Research Updates on COVID-19: Re-Infection After Recovery, Evidence of Immune Response & More

Weekly COVID-19 Research Update
May 27, 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.

Reinfection with SARS-CoV-2

There have been numerous reports of people with confirmed cases of COVID-19 recovering, testing negative for virus with PCR-based testing, and later testing positive again. Most researchers have felt that this process is most likely either an incorrect test result or detection of pieces of the virus being cleared by the immune system after recovery. However, it has been difficult to definitively determine if people can be reinfected or have a resurgence of the infection after apparently recovering.

The Korean Centers of Disease Control recently released a report on their website that described an investigation of 447 people who tested positive after previously meeting the requirements for discharge for COVID-19 (Korea CDC, 2020). The average time between the onset of initial symptoms to testing positive again after discharge was 44.9 days with a range between eight and 82 days. The tests after discharge were performed in one group as a regular screening process, regardless of symptoms, or for another group based on a reoccurrence of symptoms, such as coughs, sore throat, etc. In the screening group, 59.6% tested positive, and in the group tested when symptoms were observed, 44.7% tested positive. Of the 447 participants who tested positive after recovery that were included in the study, an epidemiological investigation and contact investigation was completed for 63.8%. In total, 790 contacts of the participants were identified (351 family and 439 others). As of May 15, no cases of COVID-19 were reported to be transmitted during the period when the individuals had a positive test after recovery. Additionally, neutralizing antibody production was confirmed in all of the participants who had a positive test after discharge from the hospital. Based on these results, the Korean CDC no longer is classifying those who have met the criteria for recovery as having the potential for transmission even if they re-test as positive.

The appropriate studies have not been done to determine the cause of the subsequent positive tests, but the researchers of the Korean study told the Wall Street Journal that the initial negative tests may have been incorrectly negative because the virus had not been fully cleared from the body and patients continued to have low levels of the virus that diagnostic tests did not detect. This can happen in the later stages of the disease when the virus is mainly present in the lungs rather than the upper respiratory tract (Rana, 2020). Researchers are still trying to define the requirements for recovery from COVID-19. These efforts are complicated by numerous examples where detection of virus is possible for long periods after symptom resolution and others where individuals experience long periods with lingering symptoms without detection of virus. However, the lack of transmission reported in the Korean study is a good sign that people do not remain infectious for long periods of time.

Immune Response to SARS-CoV-2

Evidence of an immune response that protects against reinfection (or immunity) was also observed in a study recently reported in the journal Science. The study indicated that a primate called a rhesus macaque could not be reinfected with SARS-CoV-2 a second time (Chandrashekar et al., 2020). In the study, the rhesus macaques were infected with SARS-CoV- 2, which produced large amounts of virus in the upper and lower respiratory tract, an immune response, and evidence of viral pneumonia, but severe symptoms or death were not observed. All nine of the animals produced antibodies that were found to be neutralizing when tested. After the animals were recovered, they were exposed to SARS-CoV-2 again. Much lower levels of virus were detected in the upper and lower respiratory fluids, and little or no clinical disease was observed in the animals after the second exposure. The reduced intensity of the second infection was found to be mediated by an immune response. The authors report that SARS-CoV-2 infection induced protective immunity against re-exposure in nonhuman primates.

Outcomes of Critically Ill Adults with COVID-19 in New York City

Researchers from New York-Presbyterian hospitals, affiliated with Columbia University Irving Medical Center in northern Manhattan, published an investigation in the Lancet of the outcomes of adult patients admitted between March 2 and April 1 with laboratory-confirmed COVID-19 who were defined as critically ill with acute hypoxemic respiratory failure (Cummings et al., 2020). The researchers reported the rate of in-hospital death, the frequency and duration of invasive mechanical ventilation, the frequency of use of medication to increase blood pressure to prevent shock (vasopressors), the frequency of renal replacement therapy (kidney dialysis), and the time to in-hospital clinical deterioration following admission.

During the study, 1150 adults were admitted, and 22% were deemed to be critically ill. The median age of the critically ill patients was 62 years with a range between 51 and 72, and 67% of the participants were men. There was a high number of people with at least one chronic illness (82%), and the most common conditions were hypertension (63%) and diabetes (36%). Additionally, 46% of the participants met the criteria for obesity. At the end of the observation period in the study, 39% of the participants had died, and 37% remained hospitalized. The median time before a worsening of symptoms while in the hospital was three days with a range between one and six days. Treatment with mechanical ventilation was required for 79% of the participants, 66% received vasopressors, and 31% needed renal replacement therapy. When the characteristics associated with death from COVID-19 were analyzed, the researchers found that older age, chronic cardiac disease, chronic pulmonary disease, higher concentrations of interleukin-6 (a cytokine associated with inflammation), and higher concentrations of D-dimer (a protein that indicates the abnormal formation of blood clots) were associated with in-hospital mortality.

Based on their findings, the authors report that “critical illness among patients hospitalized with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extrapulmonary organ [not the lungs or heart] dysfunction, and substantial in-hospital mortality.” The characteristics associated with poor outcomes were similar to those reported previously in Italy and China, suggesting that a similar disease course is occurring.

Max O’Donnell, one of the senior authors of the study, spoke to the Washington Post about the results (Achenbauch and Cha, 2020). He mentioned that more than 80% of people over 80 who were put on a ventilator did not survive. Based on this information he suggested that elderly patients and their family members should be aware of this result when trying to decide whether to use the invasive procedure to treat severe illness. It was also mentioned that obesity played a larger role in the outbreak in New York than in previous locales, possibly due to higher rates of obesity in the United States. It was found that 71% of the critically ill patients under the age of 50 admitted to the hospitals were obese. Another paper from the journal Clinical Infectious Diseases that was published in early April by researchers at NYU Langone reported that people with a Body Mass Index (BMI) over 30 were almost twice as likely to be admitted to a hospital with COVID-19, and if their BMI was higher than 35, they were three times as likely to die as someone with a healthy BMI.

Viral and Patient Factors Related to Clinical Outcome

Researchers in China evaluated the viral genome and patient immunological data from 326 confirmed cases of COVID-19 in Shanghai, China (Zhang et al., 2020). Based on analysis of the genomic sequence of the virus from the participants, the researchers found that there were two major types of virus involved in the outbreak in Shanghai. However, even though the genomes had differences, there was not a change in the virulence or clinical outcomes between the two types of virus. Instead, differences in the characteristics of those who were ill were associated with the outcomes. Lymphocytopenia (a condition where there are low levels of a type of white blood cell), was associated with progression of symptoms. The researchers found that this association was especially strong when there was a reduction in the number of cells called T cells at the time of hospital admission. Participants who had have high levels of cytokines called IL-6 and IL-8 were more likely to have severe or critical disease, and the increased levels of the cytokines was also correlated with decreased T-cell numbers. Based on the information from the study, the authors conclude that the determinants of disease severity stem mainly from host factors such as age, lymphocytopenia, and a cytokine response. There was no evidence of a contribution from genetic differences from the virus or the emergence of different strains.

Subgroups More Susceptible to COVID-19

A study of the characteristics of a subset of people in the United Kingdom from the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre primary care network who were tested for SARS-CoV-2 was published in the Lancet. This evaluation allowed for a determination of characteristics associated with a positive test for COVID-19. Information about the participants from the network allowed for an examination of both physical risk factors as well as the potential socioeconomic factors that might also be involved (de Lusignan et al., 2020). The association of certain physical and medical factors were similar to previous reports. Adults were more likely than children to test positive, people aged 40 to 64 years were at greatest risk of testing positive, and people with chronic kidney disease were more likely to test positive. In this study, other chronic conditions were not associated with a higher risk of testing positive. People who met the criteria for obesity were also more likely to receive a positive test than people defined as having a normal weight.

Additionally, the researchers looked at the association between deprivation, population density, and ethnicity on the risk of a positive test for COVID-19. The risk of a positive test was greater in black people (62%) than white people (15.5%). People living in urban areas had a higher risk (26.2%) of a positive test when compared to those who live in rural areas (5.6%). In more deprived areas there was a 29.5% risk of having a positive test compared to a 7.7% risk in those defined as the least deprived.

Two other reports from the United Kingdom, submitted as pre-prints, have observed that there is a contribution from age, sex, black race, and obesity to the risk for severe infection and that there is an increased risk of death from COVID-19 in people who are older, male, obese, live in a greater state of deprivation, and are part of an ethnic minority (Jordan and Adab, 2020).

The Washington Post also recently reported that 93% of the doctors who have died from COVID-19 in the United Kingdom have been ethnic minorities who were born outside the country (Adam, 2020). This statistic is even more alarming due to the fact that 44% of doctors in Britain are from ethnic minority backgrounds, and more than half the new doctors who registered in Britain last year were born overseas. The Guardian reported that two thirds of the deaths from the National Health Service were people with an ethnic minority background. Britain’s Office of National Statistics has reported that people of African descent are more than four times as likely to die of COVID-19 compared to white people in England and Wales, and people of Bangladeshi and Pakistani origin were more than three times as likely to die. Similar findings have been reported in the United States. In Milwaukee County, Wisconsin people of African descent account for about 70% of those who have died from COVID-19, but are only 26% of the population (Thebault et al, 2020). Louisiana has a similar disparity, where 32% of the state’s population are of African descent, but 70% of the people who have died are of African descent.

Cummings and colleagues who reported on the outcomes in New York City (described above) found that white people, who are not Hispanic, came to the hospital after an average of three days of symptoms while those of Hispanic descent came to the hospital after an average of five days, and those of African descent came to the hospital after an average of seven days (Achenbauch and Cha, 2020). These differences may be one of the reasons that ethnic minorities make up a larger proportion of those severely affected by COVID-19 in the United States, but the large differences across different countries suggest there may be multiple contributing factors.

Possible Long-Term Effects from COVID-19

Even after recovery from COVID-19, it is expected that many survivors will have a reduced quality of life due to damage to multiple organs. Lung damage is common from severe respiratory infections, and in studies from the SARS and MERS epidemics in 2003 and 2012, there were a high number of recovered patients with scarring of the lung tissue, which is called pulmonary fibrosis, that lead to impaired function (George et al., 2020). Pulmonary fibrosis can be a progressive syndrome that leads to declining lung function, increased fibrosis over time with a worsening of symptoms that causes a progressive reduction in quality of life and early mortality (Spagnolo et al., 2020). Some people have tissue damage that does not progress over time, but the extent of the damage may also cause substantial effects on lung function and increased mortality in the older populations that have been most affected by COVID-19.

In a study of people who had survived SARS, researchers observed participants 15 years after their recovery. The results of the study indicated that there is a period in the first two years where individuals experience recovery of abnormalities in the lungs and a reduction of functional decline. After the first two years, participants’ conditions remained stable without further improvements. At the end of the study, 4.6% of participants still had abnormalities that affected lung function. In people recovered from MERS, 33% of people were found to have lung fibrosis when they were evaluated between 32 and 320 days after they recovered. Longer follow-up times have not yet been reported.

People who develop acute respiratory distress syndrome (ARDS) from situations other than COVID-19 often survive the acute phase of illness, but a substantial number later develop progressive pulmonary fibrosis resulting in death. It has also been found that the longer the duration of the initial disease, the higher the risk that fibrosis will occur (George et al., 2020). For example, in one study, 4% of people with a disease duration of less than one week were found to have evidence of fibrosis. When the duration of disease increased to between one and three weeks, 24% were found to have fibrosis. In people who were ill longer than three weeks, 61% had fibrosis. Based on the extended length of time using mechanical ventilation observed for people with COVID19-based ARDS, it is likely that many will later experience complications from pulmonary fibrosis. The currently available information indicates that about 40% of patients with COVID-19 develop ARDS, and 20% of ARDS cases are severe (Spagnolo et al., 2020).

Other long-term complications are being reported from people recovering from COVID-19 in Italy (Horowitz, 2020). The New York Times reports that many people have lingering symptoms for weeks after testing negative for viral infection. One person they interviewed reported that she continues to have a cough, crippling fatigue, aching muscles, and shortness of breath five weeks after recovering from the infection. The director of the San Matteo hospital in the Lombardy town of Pavia stated that the convalescence after the sickness can take up to 60 days. Those who have had kidney, heart, liver, and neurological damage from COVID-19 have not yet been recovered long enough to determine what lasting effects may be occur. However, even people who had milder cases report a lack of energy and sensation of broken bones that come and go from day-to-day without an apparent reason. A 29-year-old woman reported around May 10 that she has been running a low-grade fever since the beginning of March and recently has been having stomach aches and fatigue that prevent her from working.

COVID-19 in Children

More evidence is becoming available of the different responses to SARS-CoV-2 observed in children compared to adults. While many children seem to be asymptomatic during infection with the virus there is increasing evidence of specific symptoms that may be associated with COVID-19 in children. For example, there has been an increased association between rashes and gastrointestinal symptoms in children that were not originally linked to COVID-19. Experts suggest that these types of symptoms should be included in decisions about the testing of children for COVID-19 as well as decisions about attendance of school or other activities.

Gastrointestinal Symptoms

There have been several reports recently of children examined in the hospital emergency department with what was initially identified as a possible appendicitis but was later identified as COVID-19 (Tullie et al., 2020). In one report from the United Kingdom, eight children were described as having an atypical appendicitis before rapid deterioration requiring hospitalization or intensive care support. When they first were seen at the hospital, the children all had fever, abdominal pain, diarrhea, and vomiting and were being assessed for appendicitis. There were also high levels of inflammatory proteins observed in blood work that would be expected from a ruptured appendix. Imaging of the abdomen revealed that they all had inflammation of the ileum (ileitis), a region near the end of the small intestine. The overall inflammatory response increased and caused severe symptoms requiring admittance to the intensive care unit. Some of the patients tested positive for SARS-CoV-2, but some did not. None of the children described in the report have died, but six remained in the hospital at the time of publication. The authors also noted that six of the eight children were of African or Asian descent, which may be in line with the increased susceptibility of adults who are parts of minority ethnic groups. Based on their experience, the authors recommend testing for SARS-CoV-2 before surgery for a possible appendicitis.

Two other descriptions of children who required admission to the intensive care unit due to symptoms of septic shock (now referred to as multisystem inflammatory syndrome in children, or MISC) included symptoms similar to those described by Tullie and colleagues (Dallan et al., 2020 and Pain et al., 2020). The first child was seen in the emergency room after having five days of fever, cough, painful swallowing, vomiting, and abdominal pain (Dallan et al., 2020).

Inflammatory proteins were found to be elevated, and CT scans showed terminal ileitis. The authors warn that “children might present to primary care physicians or emergency departments…with a paucity of respiratory symptoms but in septic shock or with pronounced abdominal signs mimicking peritonitis.” Peritonitis is a reaction of the lining of the abdomen after rupture of an organ, such as the appendix. The third report describes a 14- year-old who came to the emergency department with fever, abdominal pain, nausea, and vomiting, but without respiratory symptoms (Pain et al., 2020). Blood tests showed evidence of increased inflammatory proteins, and he was initially treated with antibiotics to treat possible infection from a ruptured appendix. He then developed symptoms of ARDS and cytokine storm, but had a negative PCR-based test for SARS-CoV-2. Three tests from nasal swab samples and one stool sample were found to be negative for SARS-CoV-2 using PCR-based methods, but testing for antibodies eventually showed evidence of previous COVID-19. The authors stressed that “[d]uring the ongoing pandemic, COVID-19 must be considered in patients with increased inflammatory variables and abdominal symptoms.”

Skin Symptoms of COVID-19

There have been reports of several different types of skin rashes associated with children who have COVID-19 (Guarneri et al., 2020). In one study, researchers found that 20.4% of the 88 participants had some sort of skin lesion, such as redness of the skin (erythematous rashes), hives (urticarial), or chicken pox-like marks. There has also been a recent increase in cases involving redness on the toes that can progress to blisters and sores. In some cases, burning and itching was also associated with the rash. The blisters and sores remained on the toes for a varying amount of time, between 10 and 20 days, before healing without treatment. The authors of the study hypothesize that the inflammatory and abnormal clotting components of COVID-19 may be involved in the formation of skin rashes. They recommend that children that develop blisters and sores on their toes be tested for COVID-19 even if they have no other symptoms in order to identify potential modes of transmission.

Expression of SARS-CoV-2 Receptor Reduced in Children

SARS-CoV-2 interacts with the cells it infects by attaching to a protein on the surface of the human cell called angiotensin-converting enzyme 2 (or ACE2). Researchers have hypothesized that one of the reasons that children are less likely to have more severe cases of COVID-19 is due to a smaller amount of ACE2 being produced in the upper respiratory tract (Bunyavanich et al., 2020). A group of researchers published the results of their examination of nasal cells of 305 individuals aged 4 to 60 years in JAMA. The samples were originally collected as part of a study on possible indicators for asthma between 2015 and 2018. When the samples were evaluated for the levels of ACE2 being produced, the researchers found that the amount was the lowest in the youngest children and increased with age. The difference in the amount of ACE2 present did not change based on sex or if the participant had asthma.

School Reopening

France has started lifting restrictions and is beginning to send children back to school with social distancing in place and a maximum of 15 students per class. Some of the elementary students started returning the week of May 11, and 150,000 middle school children returned the week of May 18, which corresponds to around 30% of the children in France (Associated Press, 2020). On May 18, government officials announced that 70 cases of COVID-19 had been identified in association with schools that had reopened. The education minister stated that based on the incubation period, the individuals probably had been infected before returning to school. The affected schools have been closed. Similar reopenings have been taking place in Germany, but there have been no reports of outbreaks associated with schools there. Isolated cases have been reported, and two schools were closed when a teacher at each school tested positive.

The lack of childcare, either through school or other providers, is stalling the reopening plans for some areas in the United States (Weber and Feintzeig, 2020). The Wall Street Journal reports that as of the first part of April, nearly half of child-care facilities nationwide had closed completely, and 17% remained open only for the children of essential workers. Schools have been closed until the start of the next school year in fall for 40 states. Based on the latest estimates from the Bureau of Labor Statistics, more than 50 million workers in the United States had children under the age of 18, and almost half that number had children under age six. Some workers have received extra reimbursement from their workplaces to help with childcare costs while schools were closed, but there are few options available to use the extra financial support.

Concerns about the newly emerging cases of multisystem inflammatory syndrome in children, or MISC have complicated the situation as well (Reddy, 2020). Most experts are of the opinion that the incidence of the syndrome will remain low, and that it will be rare enough not to influence decisions about opening schools or camps. However, at the moment, the officials are still collecting information to determine the number of cases in the United States and worldwide.

Potential Vaccines for SARS-CoV-2

Information on three potential vaccines was recently released (van Doremalen et al., 2020, Yu et al, 2020, and Gao et al., 2020).

One of the vaccine candidates, a DNA-based vaccine, was tested in 35 rhesus macaques as reported in the journal Science (Gao et al., 2020). A DNA vaccine encodes the genomic information for a protein from the virus, which potentially transports into cells after immunization and is used to produce a protein or proteins that activate the immune system to make antibodies. For SARS-CoV-2, the researchers used DNA corresponding to several forms of the spike protein that is found on the surface of the virus. The animals in the study were given two doses of the vaccine and evaluated after five weeks to determine if an immune response had occurred. Many, but not all, of the immunized animals produced neutralizing antibodies at levels comparable to rhesus macaques and humans who had recovered from COVID-19. Six weeks after immunization the animals were re-exposed to SARS-CoV-2 virus, and they exhibited only mild clinical symptoms and a reduced amount of virus in respiratory fluids compared to unvaccinated animals. The vaccine that utilized the full form of the spike protein had the biggest effect when compared to vaccines utilizing fragments. Some of the vaccines prevent infection in the upper respiratory tract, but all led to an immune-based protection of the lower respiratory tract.

A vaccine candidate from an inactivated form of the virus was also reported in the journal Science (Yu et al., 2020). The researchers report on the pilot-scale production of an inactivated form of SARS-CoV-2, which led to the production of neutralizing antibodies in mice, rats, and rhesus macaques. The vaccine is currently being called PiCo-Vacc. Inactivated virus has been utilized for numerous previous vaccines before SARS-CoV-2, such as polio and influenza. This type of vaccine is better understood than DNA or RNA-based vaccines, as neither of these has yet been approved for use against any disease. However, the production of inactivated virus vaccines is more difficult and time consuming than DNA or RNA-based vaccines. Three different doses of PiCo-Vacc were administered in mice and rats, and the two higher doses were given to rhesus macaques. The level of neutralizing antibodies in the primates was similar to that seen in recovered COVID-19 patients. When the rhesus macaques were exposed to SARS-CoV-2, they were protected from infection and developed only mild symptoms. During studies to develop vaccines for SARS and MERS, there was evidence that inactivated vaccines caused an undesirable pulmonary immune reaction that was similar to a weak version of the cytokine storm currently observed with COVID-19. There was no evidence of this type of a reaction in the rhesus macaques in this study, but underscores the importance of a scientifically based and cautious approach to vaccine development to ensure serious side effects are avoided.

A third vaccine candidate using an adenovirus vector was presented as a pre-print (van Doremalen et al., 2020). Adenoviruses are a type of virus that can be used to transfer selected genetic material. The types of adenoviruses used for vaccines cause non-symptomatic respiratory tract infections in humans when an infection occurs. However, when used as a vaccine, the adenovirus is injected under the skin and leads to production of the genetic sequence that was transferred, instigating an immune response in a manner similar to DNA- based vaccine. The authors of this study produced an adenovirus-vector-based vaccine, which they have named ChAdOx1 nCoV-19, that produces the spike protein of SARS-CoV-2.

Inoculation with the vaccine resulted in an immune response in mice and rhesus macaques. When exposed to SARS-CoV-2, the vaccinated rhesus macaques had low levels of virus production compared to unvaccinated animals and did not develop pneumonia. There was also no evidence of undesirable immune reactions to the vaccine itself.

Transmission of SARS-CoV-2

Researchers have been updating their models of transmission of SARS-CoV-2 based on real- world transmission information as it becomes available. Using this information they can also investigate if different forms of non-pharmaceutical interventions work better than others to contain the spread of COVID-19.

Time Period for Interventions to Have an Effect

A study in Germany, published in the journal Science, reports on how long it takes for interventions to have an effect on transmission (Dehning et al., 2020). There have been three major interventions implemented in Germany: the cancellation of large public events; the closure of schools, childcare, and non-essential stores; and finally, a strict contact ban. The results of the analysis showed that there was a two-week delay between the initiation of interventions and a measurable change in the number of confirmed cases. Based on the study, the researchers confirmed that the reductions in transmission that occurred in Germany were due to the interventions put in place by the government. Also, all three interventions were necessary to stop the exponential growth of cases, and the number of new cases only started to decrease after the third intervention was put in place. However, they found that the current level of transmission is still close to the inflection point where it could quickly revert to increasing number of cases, suggesting that continued surveillance is required for future control of the outbreak.

Superspreading Events

A study of the viral transmission at a large event in Germany was published as a pre-print by Hendrik Streeck, a virologist with the University Hospital Bonn, Germany, and reported by the Wall Street Journal (Pancevski, 2020). Based on his research, Streeck found that people who become sick at superspreading events have more life-threatening infections, and on a global scale, the most cases and the most deaths result from coronavirus superspreading events. The researchers of the study propose that the more severe symptoms and increased risk of death are the result of exposure to high levels of the virus from close and prolonged contact.

A news article in the journal Science describes the work of a number of researchers investigating the transmission of SARS-CoV-2 (Kupferschmidt, 2020). Two investigations focused on superspreading events suggest that there have been many concentrated clusters where a small proportion of people are responsible for a large proportion of infections. In one, the authors estimate that around 10% of cases lead to 80% of the spread of COVID-19. This characteristic, called the dispersion factor, may be why some identified cases of COVID-19 do not lead to widespread infection. A low dispersion factor means that there is more transmission from a smaller number of initial cases. SARS was estimated to have a dispersion factor of 0.16, MERS was 0.25, and SARS-CoV-2 is higher than SARS and MERS, but the exact value can’t be reliably determined yet. When the dispersion factor is 0.1, most of the chains of transmission die out on their own because not enough people come into contact with the sick individual. It is estimated that SARS-CoV-2 needs to be introduced at least four times in a new area before widespread transmission begins.

Transmission Dynamics

Early in the outbreak, some communities had identified small groups of people that had been infected with SARS-CoV-2 (Bohmer et al., 2020 and Rybniker and Fätkenheuer, 2020). This situation allowed for precise contact tracing and the evaluation of transmission events, incubation period, and secondary attack rates. One such occurrence was in Bavaria, Germany in January, which was described in the journal Lancet Infectious Diseases. A single individual visited Germany for work, which led to the infection of 16 other people. Contact tracing of this transmission train was performed. High risk contacts were defined as those who had cumulative face-to-face contact with a confirmed case for more than 15 minutes, direct contact with secretions or body fluids of a patient with confirmed COVID-19, or health-care workers who had worked near a patient with confirmed COVID-19 without personal protective equipment. Low- risk contacts were defined as all other contacts.

Interviews with contacts and genomic sequencing of the virus in confirmed cases allowed the researchers to develop a precise map of transmission. The median incubation period (time between exposure to the virus and the first symptoms) was found to be 4 days with a range between 2.3 and 4.3. The median serial interval (time between infection and transmission to others) was 4 days with a range between 3.0 and 5.0. The secondary attack rate (the probability that an infection occurs among susceptible people during the incubation period) within households in isolation together was high at 75%. However, when sick individuals within a household were isolated separately, the secondary attack rate was only 10%. The secondary attack rate for high-risk contacts who were not in the same household was also low (5.1%).

None of the low-risk contacts were found to be infected. Based on the information from the study, the authors conclude that infectiousness before or on the day of symptom onset was substantial, the incubation period was often very short, and false negative tests occurred. This combination of events suggests that successful long-term and global containment of COVID-19 could be difficult to achieve. In an analysis of the report, experts highlighted that other studies have also found that early transmission is common and that transmission of the virus before symptoms develop occurs in up to a half of all infection events. They also suggest that traditional contact tracing methods with manual follow-up of contacts will likely be too slow to control a fast-moving epidemic of COVID-19, and that new methods will be necessary.

The European Union and WHO have compiled a resource list of potential digital collection tools for COVID-19 at The applications range from individual risk-assessment tools to digital contact tracing with location tracking and notification when contact with an infected individual has occurred. There are numerous ethical considerations being discussed about how data is collected, stored, and used by these new collection methods.

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The information provided in this report is not intended to represent a complete compilation of all treatment options available nor is it to be interpreted as medical advice. The information is intended to serve solely as a guide to facilitate a discussion between you and your medical provider(s). Medical decisions should be made only after consultation with and at the direction of your treating physician(s).

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