Weekly COVID-19 Research Update
May 12, 2020
During the COVID-19 pandemic, it is vital to make objective and informed decisions that affect your family and loved ones. As part of Princeton Longevity Center’s strategic partnership with PinnacleCare, we are excited to bring you their Pandemic Response Research updates as a complimentary resource through the remainder of this crisis. These updates will bring you factual, objective, scientific information to help make safe decisions for you, your family and your community. Updates, while scientifically based, are easy to understand and will include both resources and references for a more clinical insight.
Inflammatory Syndrome Associated with COVID-19 in Children
There have been reports in Europe and the United States of children with exposure to COVID- 19 who develop an inflammatory response that can lead to toxic shock and hospitalization. The reported symptoms are similar to a disease called Kawasaki disease shock syndrome, which is caused by an inflammatory response of the blood vessels. In a report in the Lancet, doctors from a London hospital described the syndrome and reported a large increase in the number of children being treated for it (Riphagen et al., 2020). Descriptions of the symptoms of eight patients were included in the report, but between the time it was written and publication, 20 more children were admitted with similar symptoms. The pediatric ward normally sees one or two children per week with Kawasaki disease shock syndrome. The symptoms observed included unrelenting fever, rash, conjunctivitis (pink eye), swelling of the limbs, pain in the extremities, and significant gastrointestinal symptoms. The children who were hospitalized all developed dangerously low blood pressure. There were no signs of respiratory symptoms, but seven of the eight children in the report required mechanical ventilation to maintain cardiovascular stabilization. When tested, none of the children had an active infection of SARS- CoV-2, but two tested positive after leaving the intensive care unit.
The New York City Health Department reported that children between the ages of 2 and 15 years have been treated with similar symptoms (Joseph, 2020). The symptoms observed included rash, abdominal pain, vomiting, and diarrhea, and a number of the children had to be placed on ventilators. In a May 9 article, the New York Times reported that 73 children in the state had been identified with the syndrome, and three had died (Jacobs and Sandoval, 2020). In a report of 15 children from New York City, four had tested positive for active COVID-19, and six had antibodies but not an active infection (Joseph, 2020).
If caught early, Kawasaki disease can be treated with intravenous immunoglobulin (IVIG) so the threshold for seeking treatment in children with the symptoms described above should be very low.
There are increasing reports of deaths occurring from COVID-19 in people not at a healthcare facility, such as a hospital or nursing home. The earliest such deaths have shown that there was community spread in California almost a month before the first official death was announced in Seattle. Autopsy results of a woman who collapsed in her home of a presumed heart attack on February 6 later showed that she died from complications of COVID-19 (Miller, 2020).
Comparisons of the number of out-of-hospital cardiac arrests in the Lombardy, Italy region between the same periods in 2019 and 2020 showed an increase of 58%. When the records of individuals with recent cardiac arrest were examined, it was found that 103 of the 362 cases were suspected to have or had received a diagnosis of COVID-19, which accounts for 77% of the increase (Baldi et al., 2020).
Contribution of Cardiovascular Disease to Mortality from COVID-19
Researchers reviewed the records from 8910 people diagnosed with COVID-19 from 169 hospitals in Asia, Europe, and North America to better define the correlation between cardiovascular disease and mortality with COVID-19 (Mehra et al., 2020). They also assessed the possible link between the use of common blood pressure medications known as angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), which was a concern based on the way that SARS-CoV-2 enters the cells it infects. Overall, of those for whom discharge status was available at the time of the analysis, 5.8% died in the hospital. The factors associated with an increased risk of mortality were similar to those previously reported, including age greater than 65, coronary artery disease, heart failure, cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking. The researchers did not find an association between the use of ACE inhibitors or ARBs and mortality.
Another investigation of the effect of ACE inhibitors, angiotensin-receptor blockers, beta- blockers, calcium-channel blockers, or thiazide diuretics on the risk of COVID-19 also found no association (Reynolds et al., 2020). In the study, the records of 12,594 people who were tested for COVID-19 were examined. In the group, 46.8% were positive for SARS-CoV-2 infection.
Based on their analysis, there was no association between any medication class and an increased likelihood of a positive test, and there was also no difference in the risk for severe illness in those who tested positive for COVID-19.
There have been numerous reports of people with COVID-19 having an increased risk of clot formation (thrombosis), resulting in stroke, pulmonary embolism, or loss of blood flow to the limbs requiring amputation. A recent report in the New England Journal of Medicine suggests that the thrombosis may be linked to a disease called antiphospholipid syndrome (Bowles et al., 2020). Researchers in London examined the blood samples of 216 people with COVID-19 to look for abnormalities in the factors responsible for clot formation. There was a higher than average number of individuals with a protein called lupus anticoagulant. Lupus anticoagulant is an antibody that interacts with blood cells and cells that line blood vessels, and it is part of a group of antibodies that are generally called antiphospholipid antibodies. Lupus anticoagulant results from an autoimmune process that is most often observed in people with systemic lupus erythematosus, which is how it got its name. It does not lead to anticoagulation (a reduction in blood clotting) as the name implies. Rather, it is an antibody that interacts with coagulants in the blood, which is referred to as “anti” by scientists. When lupus anticoagulant is present, it can disrupt the blood flow in both arteries and veins and cause blood clots. There is a syndrome associated with antiphospholipid antibodies called catastrophic anti-phospholipid syndrome (CAPS) that causes the sudden development of clots in the arteries and can lead to stroke, damage to other organs such as the kidneys or liver, and loss of blood flow in the limbs (MedlinePlus, 2020). These symptoms are reminiscent of the recent reports of stroke in younger people with COVID-19. Additionally, a report from physicians in China describes a similar scenario (Zhang et al., 2020). In this New England Journal of Medicine article, the characteristics of three people were described who had antiphospholipid antibodies and multiple sites of tissue impacted by a loss of blood flow (or an infarct). One of the individuals whose symptoms were described in more detail had evidence of lack of blood flow in his legs and in his fingers, and a CT scan showed multiple infarcts in his brain.
Another short report on physician experience in the Netherlands suggests that pulmonary embolism may be a reason that individuals on mechanical ventilation stop responding to treatment (Endeman et al., 2020). The authors of the report described the treatment given to 90 patients admitted to the intensive care unit between February 27 and April 5. Prone positioning of patients on mechanical ventilation helped with recovery, and most were weaned from mechanical ventilation within two weeks of entering the intensive care unit. About 19% of the group no longer had a benefit from prone positioning within the two week period, and all of the group who stopped responding were later found to have major pulmonary embolism based on lung CT or cardiac ultrasound.
Cellular Infection Pattern
Some of the variability in the transmission and symptom profile observed with COVID-19 may stem from the location of infected cells within the respiratory tract (Cyranoski, 2020). The cells susceptible to a virus is dependent on the interaction between proteins on the outside of the virus and the outside of the cell. Because different cells produce different proteins on their surface and the viral proteins can only interact with specific cellular proteins, there is a limited number of cells a virus can infect. In the case of seasonal coronaviruses, the viruses can only interact with cells that are located in the upper respiratory tract, which causes cold symptoms. The viruses responsible for SARS and MERS are only able to interact with cells in the lower respiratory tract, leading to pneumonia. However, it has been determined that SARS-CoV-2 is able to infect cells in both the upper and lower respiratory tract, and depending on which are affected, it might explain the wide range in symptoms and severity experienced by people with COVID-19. Researchers are still trying to determine the characteristics that lead to some individuals having only an upper respiratory-type infection and others having more serious lung symptoms. The presence of the virus in the upper respiratory tract may also explain why individuals can spread the virus before showing symptoms because the virus can more easily be transported to saliva and released in droplets.
There were several announcements about the start of new human vaccine trials to prevent COVID-19. A recent review of the topic in the journal Nature reports that over 90 vaccines are known to be under development, and at least six have started human clinical trials (Callaway, 2020). The Washington Post reports there are eight active trials that have started treating people (Johnson, 2020).
Pfizer treated the first people in a clinical trial to investigate the effects of multiple versions of a potential coronavirus vaccine in healthy young people (Johnson, 2020). The trial includes four different vaccines. The initial group of participants will be monitored to determine the safety of the vaccine, and if safe, more people will be added to the trial. The vaccine is an RNA-based vaccine that is designed to enter human cells after being administered (Nathan-Kazis, 2020). The hypothetical process of immunity from an RNA-based vaccine begins when the viral RNA in the vaccine enters a cell where it is thought to be used by the cellular machinery to produce parts of the virus to be released into the blood stream by the cell (Callaway, 2020). In the bloodstream, the proteins may be identified by the immune system as foreign, leading to production of antibodies that recognize viral proteins should infection occur. To date, there have not been any RNA or DNA-based vaccines approved by the FDA, and the method has not yet been proven to work in humans. The process for making RNA-based vaccines is much easier than other types of vaccines, however, because they do not require the production of weakened viruses or whole proteins. Large amounts of RNA can be synthesized in a test tube-like environment without the need for cells to produce the material, unlike viruses or proteins.
Simultaneous Infection with Influenza and SARS-CoV-2
At the beginning of the outbreak, people who tested positive for influenza virus were excluded from having COVID-19 because it was thought that co-infection, or simultaneous infection did not occur (Cuadrado-Payán et al., 2020). There have now been confirmed cases where individuals were found to have infection with both influenza and SARS-CoV-2. Because tests for influenza were more readily available, early in the outbreak people who tested positive for flu were not subsequently tested for COVID-19, and any symptoms were attributed to flu. Based on the data reported by Cuadrado-Payán and colleagues, this is now known to not be the case.
Information from Lombardy, Italy
Officials at hospitals in Italy have begun to evaluate the crisis that emerged as large numbers of people were infected with SARS-CoV-2 (Fagiuoli et al., 2020). During the outbreak, the main hospital in the region, ASST–Papa Giovanni XXIII, saw dozens of patients admitted each day with COVID-19. On March 28, patients with Covid-19 occupied 498 of the hospital’s 779 beds, which corresponds to 64%. When the outbreak began, 25% of the staff doctors were treating patients in COVID-19 units, which progressed to 70% of doctors. There was an exponential increase in the number of people needing mechanical ventilation for respiratory failure, and 43 additional ventilators were located. Even with the additional ventilators, there were insufficient numbers available for all the people with respiratory failure, and allocation of the machines was determined by a cumulative patient score that took into account the urgency of each patient’s need and the patient’s chance of benefiting from treatment. Of the first 510 patients with confirmed COVID-19, 30% died. There was a peak of 19 deaths per day with an average number of deaths between 17 and 18 per day for several weeks. The average number of deaths per day before the outbreak was 2.5. There was also a high rate of infection of medical personnel, and 19 doctors in the Bergamo province (all between 62 and 74 years of age) have died from the disease.
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