Our take —

The Advisory Committee on Immunization Practices (ACIP) issued two reports that the benefits of mRNA vaccination against COVID-19 far outweigh the potential risks of myocarditis for all ages and sexes. Even among males 18-29 years old, who had the highest reported prevalence of myocarditis (24.3 cases per million second doses of vaccines administered vs. 3.5 cases/million second doses administered overall), the individual-level risk-benefit favored vaccination. Specific to this age/sex group, one million second vaccine doses could prevent up to 11,000 cases of COVID-19 compared to ~45 cases of myocarditis. These reports used data provided to United States’ Vaccine Adverse Event Reporting System (VAERS) between December 2020 and June 2021. During this time, 1,226 people received an mRNA vaccine and reported myocarditis within three days of their shot. Of these, 58% were among people < 30 years and two thirds occurred among males.  ACIP selected a subset of 484 young people for an assessment by a CDC physician, who found that only 67% met the criteria for myocarditis.  This would imply that the prevalence of myocarditis was overestimated. However, the prevalence may have also been underestimated since VAERS relies on passive ascertainment, i.e., voluntary submission from the public who often decide not to report adverse reactions like myocarditis to the CDC. Regardless, to support timely treatment of myocarditis, ACIP recommends increased awareness of vaccine-associated myocarditis among both providers and potential vaccine recipients. This analysis did not consider other benefits that COVID vaccines may confer besides preventing severe disease, such as preventing mild cases that progress to long COVID. As the pandemic evolves, continuous updates to these risk-benefit estimations will be required to account for new viral variants and potential changes in vaccine effectiveness.

Study design

Case Series

Study population and setting

This is a summary of two reports: (1) “Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients” by Gargano et al. and (2) “Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen and mRNA COVID-19 Vaccines” by Rosenblum et al. These reports from the Advisory Committee on Immunization Practices (ACIP) review the risks of myocardial or pericardial inflammation (myocarditis) after mRNA COVID-19 vaccines in the United States, particularly among adolescents and adults below the age of 30 years. The reports also review the risk/benefit ratio from immunization across different age and gender groups.

Summary of Main Findings

A total of 296 million doses of mRNA COVID-19 vaccines was given as of June 11, 2021 in the United States.  Fifty-two million doses (30 million first doses and 22 million second doses) were given to individuals between the ages of 12-29 years old.  Between December 29, 2020 and June 11, 2021, 1,226 cases of myocarditis associated with mRNA vaccines were reported through the Vaccine Adverse Event Reporting System (VAERS).  The median age of cases was 26 years and the median time from vaccination to symptoms was 3 days. About 58% of the cases occurred in individuals below the age of 30 years (76% males).  Since the majority of myocarditis cases were among children, adolescents and young adults, sample of 484 cases reported between May 1-June 2021 and occurring in people below the age of 30 years was selected for review by CDC physicians. Of these, 67% (median age, 19 years old; median time from vaccination to symptom onset, 2 days) met CDC criteria for myocarditis and were reviewed further.

A benefit-risk ratio for mRNA COVID-19 vaccines across different age and sex groups was calculated by assuming a 95% vaccine effectiveness in preventing severe COVID-19, hospitalization, and death over a period of 3 months, based on the rate of cases during the week of June 13-19, 2021, the rate of hospitalization during the week of June 19, 2021, and the rate of ICU admission or deaths attributed to COVID-19. COVID-19-related myocarditis, defined as myocarditis that occurred within 7 days of the 2nd dose of an mRNA COVID-19 vaccine, represented the risk. Men between the ages of 18-29 years had the highest reported prevalence at 24.3 cases of myocarditis per million mRNA COVID-19 2nd doses administered (compared to 3.5 cases/million overall).  However, even among this relatively high risk for myocarditis subgroup, 1 million second doses of COVID-19 vaccine could prevent 9600 cases of COVID-19, 300 hospitalizations, 60 ICU admissions, and 3 deaths.  The benefit is significantly greater among all other subgroups who are at lower risk for myocarditis, e.g. men over 30 years of age in whom 1 million second doses of COVID-19 vaccine could prevent 15,300 cases of COVID-19, 4598 hospitalizations, 1242 ICU admissions, and 700 deaths compared to risk of 3-4 expected myocarditis cases.  This suggests a highly favorable benefit to risk ratio even among those who have the highest risk for myocarditis due to mRNA vaccines, including males between the ages of 12-29 years of age.

Furthermore, at the population level, the reports conclude that vaccinating adolescents and young adults is critical to ensuring their return to normal pre-pandemic social and educational activities, while also limiting spread within the community and the emergence of new virus strains.  Excluding young adults and adolescents from vaccination could disproportionally increase viral spread among populations particularly at risk for COVID-19 including racial and ethnic minority groups, exacerbating the widespread disparity in COVID-19 severity and death among these subgroups.

Study Strengths

A sample of cases of myocarditis reported nationally and occurring among those younger than 30 years of age were actively reviewed and validated by CDC physicians to determine the prevalence, severity and the short-term outcomes of this adverse event.  Also, risk benefit analysis was conducted across different age and sex subgroups.

Limitations

The report does not consider new strains of SARS-CoV-2, which could affect some of the assumptions that were used to determine vaccine effectiveness in reducing rates of cases, hospitalization, or death (benefit). Relying on passive ascertainment of COVID-19-related myocarditis (VAERS) may underestimate the number of COVID-19-related myocarditis.

Value added

The paper addresses the safety concern of mRNA vaccine among adolescents and young adults in the United States and provides quantitative benefit/risk ratio analyses with further subgroup analysis by age and sex.

Our take —

This is a case series of seven male patients (14-19 years) who developed myocarditis with or without pericardial inflammation within 4 days of receiving the second dose of Pfizer-BioNTech vaccine in the United States. All patients presented with chest pain, with or without myalgia and/or fever and had elevated cardiac specific enzymes and inflammatory markers and abnormal electrocardiograms. All patients recovered quickly with standard treatments for myo- and pericarditis. While this case series provides detailed descriptions of their clinical presentation and course of treatment, the relationship between the Pfizer-BioNTech vaccine and subsequent cardiac inflammation remains unclear given the following cautions: 1) the lack of adjustment for other factors that may have affected risk for acute cardiac inflammation; 2) the impact of potential selection biases; and, 3) the lack of an appropriate comparison group for evaluating potential risk differences.

Study design

Case Series

Study population and setting

This is a case series of seven adolescent males (14-19 years) hospitalized in the US with acute myocarditis with or without pericardial inflammation (myocarditis/myopericarditis) within four days of receiving their 2nd dose of Pfizer-BioNTech vaccine in April and May 2021. The authors document their presenting symptoms, diagnostic workup, treatment(s), and status at hospital discharge.

Summary of Main Findings

All patients presented to the hospital complaining of chest pain with or without arm pain, myalgia, or fever. Initial evaluation revealed elevated cardiac enzymes (Troponin T, from 1.09 to 22.1) and inflammatory markers (ESR range: 10-40; CRP range: 6.7-18.1) at presentation, All had negative SARS-CoV-2 PCR via nasopharyngeal swap and negative antibodies against SARS-CoV-2 nuclear capsid antigen, six patients had negative other respiratory viral panel and none met criteria for MIS-C.

All patients had evidence of ST segment elevation on their electrocardiogram (ECG); two had evidence of mild ventricular strain and 1 had mildly decreased systolic function on echocardiogram. Myocardial MRIs revealed evidence of myocardial with or without pericardial inflammation in all cases. No evidence of other viral infections were identified in six of the patients as a possible cause for their myocardial inflammation. One patient underwent cardiac catheterization, which revealed normal coronary arteries. Treatment included some combination of IVIG, corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs). Three cases resolved with NSAIDs alone. Although 5 hemodynamically stable patients were initially admitted to the intensive care unit for close monitoring, all patients had significant improvement in their symptoms within few days of hospitalization.

Study Strengths

This case series provides detailed information about the presentation, diagnostic workup, treatment, and short-term outcomes among seven adolescents who developed myocardial with or without pericardial inflammation within four days of their second dose of the Pfizer-BioNTech vaccine.

Limitations

Despite testing for a variety of viral and bacterial infections that could possibly cause myocardial and pericardial inflammation, no mechanistic pathway was examined between Pfizer-BioNTech vaccine and these disorders. Cardiac biopsy was not performed, due to generally mild disease and rapid improvements in clinical status, precluding examining the potential underlying mechanism between Pfizer-BioNTech vaccine and this disorder. Furthermore, as a case study, this paper is not able to assess incidence of myocardial and/or pericardial inflammation after the second dose of the Pfizer-BioNTech vaccine in adolescents or compare incidence against background incidence in this age group. Finally, the cases were identified through personal communications, which may have resulted in significant selection biases if these individuals had other characteristics that affected their risk for acute cardiac inflammation.

Value added

The study provides detailed information on clinical presentation, treatment, and outcomes on male adolescents presenting with myocardial or pericardial inflammation following a second dose of the Pfizer-BioNTech vaccine. This will help pediatricians quickly identify this disorder, provide effective therapy, and encourage health care providers to report these events to the Vaccine Adverse Event Reporting System (VAERS).

Our take —

Between September and December 2020, there were 287 mucormycosis cases diagnosed across 16 healthcare centers in India, a two-fold increase compared to the same time period in 2019. Of these cases, 187 were COVID-19 associated mucormycosis (CAM). CAM was extremely rare (<0.3%) among hospitalized COVID-19 patients. Aside from CAM patients having more frequent hypoxia requiring ICU admission, CAM and non-CAM cases had similar clinical manifestations and outcomes. The majority of both CAM and non-CAM cases had uncontrolled diabetes. Most CAM cases were given glucocorticoids as part of their treatment for COVID-19, similar to previous smaller case series from India. It is possible that glucocorticoid treatment contributed to additional CAM cases in certain settings, but more research in larger sample sizes and with additional control for confounding is needed to further evaluate this finding.

Study design

Case Series, Retrospective Cohort

Study population and setting

This multicenter retrospective cohort study evaluated the prevalence, epidemiology, and outcomes of COVID-19 associated mucormycosis (CAM), a fungal disease, in India from September 1, 2020 to December 31, 2020, compared to mucormycosis not associated with COVID-19 (non-CAM) over the same time period. Mucormycosis was defined based on clinical and radiologic findings that showed fungi in tissue or sterile body fluids. COVID-19 diagnosis was based on detection of SARS-CoV-2 on RT-PCR or rapid antigen tests. The data from 16 health centers were used to evaluate predisposing factors and clinical manifestations of CAM and non-CAM patients, and data from 7 of these centers were used to estimate prevalence of CAM. Demographics, medical history, clinical presentation, and outcomes were extracted from patient medical records. Patients were treated for COVID-19 and mucormycosis in accordance with institutional protocols; inappropriate glucocorticoid use was defined as use of any steroid among non-hypoxic patients or when a dexamethasone-equivalent was used for 10 days or more with more than 6 mg/day.

Summary of Main Findings

Across the 16 participating centers, 295 cases of mucormycosis were diagnosed, among whom 287 had complete data and were included in the study population (mean age: 53.4 years, 25% women, 83% diagnosed on direct microscopy). Across the 7 centers with data on all hospitalized COVID-19 patients, the prevalence of CAM was 0.27% (28/10,517) in general wards and 1.6% (25/1579) in the ICU. The total number of mucormycosis cases between September 2020 and December 2020 was over twofold higher than the same time period in 2019, though the number of mucormycosis unrelated to COVID was relatively similar (92 in 2020 vs. 112 in 2019). Of the 187 CAM cases (65% of all mucormycosis cases), 61 (33%) did not have other underlying diseases, compared to only 19 of the 100 non-CAM cases without other underlying diseases. Among CAM and non-CAM cases, uncontrolled diabetes was common (63%) though newly diagnosed diabetes was more common among those with CAM (21% vs. 10%). Both groups experienced similar clinical manifestations and sites of involvement (~85% in each group with rhino-orbital or rhino-orbital-cerebral involvement), and mortality was similarly high (6-week mortality: 38%; 12-week mortality: 46%). However, patients with CAM were more likely to have hypoxia requiring ICU admission than non-CAM patients (31% vs. 9%). CAM patients were classified according to timing of onset (early: <8 days after COVID-19 diagnosis, n=29; late: ≥8 days after COVID-19 diagnosis, n=158), and although demographic, clinical characteristics, and outcomes were similar between early and late CAM groups, hypoxia and inappropriate or non-indicated glucocorticoid use was associated with development of late CAM as compared to early CAM (adjusting for age, sex, and underlying risk factors).

Study Strengths

This was a multisite study with detailed data on clinical characteristics, treatment history, and outcomes of COVID-19 associated mucormycosis, with a comparison group of adults with mucormycosis not associated with COVID-19.

Limitations

Despite its multi-site design, the sample size was still relatively small. Adjusted analyses, especially those among only CAM cases, were likely underpowered to detect associations or overfit. Consequently, many of the estimates had very wide confidence intervals and should be interpreted with caution. The study was retrospective and relied upon data available in the medical record, which may not have fully captured individual disease histories and comorbidities. The study did not report whether there was clustering of cases by healthcare center nor explore facility-level characteristics that might have enabled healthcare-associated sources of mucormycosis during the study period. Given the small sample size, analyses of mucormycosis and CAM outcomes were limited in their ability to fully adjust for treatment practices, which differed between sites.

Value added

This study is among the first and most detailed reports of COVID-19 associated mucormycosis, a rare fungal disease associated with high mortality.

Our take —

This study was conducted among 25,381 individuals with SARS-CoV-2 in Germany to estimate the infectiousness of the virus through its infection time course. Infectiousness was based on measurements of viral load and the probability of a sample yielding replicating SARS-CoV-2 in cell culture. Though the trajectory of viral load levels varied by individual and symptom severity, the overall time from a near-zero culture probability to the peak culture probability was 1.8 days, with peak viral load being one to three days before symptom onset. Compared to infection with non-B.1.1.7 (Alpha) variants, people infected with the Alpha variant had 10 times higher viral load and 2.6 times higher probability of yielding replicating virus in cell culture. Very high viral loads (more than 10^9 virus copies per swab) were detected in less than 10% of individuals, with one third of these higher viral loads among pre-symptomatic, asymptomatic, or mildly symptomatic infections. Findings also demonstrated that younger individuals had slightly lower viral loads at first positive PCR and peak culture probability compared to adults, which may have been due to differences in swab size or test timing.  This study allowed researchers to compare infectiousness proxy parameters across several characteristics (e.g. across time, by variant, by symptom severity, and by age), however, it should be noted that viral load and replicating virus are not direct measures of infectiousness.

Study design

Case Series

Study population and setting

The goals of this study were to better quantify viral infection and shedding of SARS-CoV-2, by measuring and comparing viral load (viral RNA concentration) and replicating virus isolated in cell culture. Specifically, the study aimed to estimate: 1) differences in infectiousness by age and gender, along with differences by symptom severity (e.g. pre-symptomatic, asymptomatic, symptomatic); 2) differences in infectiousness by viral variants (specifically B.1.1.7); and 3) timing and peak of infectiousness. Samples on 25,381 German individuals with at least one positive RT-PCT test from February 24, 2020 to April 2, 2021 were examined. Samples were divided into three categories: hospitalized (n=9519, 37.5%), pre-symptomatic, asymptomatic, or mildly symptomatic (PAMS) individuals receiving testing at walk-in community testing centers (n=6110, 24.1%), and other (n=9752, 38.4%). A total of 1,533 individuals had the B.1.1.7 variant. Viral loads were assessed using standard RT-PCR methodologies. The probability of viral culture was estimated using Baysesian regression by combining the estimated viral loads with cell culture isolation data from previously published work relating viral loads and culture probabilities. B.1.1.7 variants were identified using sequencing and comparisons were made using data from only testing centers that specifically reported B.1.1.7 cases.

Summary of Main Findings

Younger individuals had a lower mean log10 viral load than adults (those 20-65 years old) (0.5 lower for 0-5 year olds and 0.18 lower for older adolescents (those 15-20 years old)). Younger individuals also experienced 78% of the peak cell culture replication probability compared with older individuals, though the authors suggest this may have been due to a small swab size used for the youngest individuals in the sample. No differences were seen by gender. Very high viral loads (above 109 copies per swab) were detected in 8% of all individuals, with approximately one third of these high viral loads among presymptomatic, asymptomatic, or mildly symptomatic individuals. When comparing those with the B.1.1.7 variant with those without it, it was found that those with the B.1.1.7 variant had a higher mean log10 viral load (1.05 log10 higher), and a 2.6 times higher estimated cell culture replication probability. The estimated time from the start of viral shedding to peak viral load was 4.3 days.

Study Strengths

This study utilized multiple samples from individuals, and therefore it was possible to model viral dynamics over the time course of infection. Additionally, the large and generally varied population, by symptom severity, age, hospitalization, and variants allowed for the estimation of infectiousness parameters by a number of different characteristics.

Limitations

The authors note that the two parameters studied here: viral load and replicating virus isolate are not a direct measure of infectiousness, as behavior and context play an important role in infectiousness as well and these were not measured. Additionally, replicating virus was not measured in any of these samples, but instead relied on prior data to model culture positive probability. This analysis relies on the assumption that this prior work may be generalized to this study population.

Value added

This study furthers our understanding of SARS-CoV-2 infectiousness through the analysis of viral load, cell culture isolation, and genome sequencing data, especially to understand differences in infectiousness among those who are not symptomatic compared to those who are and those with the B.1.1.7 variant compared to others.

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.