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Our take —

This paper was a preprint and thus was not yet peer reviewed. Findings from this interdisciplinary autopsy series of 67 SARS-CoV-2 positive patients suggest endothelial dysfunction and hypercoagulability in several major organs, as well as immune dysfunction. These results provide support for previous studies suggesting key roles of endothelial damage and abnormal macrophage activation in severe COVID-19 disease. More research into potential mechanistic pathways will be key to identifying effective therapeutic strategies.

Study design

Case Series

Study population and setting

This study includes 67 consecutive autopsies on SARS-CoV-2 positive patients performed at Mount Sinai Hospital between March 20 and April 29, 2020. Mount Sinai Hospital performs all autopsies for each of the seven hospitals in the Mount Sinai Health System in New York City. The study reports on lab values for 49 patients and autopsy findings specific to several organ systems: lungs (n=25), thoracic lymph node (n=11), heart (n=25), bone marrow (n=6), spleen (n=22), kidney (n=25), liver (n=22), gastrointestinal organs (n=20), brain (n=35).

Summary of Main Findings

The median age of patients was 69 years (range 34-94), with an average time from admission to death of 9.5 days (range 0-61). Levels of Inflammatory markers (i.e. ferritin, C-reactive protein, procalcitonin, and white blood cell count), d-dimer (despite 81% of patients receiving anticoagulation therapy), interleukin-6, interleukin-8, and TNFa were all higher than the reference levels. The predominant lung findings were diffuse alveolar damage in 22/25 cases and aggregates/thrombi of medium-sized arteries, arterioles, and capillaries in 23/25 cases. Microthrombi were present in several other organ systems, including the brain, lymph, heart, and liver. Endothelial dysfunction was also common, evidenced by high levels of ACE2 expression in lung and brain parenchymal capillaries. Presence of hemophagocytic histiocytes found in lymph nodes, spleen, bone marrow, heart, and liver support previous conjectures about macrophage activation syndrome in COVID-19 patients.

Study Strengths

Compared to existing autopsy studies, the sample size is relatively large (though varies by organ system). The autopsies include comprehensive laboratory and imaging analyses.

Limitations

The clinical and demographic characteristics of patients with available tissue for each autopsy is not available. Autopsy findings were not linked to clinical characteristics. The study includes only adult patients, so findings cannot be generalized to children or adolescents, who may have different disease presentations.

Value added

The is the largest autopsy study to date with data on several major organ systems, suggesting potential mechanisms for some of the more puzzling clinical symptoms in patients with severe COVID-19 disease.

Our take —

This was a descriptive, contact tracing study in Arkansas, in which 35 out of 92 church goers and 26 of their contacts became infected, presumably from 2 symptomatic church attendees. One cannot rule out community transmission among these cases; however, the report demonstrated the consequences of attending large gatherings while symptomatic. This report also showed that in the absence of high testing coverage, people may not abide by social distancing guidelines as they may assume that they are not infected.

Study design

Case Series

Study population and setting

The report concerns a church gathering among 92 attendees in Arkansas and subsequent transmission from the gathering from March 6 to March 11, 2020.

Summary of Main Findings

The Arkansas Health Department (AHD) was notified on March 16, 2020 of a couple (husband and wife) who were the first 2 confirmed cases in a rural county. The husband was a pastor of a church and the couple attended church events from March 6 to 8, 2020 after which they developed mild symptoms. AHD later discovered that two attendees of the church had symptoms on March 6 and 7, and attended church events including several indoor events that lasted multiple hours, children collecting church offerings, and a buffet style meal. Between March 6 and 11, 2020, 92 people attended church events, and 35 (38%) became infected (including 3 deaths). There were 26 secondary cases who were contacts of the infected church cases (including 1 death). Among these contacts, the attack rate among those ≤18 years of age was 6.3%, for those aged 19–64 years was 59.4%, and for those aged ≥65 years was 50.0%.

Study Strengths

The strength of this report is that it demonstrates the use of contact tracing data to monitor the impact of gatherings (e.g. church events) on transmission when individuals are symptomatic.

Limitations

It is possible that some of the cases reported were due to community transmission outside of the church events. Also, the categorization of age-specific attack-rates includes a wide age range (19-64 years) that was the highest attack rate, although it is possible that most cases were among older individuals in this category. Furthermore, there was no testing was done among those who were asymptomatic, thus this is likely an underestimation of true transmission.

Value added

The report provides an example of how large gatherings can result in an instant outbreak of transmission.

Our take —

Emerging evidence suggests a multisystem inflammatory syndrome in children infected with SARS-CoV-2 that can cause critical illness. However, overall risks of severe illness and mortality in pediatric cases of COVID-19 remain low compared to those in adults. This case series highlights heart failure as one of a cluster of symptoms (including skin rash, conjunctivitis, and adenopathy) related to a severe inflammatory state. Patients were treated with immune globulin with apparently beneficial results.

Study design

Case Series

Study population and setting

This study included 35 children aged 1-16 years (median age 10, 51% male) who were admitted to 12 intensive care units in France and one in Switzerland between March 22 and April 30, 2020 with fever, cardiogenic shock or left ventricular dysfunction, and an acute inflammatory state (c-reactive protein>100 mg/L). Six (17%) patients were overweight; no patients had underlying cardiac disease.

Summary of Main Findings

SARS-CoV-2 infection was confirmed in 31/35 (89%) patients via PCR or antibody assay; 30/35 had positive antibody tests and 12 (34%) had a positive nasopharyngeal swab PCR. The median time between symptom onset and heart failure symptoms was 6 days; 29/35 (83%) were admitted directly to the ICU. Gastrointestinal symptoms were present in 29 (83%) patients, but chest pain was less common (n=6, 17%). No patients met the clinical criteria for Kawasaki disease, though several symptoms typically seen in Kawasaki disease were common: conjunctivitis (89%), cervical lymphadenopathy (60%), skin rash (57%), red/cracked lips (54%), and meningism (31%). At the time of ICU admission, 80% of patients met criteria for cardiogenic shock, 62% required mechanical ventilation and 28% required extracorporeal membrane oxygenation (ECMO). Patients had high concentrations of IL-6 and D-dimer, indicative of a severe inflammatory state. The left ventricular ejection fraction was below 30% in 10/35 (29%) of patients. 28/35 (80%) patients required inotropic support and all patients received immune globulin intravenously. Left ventricular function was fully restored in 25/35 (71%) of patients by a median of 2 days after admission. There were no fatalities and no thrombotic or embolic events; only 7/35 (20%) patients remained hospitalized by the end of follow-up.

Study Strengths

There was in-depth evaluation of cardiac functioning and longitudinal follow-up of critically ill patients.

Limitations

The timing of inflammatory syndrome and heart failure relative to SARS-CoV-2 infection is unclear; some patients may have been infected many days before hospital admission, as evidenced by the high proportion of positive antibody tests and low proportion of positive PCR results from nasopharyngeal swabs. Follow-up was incomplete (20% of patients remained hospitalized) and outcomes may change.

Value added

This study adds data on heart failure to the rapidly emerging literature on an inflammatory syndrome related to SARS-CoV-2 infection in children.

Our take —

In this case series from Michigan, the authors report a high prevalence of pulmonary embolism among COVID-19 patients who received CT angiography, particularly among obese patients. This adds to the growing body of evidence of hypercoagulability and thrombotic complications in COVID-19. However, further studies are needed to establish the prevalence in the wider population of patients infected with SARS-CoV-2 along with any unique risk factors.

Study design

Case Series

Study population and setting

The study included 328 patients with laboratory-confirmed SARS-CoV-2 infection who received a pulmonary computed tomography (CT) angiography study between March 16 and April 18, 2020 within a Michigan health system. Imaging was obtained for clinical care rather than for research purposes. Laboratory measurements were obtained within two days of the CT angiogram.

Summary of Main Findings

22% (73/328) of COVID-19 patients with CT angiography had evidence of pulmonary emboli (PE) on imaging. Compared to those without detected PE, those with PE were more likely to be obese (BMI >30 kg/m2; 58% vs 44%), were less likely to be taking statin medications (27% vs 46%) and had higher serum levels of D-dimer. There were no differences in ICU admission or death based on the detection of a PE. Based on the independent risk factors, the authors developed a model to predict the presence of PE and included BMI, D-dimer, use of statins, and history of PE or hypertension.

Study Strengths

Relative to previous studies reporting pulmonary embolism in COVID-19 patients, the sample size was large.

Limitations

While the authors developed a predictive score for PE, the sample size likely limits its validity; no validation tests were performed. Laboratory values used for predictive purposes were obtained concurrently with, or in some cases, after, ascertainment of PE. Because CT angiography was obtained for clinical purposes, chiefly the diagnosis of PE, the reported prevalence is likely to be a large overestimate of the underlying prevalence of PE in the COVID-19 population.

Value added

This is one of largest studies to date investigating the prevalence of pulmonary emboli in patients with COVID-19.

Our take —

This study documented a significantly elevated incidence of Kawasaki-like disease among children in a northern Italian hospital during the COVID-19 epidemic, and detected SARS-CoV-2 antibodies in 80% of these cases. Compared to the prior 5-year period, children presenting with Kawasaki-like disease during the COVID-19 epidemic were older and had more severe clinical presentations, including cardiac involvement and macrophage activation syndrome. While additional evidence is needed to establish a causal association, these findings suggest that COVID-19 may subsequently trigger a severe form of Kawasaki disease among a small percentage of children, and are consistent with early reports from other settings.

Study design

Case Series; Other

Study population and setting

The study population included all pediatric patients diagnosed with a Kawasaki-like disease (n=29, 48% male, mean age 4.9 years) at a single tertiary pediatric hospital in Bergamo, Italy from January 1, 2015 to April 20, 2020. Patients diagnosed during the COVID-19 epidemic (February 18, 2020 to April 20, 2020) were compared to those diagnosed during the preceding 5 years (January 1, 2015 to February 17, 2020). Patients presenting during the COVID-19 epidemic were tested for SARS-CoV-2 by PCR assay on nasopharyngeal and oropharyngeal swab samples; antibody response was assessed by serologic testing (IgG and IgM).

Summary of Main Findings

The incidence of Kawasaki-like disease was significantly higher during the COVID-19 epidemic. There were ten children (70% boys, mean age 7.5 years) diagnosed during the two months after the COVID-19 epidemic began, compared to 19 children (37% boys, mean age 3.5 years) diagnosed during the prior 5-year period. Among the 10 children diagnosed during the COVID-19 period, 8/10 tested positive for SARS-CoV-2 antibodies, of whom 2 also tested positive for SARS-CoV-2 via PCR; two tested negative for both. Severe disease was more prevalent during the COVID-19 period than the earlier period, including abnormal echocardiogram results (60% vs 10%), Kawasaki disease shock syndrome (50% vs. 0%), and macrophage activation syndrome (50% vs 0%); the mean age of children during the COVID-19 period was significantly higher. Children in both periods were successfully treated with intravenous immunoglobulin and aspirin, though during the COVID-19 period more children required steroid treatment (80% vs 16%); all were discharged without further complications.

Study Strengths

The cases were tested multiple times for SARS-CoV-2 infection and antibodies, demonstrating that most of the COVID-19 exposure would have been missed by PCR test alone at the time of admission for Kawasaki-like symptoms. Cases diagnosed prior to the COVID-19 epidemic were used as a comparison group.

Limitations

This study consists of a small number of cases from a single referral hospital. The incidence for the COVID-19 period appears to have been calculated using a smaller denominator of time (one month) than the seven-week period defined throughout the methods, inflating the incidence and incidence rate ratio reported, though the inference of a significant increase in cases during the COVID-19 epidemic stands nevertheless.

Value added

This was among the first published case series of Kawasaki-like disease in children during the COVID-19 epidemic.

Our take —

In a small case series from New York, a sizable proportion of children presenting to hospital for SARS-CoV-2 testing required admission and ICU care. Further study is needed to understand what proportion of all infected children develop clinical disease.

Study design

Case Series

Study population and setting

The study included 67 children with laboratory-confirmed SARS-CoV-2 infection diagnosed at a tertiary care center in New York City between March 15 and April 13, 2020.

Summary of Main Findings

Among children presenting for care, 31% (21/67) were managed as outpatients. 46 children were admitted to the hospital and had a median age of 13.1 years (67% male). Of the admitted patients, 28% (13/46) were admitted to the ICU. Obesity and asthma were not associated with the need for ICU admission, while shortness of breath and higher levels of C-reactive protein, procalcitonin, blood urea nitrogen, and pro-Brain Natriuretic Peptides (pro-BNP) were associated with ICU admission. All patients who did not require ICU admission were discharged home. Acute Respiratory Distress Syndrome (ARDS) was diagnosed in 77% (10/13) of patients requiring ICU care, six of whom required mechanical ventilation. 62% (8/13) of patients requiring ICU admission were discharged home, 4 remained in the ICU at day 14, and one died (with underlying metastatic malignancy).

Study Strengths

NA

Limitations

The small sample size limited the ability to draw inferences. Associations were not adjusted for common confounders, and it is unclear whether factors associated with severe disease are causes or consequences of COVID-19 severity. Given recent interest in non-pulmonary manifestations of COVID-19 in children, further discussion of immunologic parameters, and dermatologic and gastrointestinal presentation, would have been useful.

Value added

This study presents data on a group of children who required hospitalization, many of whom had severe disease.

Our take —

Most children admitted to intensive care for COVID-19 had significant underlying health conditions, and many had complex developmental and/or congenital disorders.  2 of 18 children requiring mechanical ventilation died by the end of follow-up, though 7 remained hospitalized.  This proportion is much smaller than that observed among adults.  Reinforcing existing evidence from North America and beyond, this study suggests a less severe clinical course for COVID-19 in children than in adults.

Study design

Case Series; Cross-Sectional

Study population and setting

This study included 48 children (median age 13 years, 52% male) with laboratory-confirmed COVID-19 admitted to pediatric intensive care units (PICUs) in 14 U.S. hospitals (out of 46 collaborating PICUs in North America) between March 14 and April 3, 2020.  Outcomes were ascertained through April 10, 2020.

Summary of Main Findings

35 children (73%) presented with respiratory symptoms.  40 children (83%) had at least one significant underlying medical condition. At admission, 69% of the pediatric patients were determined to have severe or critical illness. 18 patients (38%) required mechanical ventilation, and 21 (44%) required non-invasive respiratory support. Of the 18 patients who required mechanical ventilation, by the end of follow-up, 2 died (4.2% of all patients), 3 remained on mechanical ventilation, 7 others remained hospitalized, and 6 were discharged alive.  Among all patients who died or were discharged, the median hospital stay was 7 days, and the median ICU stay was 5 days.

Study Strengths

The study drew from a large group of institutions throughout North America.

Limitations

Few patients were included in the study, a reflection of the apparently lower likelihood of severe disease in pediatric COVID-19.  Follow-up duration was short; the fatality ratio may change with time.  Inadequate testing in North America may have resulted in missed COVID-19 diagnoses among hospitalized children.

Value added

This is the largest study to date of severe pediatric COVID-19 in the North America.

Our take —

This small case series from the UK identified an unusual cluster of cases of acute inflammatory shock, resembling atypical Kawasaki disease, in children, most of whom were of Afro-Caribbean descent. Many of these children had exposure to known cases of COVID-19, though only 2/8 tested positive with PCR, and antibody testing was not performed. This study helps call attention to a severe and poorly understood, though uncommon, pediatric manifestation of SARS-CoV-2 infection.

Study design

Case Series

Study population and setting

This study included 8 children with hyperinflammatory shock (5 of 8 male, median age 8 years, age range 4-14 years, 6 of 8 of Afro-Caribbean descent) from a pediatric network in South East England, UK, identified over a ten-day span in April, 2020.

Summary of Main Findings

All children had previously been in good health. All patients presented with fever, rash, conjunctivitis, peripheral edema, gastrointestinal symptoms, and extremity pain; most had no significant respiratory symptoms. Pleural, pericardial, and ascitic effusions were common. Patients exhibited high concentrations of inflammatory biomarkers and cardiac enzymes. All patients subsequently progressed to warm shock, and were treated with noradrenaline, milrinone, and IV immunoglobulin. 7/8 required mechanical ventilation for cardiovascular stabilization. One child died from a cerebral infarction after requiring life support, and the other 7 were discharged alive from the PICU after 4-7 days. All children tested negative for SARS-CoV-2 at admission; 4/8 had likely exposures from close family members. Two children subsequently tested positive, including one post-mortem.

Study Strengths

Cases were well-characterized.

Limitations

This initial report describes a very small cluster of cases. Although SARS-CoV-2 infection is a suspected cause of the syndrome, there were only 2 confirmed cases among the 8 children. Antibody testing was not performed; of note, in a similar case series (Verdoni et al.), 2/10 children tested positive for SARS-CoV-2 infection via PCR, but 8/10 were antibody-positive.

Value added

This was one of the very first reports of a multi-system inflammatory syndrome affecting children that appears to be related to SARS-CoV-2 infection.

Our take —

In a small autopsy series of patients dying with COVID-19, pulmonary emboli and deep vein thromboses were frequently found, even in patients without suspected clot burden. This adds important data to recent evidence of hypercoagulability in COVID-19, and adds support for the use of antithrombotic medications for patients with COVID-19.

Study design

Case Series

Study population and setting

The study included antemortem laboratory and imaging results, and postmortem autopsy and imaging findings from the first 12 patients known to have died with a SARS-CoV-2 infection in Hamburg, Germany. Autopsies were performed between 1 and 5 days after death. The median age of the patients was 73 years, and 75% were men. Before autopsy, none of the patients had a suspected pulmonary embolus or deep vein thrombosis (DVT).

Summary of Main Findings

Patients dying with COVID-19 had elevated levels of lactate dehydrogenase, D-dimer, and C-reactive protein. In 4 of 12 cases, massive pulmonary embolism was determined to be the cause of death. In a further 3 cases, bilateral DVTs were found. All patients were determined to have a pulmonary cause of death. Common findings included diffuse alveolar damage and pulmonary congestion. SARS-CoV-2 RNA was detected in all 12 pulmonary specimens, and in 9 pharyngeal specimens. Six patients were found to have virus in the blood.

Study Strengths

The study included comprehensive imaging and autopsy procedures.

Limitations

The small sample size limited the strength of any inferences. Further, because the study included the first 12 patients, there may have been selection for most sick, elderly, or frail individuals. Thus, the findings may not be generalizable to the broader COVID-19 population. Finally, there was little ability to correlate laboratory findings with autopsy results based on the information provided.

Value added

This study is among the first descriptions of autopsy results for patients dying with COVID-19

Our take —

A total of six school-related cases (three pediatric, three adult) were reported to and identified through the Computerized Infectious Disease Reporting System in Ireland prior to school closure on March 12, 2020. All but one of these cases had symptoms, and no onward transmission to children from these cases was identified. Results should be interpreted with caution as the number of cases included in this analysis is limited by the closure of schools soon after cases were introduced in Ireland, and no testing was performed on asymptomatic contacts.

Study design

Case Series

Study population and setting

SARS-CoV-2 notifications to public health departments in the Republic of Ireland were screened for school-related COVID-19 cases and their contacts prior to school closure on 12th March. Eligible cases and contacts included those less than 18 years old and adults who had been present at school settings. Contact-tracing records were reviewed for potential cases of secondary transmission.

Summary of Main Findings

Three pediatric cases (10-15 years old) and three adult cases (>18 years old) were identified; none of which were infected in the school setting. All cases identified had symptoms, except for one pediatric case who was identified through investigation of a household cluster. A total of 1155 school-related contacts of these six cases were identified. No onward transmission to children from these cases was identified in a variety of settings; the only onward transmission detected was between the adult cases and other adults in a work environment.

Study Strengths

This study used surveillance and contact tracing data to identify potential onward transmission in the school-setting.

Limitations

To be identified as a case in this study, the individual needed to have had symptoms or been part of a known cluster and identified through the computerized infectious disease reporting system; less can be said about asymptomatic cases that may have been tied to the initial 6 cases or transmission from asymptomatic carriers. Additionally, only symptomatic contacts were tested. There were only six total cases identified, meaning that any inference about onward transmission should be interpreted with caution.

Value added

This is one of the first studies of transmission in a school setting.