Weekly COVID-19 Research Update
June 3, 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.
Overview of the Clinical Trial Process
As there have been a number of discussions about clinical trials for COVID-19 recently, the following is a brief overview of the goals of the different phases of a clinical trial. In general, the early phases of testing focus on safety and the optimum dosing of the drug, and therefore Phase 1 trials are sometimes referred to as “Dose Escalation Trials”. Phase 2 and 3 studies are used to examine if the drug is effective in treating the condition.
As more information becomes available, a consensus is forming that anti-viral drugs may be more effective earlier in SARS-CoV-2 infection to reduce virus replication, while anti- inflammatory medications may be better suited to hospitalized individuals experiencing severe symptoms from an elevated immune response (Lancet, 2020). The amount of virus that is produced is highest early in the infection, and later symptoms are more related to disruption of the immune response rather than viral production.
The recently released study results on remdesivir corroborate the idea that use of antiviral medications is less effective at later stages of COVID-19 (Herper, 2020). In the report, researchers indicate that use of remdesivir shortens the length of time individuals were hospitalized with COVID-19 from 15 days to 11 days. However, when the information was assessed for different subgroups of the study, the beneficial effects were not observed in people who already required mechanical ventilation or extracorporeal membrane oxygenation when remdesivir treatment was initiated. In participants who were hospitalized, but did not require supplemental oxygen, use of remdesivir led to a 38% shorter hospital stay. However, those on mechanical ventilation or extracorporeal membrane oxygenation only had a decrease of 0.05% in the length of hospitalization. The largest benefit, a 47% faster recovery, was observed for those requiring supplemental oxygen, but not mechanical or continuous positive airway pressure (CPAP) ventilation (Van Beusekom, 2020).
Anakinra is an anti-inflammatory medication that inhibits two forms of cytokines, and the effect of anakinra on the cytokine storm that occurs in some severely ill people with COVID-19 is being investigated. As of May 21, ten active clinical trials have been registered on ClinicalTrials.gov involving anakinra treatments for COVID-19 (King et al., 2020). Experts have raised some concern, however, over the design of the studies, and a lack of a common diagnostic criteria to identify those who would benefit most from the treatment. Inhibiting cytokines reduces the immune response, which could also prevent efficient viral clearance of SARS-CoV-2. However, as mentioned above, those experiencing the hyper-inflammatory response associated with severe COVID-19 are normally past the stage of infection where virus production is high and control of the immune response is more important than reduction of viral replication.
Convalescent plasma is a treatment similar to a blood transfusion where the plasma component of blood collected from an individual who has recovered from a disease is used to deliver antibodies against the virus. A preprint was released of the results of a study performed at Mount Sinai Hospital in New York City involving 39 participants who were hospitalized with severe COVID-19 to investigate the effects of convalescent plasma (Liu, 2020). The outcome of participants who received convalescent treatment was compared to the outcome of other patients who did not receive the treatment using medical records for comparison. When the characteristics of participants were evaluated 14 days after the transfusion, it was found that those given convalescent plasma were more likely to have an improvement in their condition or to remain stable. Participants receiving convalescent plasma who were not intubated had a better rate of survival when compared to untreated patients who were not intubated. However, participants who required mechanical ventilation did not have a better survival rate after transfusion with convalescent plasma than untreated patients. The antibodies in convalescent plasma target virus particles in order to reduce the viral load, and the results of this study support the hypothesis that the patients who are the most ill do not benefit as much from antiviral treatments.
The WHO has suspended its trial investigating the effects of hydroxychloroquine on individuals with COVID-19 after researchers reported the outcome of a study in the Lancet that indicates patients treated with either hydroxychloroquine or chloroquine were more likely to die than those not taking the medications (Vera and Howard, 2020). The executive group in charge of the WHO trial, called the SOLIDARITY trial, will be reviewing outcome data from other trials as well as interim data from the SOLIDARITY trial to determine if it should be continued.
Other parts of the trial investigating other treatments are continuing.
The number of potential vaccines for COVID-19 progressing to human trials is steadily increasing, and there have been positive preliminary results reported from some of the trials. Experts have raised concern about the future acceptance of a vaccine and a growing resistance to immunization (COCONEL, 2020). A survey from France reports that 26% of people would refuse a vaccine if one becomes available. Importantly, this survey was conducted during the worst of the outbreak in Italy and Spain. It is possible that this number will increase if the perceived threat of infection decreases. In a survey of adults in the United States conducted on April 15, 23% of respondents said they would not be willing to be vaccinated once a vaccine becomes available (Shaffer DeRoo, 2020). A second study found that 30% of the respondents would not get the vaccine right after it was available due to concerns about safety.
It is estimated that between 55% and 82% of the population will need to have immunity to COVID-19 in order to prevent transmission (Schaffer DeRoo et al., 2020). When accounting for the number of people with health issues that would prevent them from being vaccinated, experts suggest that a vaccine refusal rate higher than 10% would threaten the attainment of so-called herd immunity. Distrust of the vaccine also appears to be highest in those who are the most affected by COVID-19. In the French study, 37% of people who were in the low-income subgroup said they would not get the vaccine, and 22% of people older than 75 years also reported an unwillingness to get vaccinated.
In order to have successful immunization of the population it will be necessary to have an organized public health campaign. Experts are suggesting that transparency in the process and a frank discussion about the risks associated with a potential vaccine is one vital part of a successful vaccine program. During the H1N1 flu pandemic in 2009, there was a public debate in France about the safety of the vaccine due to concerns about hasty production without enough safety testing. French authorities chose to limit conversations on measures taken to ensure the safety of the vaccine based on a belief that it might provoke irrational fears rather than quell them. As those opposed to the vaccine became more vocal, the officials were forced to defend themselves over perceived mismanagement rather than promote the safety and efficacy of the new flu vaccine. The vaccine campaign promoting vaccination for H1N1 led to only an 8% vaccination rate (COCONEL, 2020).
Previous research has shown that physicians are the most important influencers on decisions about vaccines, and strong recommendations by physicians can bolster public and individual support for vaccinations. Additionally, beginning vaccination programs with healthcare workers would ensure both protection of the workforce and visible support for the program.
The most vital part will be having a vaccine to support that has not bypassed established safety standards in order to rush it to the public. Problems have occurred in the past when speed was valued more highly than safety (Trogen et al., 2020). When the inactivated polio vaccine was released in 1955, it had been proven safe through multiple studies. However, production of the vaccine was not well-regulated and serious mistakes were made by the companies making the vaccine. These mistakes led to contamination of the vaccine with live polio virus and infection of the children being vaccinated. A second incident occurred in 1976 with the attempted rushed production of an influenza vaccine. Safety standards were not enforced, and one manufacturer produced a vaccine using the wrong strain of influenza, leading to adverse reactions in children who received the vaccine without the required immune response. In response to these failures, regulatory oversight for the production of vaccines was increased. Technological advances have been made and safety procedures are in place to protect the public from substandard practices if they are followed.
Final Results from a Phase 1 study of an Adenovirus COVID-19 Vaccine
A dose escalation trial of an adenovirus-based vaccine was performed in Wuhan, China that involved 108 healthy adults between the ages of 18 and 60 years (Zhu et al., 2020). There were three dose groups in the study, which were given by injection into the muscle. Safety of the vaccine was monitored for 28 days after inoculation. At least one adverse reaction was reported by 83% of participants in the low dose group, 83% participants in the middle dose group, and 75% participants in the high dose group within seven days of vaccination. The most common injection site adverse reaction was pain, which occurred in 54% of vaccine recipients. The most commonly reported systemic reactions were fever (46%), fatigue (44%), headache (39%), and muscle pain (17%). The extent of the reported reactions in all of the dose groups were classified as mild to moderate in severity. No serious adverse events were reported in the 28 days of the study. The researchers found that the level of antibodies, including neutralizing antibodies, increased at day 14 compared to the initial levels, and the highest levels were measured 28 days after vaccination.
Physiological Effects of COVID-19
An editorial in the Lancet describes the symptoms and physical changes that are most often associated with COVID-19 (Lancet, 2020). People who are hospitalized with the disease often experience complications including pneumonia, sepsis, and respiratory failure with a smaller subset of people experiencing severe systemic disease and multiorgan failure. With time, it has also been established that disruptions in the system responsible for controlling blood clot formation (or thrombosis) is observed in both severely ill people and those with milder symptoms not requiring hospitalization.
Blood Clot Formation, or Thrombosis
The most recent information suggests that between 16% and 49% of people admitted to the intensive care unit with COVID-19 experience complications associated with thrombosis (Lancet, 2020). At this time, researchers have not been able to determine if the effects on thrombosis are caused directly by SARS-CoV-2 or are a consequence of the sometimes extreme immune response to infection by the virus.
A group of researchers found that there is a subgroup of hospitalized individuals with COVID-19 that do not respond to anti-coagulation treatment as reported in the Lancet (Maier, 2020). In the fifteen people treated with this problem, it was found that they all had an increased viscosity of their blood compared to normal levels. As viscosity increases, liquids become thicker and do not flow as well. When blood becomes hyper-viscous, it damages the cells that line blood vessels and causes thrombosis. Measurement of the components in the blood from affected individuals showed that there was a large amount of a protein called fibrinogen, which is one of the components that modulates blood clotting. High levels of fibrinogen are often reported when there is increased inflammation in the body, which is a potential link between the increased inflammatory response from COVID-19 and an increased rate of thrombosis. One of the treatments for hyper-viscosity is to exchange the plasma component of blood, and the researchers are currently investigating the response of critically ill individuals to this treatment.
Postmortem Examination of Individuals with COVID-19
Researchers reported the results of an evaluation of lung tissue from individuals who had died from COVID-19 or influenza and healthy lung tissue from organ donations (Ackermann et al., 2020). The researchers used a variety of observational methods that allowed for the assessment of the physical differences, molecular differences, and genetic differences between the tissues. People who had died from COVID-19 had severe cellular injury from the growth of the SARS-CoV-2 virus, which was visible in images taken with an electron microscope.
There was both damage inside the cells as well as damage to the cell membranes, leading to rupture of the cells. There was also evidence of widespread thrombosis within the blood vessels in the lungs of people with COVID-19 that caused blockage in the capillaries supplying the alveoli (sacs in the lungs where oxygen is exchanged for carbon dioxide). The researchers observed a large amount of new blood vessel growth that was not evident in people with influenza, which suggests that new blood vessels were created to improve blood flow to the lungs. There were also some large differences in the genes that were expressed in people with COVID-19 compared to those with influenza, suggesting that each virus leads to a different cellular response.
Another group of researchers reported on the full autopsies of ten individuals who had died from COVID-19 at the University Medical Center Augsburg Germany between April 4 and 9 (Schaller et al., 2020). The median length of time between admission and death was 7.5 days with a range between one and 26 days. Live virus was still present in the respiratory tracts of all of the individuals at the time of autopsy. There was evidence of lung damage to the alveoli in all of the cases, which was consistent with acute respiratory distress syndrome (ARDS). There was also a large amount of scar tissue formation (fibrosis). Six of the individuals were found to have mild inflammation of the heart tissue (myocarditis) or the outer lining of the heart (epicarditis). There were also small amounts of fibrosis in the liver, but no other abnormalities were observed in other organs. In this study, the researchers report that alveolar damage and SARS-CoV-2 viral particles in the respiratory tract were the predominant findings and constituted the leading cause of death, both in patients who had had invasive ventilation and those without. The damage resulting from inflammation of heart and liver tissue was minimal and not expected to have contributed to the cause of death.
Risk Score to Determine Occurrence of Critical COVID-19
Being able to identify individuals who are more at risk for a progression of COVID-19 to severe symptoms would be helpful for knowing who should receive specific treatment (Liang et al., 2020). Researchers in China published their investigation of the medical records from 1590 patients who were diagnosed with COVID-19 at 575 hospitals in 31 provincial administrative regions as of January 31 in JAMA. Based on the information, they were able to develop a risk score, called COVID-GRAM, that provides an estimate of the risk that a hospitalized patient with COVID-19 will develop critical illness. The investigation looked at 72 characteristics that might contribute to a risk of critical illness, and ten were found to be associated with more severe COVID-19. The ten characteristics included chest radiographic abnormality, age, coughing blood (hemoptysis), shortness of breath (dyspnea), unconsciousness, number of other chronic conditions (comorbidities), cancer history, neutrophil-to-lymphocyte ratio (two types of white blood cells), lactate dehydrogenase (a way to measure tissue damage from infection), and direct bilirubin (a measure of a protein produced by the liver). The score has been translated into an online risk calculator that is freely available to the public at http://22.214.171.124/ . The score was then validated with information from a different set of medical records from 710 patients. The actual number of people in this second group who developed critical illness was 12.3%, and 1.1% died. The risk score was able to correctly characterize 88% of the people in the validation group.
Younger People are More Likely to be Infected as Epidemic Moves to New Areas
As the number of cases of COVID-19 has increased in South America and Central Asia, researchers have observed that younger people are more likely to have severe symptoms and die compared to populations in previous regions of the world (McCoy and Traiano, 2020). For example, officials in Brazil have reported that 15% of the deaths have been in people under the age of 50, which is ten times as much as seen in Italy or Spain. There is also a higher hospitalization rate in younger people with two thirds of those admitted younger than 49. In Mexico, around 25% of those who have died were between 25 and 49. India is seeing similar trends, and officials report that nearly half of those who have died are under the age of 60.
The current opinion is that the change is linked to the increased level of poverty in these countries that leads to a higher population density and an increased need to keep working rather than staying in isolation. Both of these situations would be expected to cause more of the population to be exposed to the virus when compared to wealthier nations.
Extended Viral Shedding
Multiple studies have shown that some individuals shed viral RNA for extended periods of time after being found to be recovered and discharged from the hospital (Wu et al., 2020). As mentioned in last week’s PinnacleCare summary, a report from the Korean CDC indicates that while viral RNA can be detected for extended periods of time in some people, they do not infect others during this time. A similar study in Hunan, China that was reported in JAMA evaluated 60 people who had been officially discharged from the hospital after COVID-19 and found that 10 had positive results using PCR-based testing. None had clinical symptoms except for two individuals with multiple underlying conditions who had an occasional cough. The positive test after discharge occurred between four and 24 days after initial discharge and no local cases or healthcare cases were reported in the areas where the participants lived. This study is in agreement with the previously reported Korean study that while people may shed viral RNA at detectable levels for long periods of time, they do not cause infections in local contacts or healthcare workers.
Framework for Recommending a Safe Return to Work
Marc R. Larochelle, from the Boston University School of Medicine and Boston Medical Center, in Boston, Massachusetts has proposed a framework in the New England Journal of Medicine that can be used in discussions of safety during a return to a workplace (Larochelle, 2020). The framework is based on the level of risk of contact with SARS-CoV-2 at work as proposed by the Occupational Safety and Health Administration (OSHA) and the level of individual risk for developing severe symptoms identified by the CDC. Figure 1 is adapted from the article and outlines the recommendations.
Figure 1. Proposed Framework for working on site during the COVID-19 pandemic. If the individual falls under category A, a return to the work place is feasible. Those who fall under category B should use special precautions if they return to the workplace, and those in group C should not return to the workplace until conditions change. Specific recommendations are listed below.
A: Wear a mask outside the home, practice recommended hand hygiene, and use PPE as directed.
B: Discuss individual risks and opportunities to mitigate exposure and to consider stopping work. Counsel patient to take all precautions outlined in A.
C: Consider not working at the workplace due to the high risk of continuing to work.
Counsel patient to take all precautions outlined in A.
The CDC also has added to some of its recommendations for the workplace (New York Times, 2020). The changes include giving employees temperature and symptom checks when they arrive at work, moving desks six feet apart, erecting plastic shields around work areas that cannot be moved and are six feet or more apart, prohibiting seating in common areas, and having everyone wear face coverings at all times (CDC, 2020).
Variation in the Rate of False-Negative Results with Time
Researchers recently published an article in the Annals of Internal Medicine that evaluates the possibility of receiving a false-negative result for COVID-19 with PCR-based tested correlated to the time since infection (Kuckirka et al., 2020). The researchers examined available publication that report the accuracy of PCR-based tests and then calculated the false-negative rates. The probability of a false-negative is high four days before the onset of symptoms and then falls until three days after the onset of symptoms. Four days after symptoms begin the false-negative rate begins to increase again.
Use of Cloth Masks
There has been considerable debate over whether the use of non-medical, cloth masks is helpful in preventing the transmission of SARS-CoV-2. Two recent articles present evidence to support the use of masks for the reduction of transmission of the virus.
A study from China has shown that continuous use of masks in the home before symptoms begin can reduce the transmission of COVID-19 between family members in the same home (Wang et al., 2020). The study involved 335 people from 124 families between February 28 and March 27 in Beijing, China. The characteristic being studied is called the secondary attack rate, which is the probability that transmission from a single individual occurs among people within a specific group. The overall secondary attack rate in families in this study was 23%. If the person infected from outside the family (also called the primary case) and their family contacts began face mask use in the home before the primary case developed symptoms, there was a 79% reduction in transmission. However, use of a mask after symptoms began was not effective in reducing transmission. This is one of the first publications that was able to show that transmission of the disease itself was reduced with use of masks.
Other studies have focused on the amount of particles or virus stopped by a mask or the amount of surface deposit of respiratory fluids associated with and without mask use.
Unfortunately, the type of masks used in the study was not specified, and the direct effect of cloth masks versus medical masks on transmission of COVID-19 is still not known (Lee, 2020).
It is known that medical masks are better at stopping particle movements, but there is increasing evidence that cloth masks do have a benefit in preventing infectious material from reaching people’s mouth or nose as described in an editorial published in the Annals of Internal Medicine (Clase et al., 2020). Cloth is too porous to stop individual virus particles, but larger particles, such as droplets of respiratory fluid, can be stopped by cloth masks. The filtration efficiency is a measure of the ability of a material to block transmission. Research has shown that the amount of filtration efficiency by a material is dependent on the size of the particle and not the contents, or type of virus, within the particles.
The filtration efficiency for different types of cotton ranges between 43% and 94% for aerosol- sized particles of 0.2 microns and increases with the number of layers used. For comparison, medical masks were found to have a filtration efficiency of between 98% and 99% in this study. In another experiment, a single layer of a scarf, sweatshirt, t-shirt, or towel had a filtration efficiency between 10% and 40% for small aerosol particles (0.075 microns). Experiments of bacterial transmission through aerosols showed that tea towels had a filtration efficiency of 83% with a single layer and 97% with two layers while medical masks blocked 96% in this study. The filtration efficiency of a single layer of a tea towel has been reported to be 72% for viral transmission through aerosols and 51% for a single layer of t-shirt fabric. Medical masks in this study had a filtration efficiency of 90%. However, researchers have found that a very high filtration efficiency may not be necessary to block a clinically meaningful amount of infectious material.
Based on the review of the published evidence, the authors of the editorial conclude that there is “high-quality, consistent evidence that many (but not all) cloth masks reduce droplet and aerosol transmission and may be effective in reducing contamination of the environment by any virus, including SARS-CoV-2.” They also state that even a small reduction in transmission of the current world-wide pandemic might lead to sufficient benefits because reduced outward transmission and reduced contamination of the environment are the currently the only way in which to control the outbreaks until treatments or a vaccine become available.
The Japan Pediatric Association warned that masks should not be worn for children under the age of two (Guy and Wakatsuki, 2020). Because young children may not be able to easily communicate, use of a mask makes it difficult to notice changes in face color, expression, and breathing that would normally be used to keep a baby safe. Specifically, there is a risk of difficulty breathing and heat stroke with mask use in children under two. The narrower airway of small children also makes it more difficult to pull air through a mask. Mask use also leads to an increased risk of aspirating vomit.
Extent of the COVID Pandemic Compared to Influenza in the United States
The number of COVID19-related deaths in the United States as of early May was approximately 65,000 people. The value is similar to the estimated number of seasonal influenza deaths reported annually by the CDC. There are factors, however, that make the numbers inequivalent (Faust and Del Rio, 2020). First, the influenza information reported is a calculated estimate based on a limited number of cases. Between 2013 and 2019, the estimated deaths for influenza ranged between 23,000 and 61,000, but the actual number of counted influenza deaths ranged from 3,448 to 15,620 in a year. The number of deaths currently reported for COVID-19 are the counted number of deaths rather than an estimate, which would include a calculation of how many cases were missed.
A better comparison between COVID-19 and influenza is the counted deaths per week for each disease, which allows for a comparison over the same time-frame. The weeks ending April 14 and April 21 were amid the peak in the number of COVID-19 deaths in the United States at this time with 14478 and 15455 deaths, respectively. In contrast, the highest number of deaths per week for influenza between 2013 and 2020 ranged from 351 (in week 11 of 2016) to 1626 (in week 3 of 2018). Therefore, the number of COVID19-deaths for the week ending April 21 was 9.5 to 44.1-times larger than the peak week of counted influenza deaths during the past seven influenza seasons. The mean number of counted deaths during each peak week of influenza seasons from 2013-2020 was 752.4, which indicates that there is a mean 20.5 fold increase in the number of deaths in a peak week of COVID-19 compared to influenza.
The other major difference between yearly influenza outbreaks and COVID-19 is the number of people being treated at the hospital. In areas where there are significant outbreaks, the number of people being treated for COVID-19 overwhelms the capacity of local hospitals, which does not occur during yearly influenza outbreaks.
The potential undercounting of COVID-19 deaths is highlighted in an article published in the Lancet describing the number of excess deaths observed in retirement homes in the United Kingdom (Burki, 2020). Based on information from the United Kingdom Office for National Statistics (ONS), there were 12,526 confirmed or suspected deaths in care homes involving COVID-19 between March 2 and May 1 in England and Wales. The extent of undercounting can be observed in the fact that when the overall number of deaths from 2020 in care homes was compared to the overall number of deaths in 2019, there were 20,000 more deaths that occurred in 2019. While not all of these deaths may be attributed to COVID-19, the magnitude of the spike is larger than the normal variation that occurs from year to year.
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