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EPIDEMIOLOGICAL EVIDENCE FOR ASYMPTOMATIC TRANSMISSION Several authors reported clusters of infections in China where epidemiological findings suggest the possibility of transmission by asymptomatic patients. Zhou J et al. reported two transmission events by asymptomatic patients in ZhuZhou, China.34A 37-year-old woman was isolated for observation after returning from Wuhan on January 22, 2020. Viral RNA was only detected in the 5th specimen taken on February 15, and she remained asymptomatic up to March 2 when her test turned negative and showed no pulmonary imaging changes. Meanwhile, her father was diagnosed of COVID-19 on February 12, 3 days before viral RNA was detected in the woman's specimen. An asymptomatic patient who returned from Wuhan appears to have infected her mother-in-law and father-in-law. Zhou et al. conclude that asymptomatic SARS-CoV-2 carriers can spread the virus before viral RNA was detected. It should be noted that they did not provide any information on potential alternate sources of infection or on the reliability of the testing done. Zhang J et al. reported a family cluster of 5 in Beijing. The index case was the only one in the cluster who had been to Wuhan; he returned to Beijing in January and invited his nephew (M/32) for dinner that day. This nephew became ill 3 days later and was diagnosed 2 days after symptom onset. Around that time, the index patient's wife (F/45) had a fever and they heard of a relative in Wuhan having COVID-19. As a result, the index patient and family visited a hospital to be assessed and the index and 4 family members (including the nephew and wife) were diagnosed with COVID-19. Both the index patient and a family member remained asymptomatic throughout the observation up to the end of February. The index patient's chest radiograph showed ground glass opacities but that of the other asymptomatic family member was normal. The authors believe the index patient passed the infection on to his family despite having no symptoms himself. However, details of other family members' contact history were not given to rule out potential alternate sources of infection.35A study by Bai Y et al. reported on an asymptomatic individual who transmitted COVID-19 to five family members in Anyang. She tested positive 18 days after her presumed exposure, with a negative test on day 16 and two negative tests on days 26 and 29. Although the authors argue that the asymptomatic individual was the source of infection for the family members, the family visited a hospital as well. Although the hospital reported no COVID-19 cases at that time, this is a potential alternative source of exposure.36Hu Z et al. reported on an asymptomatic case who appears to have acquired his infection in Hubei province and transmitted his infection to his wife, son and daughter-in-law who lived with him in Nanjing. His family members denied any other known exposures to confirmed or suspect COVID-19 patients.30Lavezzo E et al. reported on 3 cases who appeared to have acquired their infection based on contact with asymptomatic individuals. The cases were identified on the second of two point-prevalence surveys that took place at the end of a two-week lockdown of the municipality of Vò, Italy: case 1 had exposure to 4 infected relatives who did not have any symptoms at the time of contact; case 2 had a meeting with an asymptomatic case before the lockdown; case 3 shared
COVID-19 –What We Know So Far About...Asymptomatic Infection and Asymptomatic Transmission 7 the same flat with two asymptomatic relatives. The authors noted that all the asymptomatic individuals never developed symptoms during the two-week lockdown.4VIROLOGICAL EVIDENCE FOR ASYMPTOMATIC TRANSMISSION Several studies reported high viral loads in asymptomatic individuals as measured by real-time RT-PCR. Arons MM et al.37 cultured the real time RT-PCR-positive specimens from two point-prevalence surveys in a skilled nursing facility as part of an outbreak investigation, as described in Kimball A et al.6 above. Viral growth was observed for 13/20 symptomatic residents, 17/24 presymptomatic residents, 1/3 asymptomatic residents. Viable virus was isolated from 6 days before to 9 days after symptom onset. In addition, high viral RNA loads were detected in all groups with median cycle threshold values at 24.8 in those with typical symptoms and 25.5 for those who were asymptomatic. This suggests the potential for substantial viral shedding in asymptomatic cases. No correlation was observed between cycle threshold values and time from symptom onset.37Zou L et al. noted that an asymptomatic individual had similar viral loads from nasal and throat swabs compared to 17 symptomatic individuals.38Roxby AC et al. noted that the viral load in 3 generally asymptomatic residents (one developed a mild cough) of an independent living community were similar to those reported among ill hospitalized patients.16Kam K et al. noted a high viral load in a nasopharyngeal specimen from a generally well baby. Nasopharyngeal specimens were positive for 16 days and one stool specimen was also positive.39Hoehl S et al. observed COVID-19 virus in cell culture in throat specimens from two repatriated passengers who tested positive by RT-PCR. One patient developed slight rash and minimal pharyngitis the day after testing but both persons remained well and afebrile during the 7 days after hospital isolation.28Cereda D et al. noted that the median viral RNA levels in nasal swabs were not statistically different between 295 symptomatic and 17 asymptomatic obstetric cases: 5.0 log10 RNA copies/mL (range 1.7-10.1) vs 4.7 log10 copies/mL (range 2.1-7.1), (P=.51).22Transmission During the Incubation Period There is both epidemiological and virological evidence, as well as inferences from modelling and statistical analysis, that point to transmission from people prior to their symptom onset. EPIDEMIOLOGICAL EVIDENCE FOR PRESYMPTOMATIC TRANSMISSION Several studies describe potential transmission prior to symptom onset, i.e., in the incubation period. In most instances, the contacts who acquired the infection reported no other known sources of exposure other than a case who was in their incubation or early symptomatic period. Hijnen D et al. reported an outbreak amongst at least 11/13 attendees (one attendee was not tested) from seven countries at a 2-day conference in Munich, Germany in February, when under 20 cases of COVID-19 had been diagnosed in the country. The index patient (a physician
COVID-19 –What We Know So Far About...Asymptomatic Infection and Asymptomatic Transmission 8 was believed to have been infected when examining a patient in Italy two days before the start of the conference) developed symptoms only after he had left the conference.2Rothe C et al. reported an outbreak in Germany resulting from a business meeting in late January.40Böhmer MM et al. reconstructed the transmission events with epidemiological findings and whole genome sequencing of 13 of the 16 subsequent cases.41 The index case was a Chinese resident from Shanghai who had had contact with her parents from Wuhan before visiting Germany in January for work reasons. Presymptomatic transmission likely occurred from patient 4 (symptom onset on January 24) to patient 5, as patient 5 did not meet the index case but had encounters with patient 4 on January 22 when they sat back to back in the canteen and patient 5 turned to ask patient 4 to borrow the salt shaker from their table. Böhmer MM et al.noted that presymptomatic transmission is strongly supported by virus sequence analysis. In addition, presymptomatic transmission could possibly have occurred for 5 more cases.41Jang S et al. reported on the active surveillance results of a COVID-19 cluster associated with fitness dance classes. On February 15, 2020, a 4-hour workshop for 27 fitness instructors took place in Cheonan, South Korea (approximately 200 km from Daegu where an outbreak was emerging). After discovering cases in Cheonan linked to fitness dance classes, the workshop was investigated. Eight of the 27 instructors at the workshop were found to be infected with SARS-CoV-2. One of these instructors was from Daegu, and therefore was the presumed source case for the outbreak, and developed symptoms on February 18, 2020, three days after the workshop.23Cheng HY et al. conducted a prospective study that enrolled all the initial 100 confirmed cases in Taiwan from January 15 to March 18, 2020 and their 2,761 close contacts. All close contacts were quarantined at home for 14 days after their last exposure to the index case, and any typical symptoms triggered testing. High-risk contacts (e.g., household and hospital contacts) were tested regardless of symptoms. No secondary clinical cases were detected from all 91 close contacts of the 9 asymptomatic patients. Cheng et al. identified 22 secondary cases, 18 of whom had symptoms. They determined a secondary clinical infection risk of 0.7% (95% confidence interval (CI): 0.4% - 1.0%) among 2,761 close contacts. For the 299 contacts with exclusive presymptomatic exposures to the index case, the secondary clinical attack rate was 0.7% (95% CI, 0.2%-2.4%). The authors noted that the actual contribution of early transmission could be greater as they did not completely identify contacts before symptom onset of the index cases.42Wei WE et al. reviewed the clinical and epidemiological records of all 243 cases in Singapore to determine whether presymptomatic transmission might have occurred. Of these cases, 157 were locally acquired with 10 (6.4%) attributed to presymptomatic transmission within 7 clusters, where investigation did not identify any other potential sources of infection. The authors noted that although an unknown source might have caused some of these infections, given that COVID-19 prevalence was very low during the period under investigation and strong surveillance systems were in place, presymptomatic transmission was deemed the most likely mode of transmission. The authors also note that recall bias related the onset date of symptoms might add uncertainty to the duration of the presymptomatic period.43Multiple authors also reported clusters of infections in China where the transmission histories suggest the occurrence of presymptomatic transmission. It should be noted that due to circulation of COVID-19 in China during that time, it is possible that there was another unrecognized source of infection, in addition to the cases reported.