Weekly COVID-19 Research Update
April 23, 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.
What is a “Pre-Print?”
Much of the information being reported in the news about the scientific characteristics of COVID-19 is coming from journal articles called “pre-prints.” A pre-print is a form of a scientific article that has not yet been submitted for publication by a journal through the peer-review process. Normally, before publication, scientific articles undergo review by at least two other subject matter experts, which is a process called peer review. This process allows the journal editors to determine if the protocols and procedures were correctly performed and if the conclusions reported by the authors are reasonable based on the data from experiments.
There is a strong emphasis for researchers to publish their results as a means to advance their careers. However, there are barriers to publishing for underrepresented groups and scientists in the early stage of their careers. An alternative to publication of research in a journal is to present new research at scientific conferences, but this can be an expensive endeavor, especially for scientists not located in the United States or Europe. One way to address this problem is to allow scientists to self-publish their work online before peer-review. One of the most often cited pre-print groups, called medRxiv, was founded by Cold Spring Harbor Laboratory, Yale University, and BMJ, a medical journal with a large online presence (https://www.medrxiv.org/content/about-medrxiv). The founders state that medRxiv was started to provide
“a platform for researchers to share, comment, and receive feedback on their work prior to journal publication. medRxiv aims to improve the openness and accessibility of scientific findings, enhance collaboration among researchers, document provenance of ideas, and inform ongoing and planned research through more timely reporting of completed research.”
As the peer-review process can also be time consuming, and scientists can use pre-prints to discuss results openly without the risk of losing credit for their work.
Because research on COVID-19 is progressing rapidly, many researchers have presented their results via the pre-print system. Some of these reports have been verified by subsequent research, but because of the nature of pre-prints, there is a higher likelihood that they may be found to be incorrect. Therefore, information presented through a pre-print should be regarded with caution until the peer-review process can be completed.
Viral Shedding and Transmissibility
There were several important reports recently released describing updated information on the viral shedding and transmissibility of SARS-CoV-2.
Length of Transmissibility of SARS-CoV-2
In a communication published in Nature Medicine, researchers reported on a study of viral shedding and transmissibility of SARS-CoV-2 (He, 2020).
If the serial interval is shorter than the observed incubation period, this indicates that a significant portion of transmission may have occurred before infected persons have developed symptoms. To determine if this is true with COVID-19, researchers collected 414 throat swabs from 94 participants who had been admitted to the Guangzhou Eighth People’s Hospital. There was evidence of a high level of virus particles near the time of symptom onset with a decrease in the amount over time. The detection limit for virus in throat swabs was reached about 21 days after hospital admission. The serial interval was calculated from data obtained in mainland China and outside of the country, and the incubation period used was calculated in a separate study. Based on this information, the researchers determined that people infected with SARS- CoV-2 were able to infect others approximately 2 days before symptom onset and infectiousness peaked at 0.7 days before symptom onset.
Therefore, people infected with SARS-CoV-2 are most likely infectious about two days before they experience any symptoms and are the most infectious right BEFORE symptoms start.
The researchers also report that the estimated proportion of pre-symptomatic transmission was 44% in the group of individuals in this study. The ability to infect others was found to decline quickly within seven days of symptom onset. Previous reports have indicated that virus can be detected in throat swabs for up to 37 days in some survivors, but these tests only identified the presence of viral material and not whether the virus was still able to cause new infections. In virus culture experiments, live virus could not be produced from throat swabs after approximately eight days. Overall, the authors suggest that the infectiousness profile of COVID- 19 is more similar to influenza, where pre-symptomatic transmission is common, than SARS, where infection occurs mainly after symptoms start.
The high prevalence of pre-symptomatic transmission of COVID-19 was corroborated from areas with high levels of contact screening, including Singapore and Tianjin. Based on information in these areas, the pre-symptomatic transmission was estimated to be between 48% and 62%.
The authors of this study also calculated the potential efficacy of contact tracing and isolation of sick individuals. They found that if more than 30% of transmission occurred before symptom onset, it would be necessary to identify more than 90% of all of the contacts of an infected person in order to alter transmission rates. For many locales, this amount of coverage would be unattainable, suggesting that other public health measures may be needed.
There was also evidence of the occurrence of asymptomatic or pre-symptomatic transmission of SARS-CoV-2 at one of the skilled nursing facilities in King County, Washington in February (Kimball, 2020). The information was reported in the CDC publication Morbidity and Mortality Weekly Report. After COVID-19 began to spread, CDC officials performed symptom assessments and SARS-CoV-2 testing for 93% of the residents of the facility. Residents
were categorized as asymptomatic or symptomatic based on the absence or presence of fever, cough, shortness of breath, or other symptoms on the day of testing or during the preceding 14 days. A total of 30% of the residents tested positive for SARS-CoV-2 infection. At the time of testing, 43% of those who tested positive had symptoms, and 57% were asymptomatic. Most of the people who were asymptomatic at the time of testing later developed symptoms.
Importantly, the researchers conclude that symptom-based screening, in the place of testing, could fail to identify approximately half of the infected population, which reiterates the need for continued expansion of testing capacity.
Aerosol Transmission of SARS-CoV-2
In a pre-print from researchers at the University of Nebraska, measurement of viral shedding was performed on 11 early cases of COVID-19 (Santarpia, 2020). The cases were cared for in the Nebraska Biocontainment Unit for individuals requiring hospital care and at the National Quarantine Unit for isolation of asymptomatic or mildly ill individuals not requiring hospital care. The researchers organized an ongoing study to obtain surface and air samples in two biocontainment rooms and nine quarantine isolation rooms where individuals who tested positive for SARS-CoV-2 were being monitored. Three types of samples were collected on day 10 of treatment in the biocontainment rooms and between days 5 and 9 in the quarantine rooms: surface samples, high-volume air samples, and low-volume personal air samples.
Surface samples were collected from room surfaces, personal items, and toilets. The samples were tested by detection of viral RNA using PCR-based methods. This testing method can determine if the genomic material from the virus is present, but does not ascertain if it is present in an infectious form.
Based on PCR-based testing, there was a high level of viral RNA found on surfaces in the room. For example, 76.5% of all personal items sampled were determined to be positive for SARS- CoV-2, and samples from the toilets attached to the room were 81.0% positive. Additionally, 75.0% of the bedside tables and bed rails and 81.8% of the window ledges were found to have viral RNA. The floor beneath patients’ beds and the ventilation grates in the biocontainment unit were also sampled, and all five floor samples, as well as 4 of the 5 ventilation grate samples tested positive by PCR. A high level of viral RNA was also observed in air samples from both the biocontainment unit and the quarantine units.
The authors conclude that “taken together, these data indicate significant environmental contamination in rooms where patients infected with SARS-CoV-2 are housed and cared for, regardless of the degree of symptoms or acuity [degree] of illness.”
There was contamination observed in all of the types of samples. However, there was a higher percentage of positive samples detected in the biocontainment unit where patients were hospitalized for inpatient care compared to the quarantine unit. Also, the amount of RNA detected dropped between subsequent sampling days, as would be expected with reduced viral shedding over time. The dispersion of the RNA within the rooms, far from patients, suggests that viral aerosol particles are produced by individuals that have COVID-19, even in the absence of cough.
Importantly, these results suggest that virus expelled from infected individuals, including from those who are only mildly ill, may be transported by aerosol processes in their local environment, potentially even in the absence of cough or aerosol generating procedures.
Use of airborne isolation precautions including N95 filtering respirators and powered air purifying respirator (PAPR) use adequately protected healthcare workers in both the biocontainment unit and the quarantine areas.
Based on this report and some others from China, members of the Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats at the National Academies of Science sent a letter to the Office of Science and Technology Policy at the Executive Office of the President (NRC, 2020). The letter states that while “the current SARS-CoV-2 specific research is limited, the results of available studies are consistent with aerosolization of virus from normal breathing.”
Treatment Updates
There has been additional information released on several of the potential treatments being tested for COVID-19. No treatments have been identified that are capable of preventing or treating COVID-19.
A review of ongoing research published in JAMA on April 13, 2020 found that there were 351 active trials referring to COVID, coronavirus, or SARS-CoV-2 listed on ClinicalTrials.gov, the National Institutes of Health clinical trial database (Sanders, 2020). Of those, approximately 109 referred to pharmacological treatments. Of these 109 trials, 82 are interventional studies, with 29 placebo-controlled trials. Based on the investigator-supplied description of the studies, there are 11 Phase 4, 36 Phase 3, 36 Phase 2, and 4 Phase 1 trials. Twenty-two trials were not categorized by phase or not applicable.
Remdesivir
Preliminary analyses of Phase 3 trials investigating the use of remdesivir for severe cases of COVID-19 are beginning to be available. A clinical trial at the University of Chicago Medicine included 125 participants with COVID-19, and 113 were reported to have had severe disease (Feuerstein, 2020). The 125 participants were all treated with daily infusions of remdesivir. A video discussion between Kathleen Mullane, the physician in charge of the study, and other University of Chicago faculty members related Dr. Mullane’s experience during the trial. She described that participants had rapid recoveries in fever and respiratory symptoms, with nearly all patients discharged in less than a week, and that only two had died. This trial included people with severe disease and therefore did not include a placebo group for ethical reasons. Dr. Mullane reports, however, that participants in the study were not on ventilators for as long as has been reported from hospitals around the United States.
The study at the University of Chicago is part of a larger study being organized by Gilead, the maker of remdesivir. In this study, 2,400 participants with severe COVID-19 have been enrolled at 152 sites around the world. Another study is also ongoing that includes 1,600 participants with moderate COVID-19 symptoms at 169 sites.
A peer-reviewed account of remdesivir treatment of patients with COVID-19 through compassionate use protocols also indicates promising results (Grein, 2020). In the report, the researchers describe the outcome of 61 patients who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Of those who received treatment, eight could not be evaluated due to a lack of records after treatment. At the start of treatment, 57% were receiving mechanical ventilation, and 8% were receiving extracorporeal membrane oxygenation. The participants were followed for a median of 18 days after treatment. After treatment, 68% had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 47% of participants were discharged, and 13% died. The calculated mortality was 18% among patients receiving invasive ventilation and 5% among those not receiving invasive ventilation. For comparison, the authors mention a recent randomized, controlled trial of lopinavir–ritonavir in patients hospitalized for COVID-19, where the 28-day mortality was 22%, but only one of the 199 participants was on mechanical ventilation at the start of treatment. Generally, reports of the mortality rate for severe cases range from 17% to 78% based on overviews of the available data. This information suggests that the mortality rate in this of remdesivir study is an improvement, but comparative studies are still needed.
Phase 2 Clinical Trial for Selinexor
Karyopharm Therapeutics Inc. announced on April 20 that they had given the first participant a dose of selinexor to investigate its effect on hospitalized patients with severe COVID-19 (Karyopharm, 2020). Based on cellular studies, researchers from the company report that selinexor has been found to inhibit the function of proteins that are necessary for the replication of SARS-CoV-2 and the body’s inflammatory response to the virus. The drug is currently approved by the FDA for treatment of relapsed or refractory multiple myeloma.
Previous research of selinexor has shown that it can interfere with the replication of other viruses such as influenza and respiratory syncytial virus. The human protein that is inhibited by selinexor, called XPO1, has been identified as having multiple interactions with SARS-CoV-2 viral proteins during infection. Application of selinexor to cells that were infected with SARS- CoV-2 led to a 90% reduction in the amount of virus produced in the cell. Further studies also showed that selinexor could also prevent infection of cells by newly produced virus.
In their press release, Karyopharm stated that they have sufficient supply of selinexor for current and expected commercial patients with multiple myeloma, for ongoing clinical trials in patients with various cancers, as well as for this study in patients with COVID-19.
Potential Shortages of Other Medications
The Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota announced preliminary findings from its Resilient Drug Supply Project (Robideau, 2020). The project focuses on the supply chains and global disruptions for the most critical drugs for life- saving and life-sustaining treatment. Based on their research, the scientists found that there are 156 critical drugs which are likely to have their supply chain disrupted due to the COVID-19 pandemic. Because of difficulty in accessing information from private companies, the CIDRAP report was not able to identify the precise health risk of drug shortage to the U.S. healthcare system due to the lack of structural transparency and available supply chain data about drugs.
They also report that “if pharmaceutical companies, their suppliers, and contract manufacturers do not disclose supply chain information on critical drugs, including their current inventory and relative dependency on any China/India-based supply chain, it is assumed that some of the 156 critical drugs will be in short supply within the next 90 days.” The complete list of drugs has not yet been made public, but examples given by investigators in the study include epinephrine, various antibiotics, and albuterol (Roos, 2020).
Vaccine Increases the Response to Viral Infection
There are preliminary reports that immunization with a specific vaccine may have a general effect of increasing the body’s immunity thereby reducing the risk of severe infection by SARS- CoV-2 (Branswell, 2020 and WHO, 2020). The Bacille Calmette-Guerin (BCG) vaccine is used to vaccinate newborn infants for tuberculosis in areas where the disease is common. There is some evidence of an association between the rates of use of the BCG vaccine and a lower rate of COVID-19 infections. Researchers warn however, that the correlation between the numbers may be a coincidence and not a cause-and-effect relationship. It has been mentioned that the outbreaks in the countries where BCG vaccine is used more often started later than outbreaks in Europe and the United States, where use of the BCG vaccine is rare. Therefore, the rate of transmission in the vaccinated countries may currently look smaller only because the outbreak is at an earlier stage.
Survey of Interactions between Human and Viral Proteins
To better understand the manner in which human and viral proteins interact, a group of researchers produced 26 of the 29 proteins encoded by the SARS-CoV-2 genome in human cells (Gordon, 2020). The viral proteins were then isolated, and the human proteins that interacted with the viral proteins were identified. This experiment identifies potential interactions between human and viral proteins that can be targeted with potential drug candidates. The researchers identified 332 interactions between viral proteins and human proteins. Cross- referencing this list with available drugs that are designed to affect the human proteins, they found 67 interactions that can be targeted and 69 potential drugs that have previously been approved by the FDA, studied in clinical trials, and/or investigated in preclinical trials. The breakdown of potential drugs based on approval status is 27 drugs approved for other diseases, 14 investigational new drugs (in clinical-trials for other uses), and 28 pre-clinical candidates (not yet tested in humans). The researchers are currently performing experiments to determine if any of the identified compounds are able to affect infection of cells by SARS-CoV-2. Because the interactions are between viral and human proteins, drugs that prevent the interaction may be more resistant to mutations in the virus because the virus cannot change much without losing the ability to interact with the human protein. The research also may help better outline the viruses life-cycle inside human cells based on the types of proteins identified, which can also lead to better understanding of treatment and transmission of COVID-19.
Public Health Plans
Multiple research groups from around the globe have released detailed plans on ways to proceed now that there is evidence that initial efforts at social distancing and stay at home orders are having an effect on transmission rates in the United States and other countries.
United States officials have released a less detailed but similar version of these plans, but have stated that state governments will need to coordinate and implement the plans. Some states are beginning to implement the recommendations. For example, Massachusetts announced a new contact-tracing program has been implemented to hire 1,000 people in public health roles that allow for monitoring of transmission, and newly hired employees have already began calling people who had potential contact with COVID-19 (Barry, 2020). Groups of governors and other state officials have formed coalitions to implement recommendations together, allowing for a coordinated approach for regions with extensive interactions, including California, Washington, and Oregon in the west and New York, New Jersey, Connecticut, Pennsylvania, Rhode Island, Delaware, and Massachusetts in the east while in the Midwest the governors of Ohio, Wisconsin, Minnesota, Illinois, Indiana, and Kentucky announced the partnership (Soucheray, 2020).
Investigation of Non-Pharmaceutical Interventions in Wuhan
More information is becoming available about the public health response and its effects on COVID-19 transmission in Wuhan, China (Hartley, 2020 and Pan, 2020). Pan and colleagues recently published a peer-reviewed report in JAMA that shows the effect of different public health interventions on the control of the outbreak.
The confirmed case rate per million people increased from 2.0 in the first period to 45.9 in the second period. It then greatly increased during the third period to 162.6, when restrictions were initially put into place. During the fourth period, the confirmed case rate per million people began to decrease to 77.9, and finally to 17.2 after February 16. There was also a similar trend within the five time periods showing an initial increase and then decrease in the percentage of people with severe symptoms.
This analysis shows the association between non-pharmaceutical interventions and a reduction in transmission as well as the number of cases with severe symptoms. The number of people infected by each confirmed case fluctuated above 3.0 before January 26, decreased to below 1.0 after February 6, and decreased further to less than 0.3 after March 1.
They also found that there were higher rates of infection in younger individuals than was initially reported. There was a high rate of infection for infants under a year of age compared to initial reports. There were also a reported 12.7 per million infections in people aged 20 to 39 in the Wuhan area, suggesting that while severe symptoms were less prevalent in this age group, they would still have contributed to the transmission of infections.
Serological Studies
There are several large serological studies under development in the United States (Cohen, 2020). Serological studies, also called serosurveys, test for antibodies in the blood that are produced during and after an infection. Serological tests can measure the amount of antibodies produced by an individual and give an estimate of the time period when they were infected.
Broad dating of the infection is possible because the body produces a different response at different times during an infection. It is possible to tell if someone was infected a week or two ago versus four to six weeks or longer.
A study funded by the National Institutes of Health involves six metropolitan regions in the United States, Seattle, New York City, San Francisco Bay area, Los Angeles, Boston, and Minneapolis. Each site is saving 1000 samples a month from regional blood centers. Because of the requirements for blood donation, the age, gender, and, zip code of the donor’s residence is known for each sample. A total of 6000 samples are expected to be collected during the period between March and July. Assessment of the samples allows for both an overall estimate of the number of people who had COVID-19 as well as the timing of the infections as the number changes over time. A representative from the group coordinating the project, Michel Busch at the Vitalant Research Institute at the University of California, San Francisco, told reporters at the journal Science that they have results from the samples acquired in Seattle in March and those from the last week in March that were collected in New York City. They are not yet releasing the results because donor-based incidence data is expected to lag behind the general population’s incidence by a month or two due to the fact that blood donors are required to be healthy and free of a fever.
The CDC has also planned three larger, nationwide serosurveys using blood donations to assess antibodies present in the United States population. This study is expected to enroll around 50,000 donations in September and December of 2020 and November 2021. The WHO is also organizing a large serosurvey called SOLIDARITY II that will test for antibodies in more than six different countries at this time (Gander, 2020). Additional countries will be added as they are able to participate. As of April 1, four studies had already begun using specimens previously collected.
Use of donated blood allows for sampling of a different subset of people than other population studies underway. For example, University of California, San Francisco and the University of Washington are performing serosurveys by neighborhood by going door to door to collect small blood samples for testing. Because a different section of the population is investigated in the different studies, researchers get a broader range of information when the information is later combined.
In general, serosurveys for COVID-19 are complicated by the presence of seasonal coronaviruses that cause cases of colds every year. In studies, researchers have seen that there is an associated boost in the amount of pre-existing antibodies to the seasonal strains of coronavirus which may have a reaction with the spike proteins of the SARS-CoV-2. This phenomenon, called cross-reactivity, could complicate the accuracy and interpretation of the results of the study because of the possibility of false positive results.
Pandemic and Post-Pandemic Transmission Dynamics
As might be expected, there is an intense interest on how the transmission of SARS-CoV-2 will evolve as the pandemic proceeds and in the period after pandemic spread is interrupted (Kissler, 2020). The manner in which SARS-CoV-1, which led to the SARS outbreak in 2003, was contained through isolation of the sick and tracing of contacts does not seem feasible due to the pre-symptomatic transmission of SARS-CoV-2.
There is a possibility that COVID-19 cases will wax and wane with the seasons as happens during seasonal infections from milder forms of the coronavirus. Seasonal transmission of viruses is not well understood, but is thought to stem from changes in the external environment over the year, changes in human behavior, fluctuations in the immune system’s defense mechanisms, and alterations of virus infectivity (Pica and Bouvier, 2012). For example, it has been found that increased humidity levels, as would occur during summer, leads to a reduction in the infectivity of influenza virus due to changes in the virus stability and changes in respiratory droplet size.
To determine the long-term transmission patterns of SARS-CoV-2, it will be necessary to understand the degree of seasonal variation in transmission, the duration of immunity after infection, and the degree of cross-immunity between SARS-CoV-2 and other seasonal coronaviruses. A group of researchers published their study of the variables associated with the COVID-19 pandemic in the journal Science after appropriate peer review.
Investigation of the seasonal coronaviruses (called HCoV-OC43 and HCoV-HKI1) that cause cases of what is referred to as the common cold shows that wintertime climate and host behaviors facilitate transmission only in the colder months and that immunity to both seasonal coronavirus wane within a single year. The peak of transmission for HCoV-OC43 and HCoV- HKI1 occurs between October and November with a lower amount of transmission between February and May. Estimates based on seasonal rates of HCoV-OC43 and HCoV-HKI1 suggest that the immunity for both strains is around 45 weeks with some cross-reactivity between strains. There is some evidence of cross-reactivity in the immune response for different coronaviruses as evidenced in experiments with seasonal strains and SARS-CoV-1.
Based on the information known about other coronaviruses, researchers have modeled possible scenarios of the transmission of SARS-CoV-2 through 2025.
The researchers also prepared models to determine the effect of social distancing on transmission based on their previous calculations. In all possible scenarios, the lifting of social-distancing restrictions led to a resurgence of infection, but there were some differences in the timing and size of the second wave of infections if the characteristics of the virus differed.
If there is a one-time implementation of social distancing and the virus is NOT affected by seasonal changes, the single episode of social distancing reduces the peak of transmission during the pandemic, but the resulting second wave of infection is nearly the same size as the peak resulting from uncontrolled transmission from the start. The large amount of resurgence is due to the fact that there was no population immunity acquired during social distancing due to the effective reduction in transmission during social distancing. By changing the duration and intensity of social distancing, more people in the community become immune and the intensity of the peaks can be altered.
If there is one-time implementation of social distancing, but the virus IS affected by seasonal changes, the peak of a resurgence of infection after relaxation of restrictions is expected to be larger than that experienced with uncontrolled transmission as it will occur during the autumn and winter.
Based on the models, none of the one-time interventions were able to maintain the number of critical care cases below the capacity of hospitals to care for them.
If intermittent social distancing was adopted, it would be possible to prevent hospital capacity from being overloaded. If there is a seasonal change in transmission and with a three week lag in the peak of critical cases after the start of social distancing, social distancing in the summer months could be less frequent, and the length of time between restrictions would increase over time as more people acquired immunity.
Based on the current level of critical care capacity, the duration of the SARS-CoV- 2 pandemic would last until 2022 with social distancing in place 25% of the time with seasonality or 75% of the time if there is no change in transmission with the seasons.
When critical care resources are increased, population immunity can be accumulated more rapidly because there is room for treatment of a larger number of the individuals with severe symptoms at the same time. This would lead to a reduction in the overall length of the epidemic and a reduction in the total length of the social distancing restrictions. Additionally, if a otential treatment is found that halves the number of infections that require hospitalization, there is a similar effect as doubling the critical care capacity.
The authors conclude that:
“One-time social distancing efforts may push the SARS-CoV-2 epidemic peak into the autumn, potentially exacerbating the load on critical care resources if there is increased wintertime transmissibility. Intermittent social distancing might maintain critical care demand within current thresholds, but widespread surveillance will be required to time the distancing measures correctly and avoid overshooting critical care capacity. New therapeutics, vaccines, or other interventions such as aggressive contact tracing and quarantine – impractical now in many places but more practical once case numbers have been reduced and testing scaled up – could alleviate the need for stringent social distancing to maintain control of the epidemic. In the absence of such interventions, surveillance and intermittent distancing (or sustained distancing if it is highly effective) may need to be maintained into 2022, which would present a substantial social and economic burden.”
COVID Symptoms and Severity
As additional information is collected, researchers are reporting that many of the trends seen in China and other countries earlier in the outbreak are still true. A report describing 799 patients in China investigated the characteristics of the 113 of the group who died to determine if there were any correlations (Chen, 2020). The outcome of the study accentuated many of the same results observed in previous trials. The people who died in this group were older, 73% were male, and they were more likely to have hypertension (48% versus 14%) or cardiovascular issues (24% versus 4%) than individuals who survived. Survivors were also less likely to have complications such as acute respiratory distress syndrome, respiratory failure, sepsis, acute cardiac injury, heart failure, alkalosis (a low level of carbon dioxide in the blood that results from rapid or deep breathing), hyperkalemia (increased levels of potassium in the blood), acute kidney injury, and hypoxic encephalopathy (brain injury caused by oxygen deprivation to the brain).
A study analyzing data from people in California, Oregon, and Washington state also corroborated much of the earlier information (Lewnard, 2020). Those with severe symptoms were more likely to be older and older patients experienced higher risks of ICU admission and death. There was also an increased risk of ICU admission and death in men compared to women. Also, the number of people infected by each of the participants in the study decreased as social distancing was implemented.
Additional System Damage during COVID-19
The above report aligns with another recently released study that shows that there is a high amount of damage to systems besides the lungs. While lack of oxygen would be expected to be a common cause of death, physicians are reporting that the acute cause of death is most often cardiovascular in nature (Horton, 2020).
There is also evidence of extreme immune responses that are compounding the symptoms observed in severely ill people with COVID-19 (Ledford, 2020). There is evidence in some people of high levels of a type of immune-system protein, called cytokines, which are normally used to send signals from damaged tissue to bring other immune components to the area.
Macrophages are a type of immune cell that is recruited by the production of cytokines, and they release molecules that promote an inflammatory response. An oversized immune response, sometimes called a cytokine storm, can cause additional tissue damage. However, as mentioned below, use of systemic corticosteroids, which is a typical treatment to reduce an immune response, has been shown to lead to worse outcomes, suggesting that overall reduction of the immune system is not helpful in the treatment of COVID-19.
Association with Chronic Respiratory Disease
In most cases, respiratory infections have been found to pose additional risks to individuals with chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). However, analysis of people who have become infected with COVID-19 suggests that people with chronic respiratory diseases are not more likely to get COVID-19 than the general public, unlike individuals with diabetes and hypertension (Halpin, 2020). The lack of an effect could be due to incomplete reporting of people with respiratory disease, but based on a review of the reports, the authors conclude that this is not likely. Researchers are now attempting to determine why people with chronic respiratory disease are not more susceptible to COVID-19. Two possibilities are that changes in the lungs of people with chronic respiratory disease prevent infection with SARS-CoV-2 or that treatments commonly used for chronic respiratory disease protects people from infection. The first possibility, where respiratory disease itself has a protective effect is unlikely based on information that after infection, people with COPD have an increased mortality.
Instead researchers have found that use of inhaled corticosteroids and bronchodilators suppresses coronavirus replication and the production of cytokines, which is a part of the intense immune response associated with COVID- 19.
This is in contrast to findings that show that use of systemic corticosteroids, which are given orally or intravenously and are delivered through the blood stream, effecting the whole body, slows the recovery from SARS and MERS infections.
Additional Symptoms
There is more evidence that a loss of smell and taste is associated with early symptoms of COVID-19 (Nature, 2020). Researchers in the United Kingdom developed a symptom tracking app for smart phones that allows users to record health information on a daily basis. When the researchers analyzed the information they collected between March 24 and 29, they observed that users who tested positive for COVID-19 were three times more likely to report losing their sense of smell and taste than were those who had symptoms of the virus but tested negative. Other symptoms that were commonly reported by people who tested positive for COVID-19 were fever, persistent cough, fatigue, diarrhea, abdominal pain, and loss of appetite. Based on the number of people using the app, the researchers found that as of April 1, 4.9% of the app users were likely to have the virus. From the information they collected on the smartphone app, they extended their calculations to the whole population of the United Kingdom and found that an estimated 1.9 million people between the ages of 20 and 69 likely have symptomatic COVID- 19 as of April 1. More recent analysis from the group suggests that the number of infections is falling and that social distancing may be having an effect in the United Kingdom.
References
Barry E. An Army of Virus Tracers Takes Shape in Massachusetts. The New York Times. Published April 16, 2020 and updated April 17, 2020. Accessed on April 17, 2020 at https://www.nytimes.com/2020/04/16/us/coronavirus-massachusetts-contact-tracing.html
Bendavid E et al. COVID-19 Antibody Seroprevalence in Santa Clara County, California. MedRxiv. Published April 11, 2020. Accessed on April 17, 2020 at https://doi.org/10.1101/2020.04.14.20062463
Branswell H. Why a decades-old TB vaccine is getting attention in the fight against Covid-19. STAT News. Published April 14, 2020. Accessed on April 15, 2020 at https://www.statnews.com/2020/04/14/decades-old-tb-vaccine-attracts-attention-and- skepticism-as-a-potential-weapon-against-covid-19/
Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study [published correction appears in BMJ. 2020 Mar 31;368:m1295]. BMJ. 2020;368:m1091. Published 2020 Mar 26.
Cohen J. Unprecedented nationwide blood studies seek to track U.S. coronavirus. Science. Published April 7, 2020. Accessed April 14, 2020 at
https://www.sciencemag.org/news/2020/04/unprecedented-nationwide-blood-studies-seek- track-us-coronavirus-spread
Feuerstein A and Herper M. Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment. STAT News. Published April 16, 2020. Accessed on April 17, 2020 at https://www.statnews.com/2020/04/16/early-peek-at-data-on-gilead-coronavirus-drug- suggests-patients-are-responding-to-treatment/
Gander K. What is a serosurvey? Blood of Americans sought to reveal the true scale of the nation’s COVID-19 epidemic. Newsweek. Published April 4, 2020. Accessed on April 14, 2020 at https://www.newsweek.com/what-serosurvey-blood-americans-sought-reveal-true-scale- nations-covid-19-epidemic-1496855
Gordon DE, et al. A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing. bioRxiv. Published March 27, 2020. Accessed on April 14, 2020 at https://doi.org/10.1101/2020.03.22.002386
Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19 [published online ahead of print, 2020 Apr 10]. N Engl J Med.
2020;10.1056/NEJMoa2007016.
Halpin DMG, Faner R, Sibila O, Badia JR, Agusti A. Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection? [published online ahead of print, 2020 Apr 3]. Lancet Respir Med. 2020;S2213-2600(20)30167-3.
Hartley DM, Perencevich EN. Public Health Interventions for COVID-19: Emerging Evidence and Implications for an Evolving Public Health Crisis [published online ahead of print, 2020 Apr 10]. JAMA. 2020;10.1001/jama.2020.5910.
He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19 [published online ahead of print, 2020 Apr 15]. Nat Med. 2020;10.1038/s41591-020- 0869-5.
Horton R. Offline: COVID-19-bewilderment and candour. Lancet. 2020;395(10231):1178.
Karyopharm. Karyopharm Announces Dosing of First Patient in Randomized Study Evaluating Low Dose Selinexor in Patients with Severe COVID-19. Published April 20, 2020. Accessed on April 20, 2020 at https://www.globenewswire.com/news- release/2020/04/20/2018499/0/en/Karyopharm-Announces-Dosing-of-First-Patient-in- Randomized-Study-Evaluating-Low-Dose-Selinexor-in-Patients-with-Severe-COVID-19.html
Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility — King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep 2020;69:377–381. Accessed on April 14, 2020 at https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm#suggestedcitation
Kissler SM, Tedijanto C, Goldstein E, Grad YH, Lipsitch M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period [published online ahead of print, 2020 Apr 14]. Science. 2020;eabb5793.
Ledford H. How does COVID-19 kill? Uncertainty is hampering doctors’ ability to choose treatments. Nature. Published April 9, 2020. Accessed on April 14, 2020 at https://www.nature.com/articles/d41586-020-01056-7
Lewnard JA, et al. Incidence, clinical outcomes, and transmission dynamics of hospitalized 2019 coronavirus disease among 9,596,321 individuals residing in California and Washington, United States: a prospective cohort study. MedRxiv. Published April 16, 2020. Accessed on April 17, 2020 at https://www.medrxiv.org/content/10.1101/2020.04.12.20062943v1
National Institutes of Health. NIH begins study to quantify undetected cases of coronavirus infection. Published April 10, 2020. Accessed on April 14, 2020 at https://www.nih.gov/news- events/news-releases/nih-begins-study-quantify-undetected-cases-coronavirus-infection
National Research Council 2020. Rapid Expert Consultation on the Possibility of Bioaerosol Spread of SARS-CoV-2 for the COVID-19 Pandemic (April 1, 2020). Washington, DC: The National Academies Press. https://doi.org/10.17226/25769.
Nature. Tracking-app data suggest loss of smell is a key COVID-19 symptom. Nature. Published April 8, 2020. Accessed on April 14, 2020 at https://www.nature.com/articles/d41586- 020-00154-w
Pan A, Liu L, Wang C, et al. Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China [published online ahead of print, 2020 Apr 10]. JAMA. 2020;e206130.
Pica N, Bouvier NM. Environmental factors affecting the transmission of respiratory viruses.
Curr Opin Virol. 2012;2(1):90–95.
Robideau B. CIDRAP finds supply chain risks availability of critical drugs during COVID-19 pandemic. Published March 26, 2020. Accessed on April 16, 2020 at https://twin- cities.umn.edu/news-events/cidrap-finds-supply-chain-risks-availability-critical-drugs-during- covid-19-pandemic
Roos R. Experts say COVID-19 will likely lead to US drug shortages. CIDRAP News. Published March 27, 2020. Accessed on April 21, 2020 at https://www.cidrap.umn.edu/news- perspective/2020/03/experts-say-covid-19-will-likely-lead-us-drug-shortages
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review [published online ahead of print, 2020 Apr 13]. JAMA. 2020;10.1001/jama.2020.6019.
Santarpia JL. Transmission Potential of SARS-CoV-2 in Viral Shedding Observed at the University of Nebraska Medical Center. MedRxiv. Published March 26, 2020. Accessed on April 14, 2020 at https://doi.org/10.1101/2020.03.23.20039446
Soucheray S. As part of US COVID-19 reopening steps, Midwest governors form coalition. CIDRAP News. Published April 16, 2020. Accessed on April 17, 2020 at https://www.cidrap.umn.edu/news-perspective/2020/04/part-us-covid-19-reopening-steps- midwest-governors-form-coalition
World Health Organization. Bacille Calmette-Guérin (BCG) vaccination and COVID-19. Published April 12, 2020. Accessed on April 15, 2020 at https://www.who.int/news- room/commentaries/detail/bacille-calmette-guérin-(bcg)-vaccination-and-covid-19
