Evidence Supporting Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 While Presymptomatic or Asymptomatic

Recent epidemiologic, virologic, and modeling reports support the possibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission from persons who are presymptomatic (SARS-CoV-2 detected before symptom onset) or asymptomatic (SARS-CoV-2 detected but symptoms never develop). SARS-CoV-2 transmission in the absence of symptoms reinforces the value of measures that prevent the spread of SARS-CoV-2 by infected persons who may not exhibit illness despite being infectious. Critical knowledge gaps include the relative incidence of asymptomatic and symptomatic SARS-CoV-2 infection, the public health interventions that prevent asymptomatic transmission, and the question of whether asymptomatic SARS-CoV-2 infection confers protective immunity.

DOI: https://doi.org/10.3201/eid2607.201595 Recent epidemiologic, virologic, and modeling reports support the possibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission from persons who are presymptomatic (SARS-CoV-2 detected before symptom onset) or asymptomatic (SARS-CoV-2 detected but symptoms never develop). SARS-CoV-2 transmission in the absence of symptoms reinforces the value of measures that prevent the spread of SARS-CoV-2 by infected persons who may not exhibit illness despite being infectious. Critical knowledge gaps include the relative incidence of asymptomatic and symptomatic SARS-CoV-2 infection, the public health interventions that prevent asymptomatic transmission, and the question of whether asymptomatic SARS-CoV-2 infection confers protective immunity. outbreak, when transmission in the community may have been undetected.
However, cases of presymptomatic transmission have been reported from other countries before widespread community transmission occurred. A report from Germany documented infection of a German businessman after exposure to a mildly symptomatic colleague visiting from China (18). Before becoming symptomatic, this businessman exposed 2 other colleagues who subsequently received a COVID-19 diagnosis but did not have contact with the primary patient from China or any other known source. A report from Singapore described 7 COVID-19 clusters resulting from presymptomatic transmission; presymptomatic primary patients varied from persons with travel from high-incidence countries to persons exposed in the local community (19). All primary patients experienced distinct periods of initial exposure and presymptomatic close contact with secondary patients who had no other known exposure risks. The incubation periods for presymptomatic primary patients with distinct exposures ranged from 3 to 11 days; for presymptomatic primary patients with travel history to an area with active transmission, the time from last exposure to symptom onset ranged from >2 to >9 days.

Virologic Evidence
Currently, SARS-CoV-2 infection is primarily diagnosed by detection of viral RNA via reverse transcription PCR (RT-PCR) or by viral culture and demonstration of cytopathic effect (20). Although RT-PCR identifies viral RNA and cannot determine whether infectious virus is present, infectiousness can be in-ferred from cycle threshold (C t ) values. The RT-PCR C t value represents the number of PCR cycles required to detect SARS-CoV-2 RNA; lower values indicate higher viral load and imply higher infectiousness (20)(21)(22). The exact RT-PCR C t values associated with the presence of infectious SARS-CoV-2 is unknown, but infectious virus has been isolated from a specimen with an RT-PCR C t of 34 (23).
Four reports documented the presence of SARS-CoV-2 RNA with lower C t values in samples collected from persons in whom symptoms of COVID-19 never developed (24-27) ( Table 2). Two reports described specimens with low RT-PCR C t values among presymptomatic and asymptomatic residents of a nursing home identified as part of the same outbreak investigation (23,28). Among these reports, RT-PCR C t values for SARS-CoV-2 RNA in asymptomatically infected persons ranged from 14 to 40 (23)(24)(25)(26)(27). The study with data on presymptomatic infected patients reported an average RT-PCR C t value of 24 (range 15-38) (23). Two reports described culture of infectious virus from persons with asymptomatic (24) and presymptomatic (23) SARS-CoV-2 infection. Although these reports did not identify actual virus transmission while presymptomatic or asymptomatic, the low RT-PCR C t values (i.e., high viral load) and ability to isolate infectious SARS-CoV-2 provide plausible virologic evidence for SARS-CoV-2 transmission by persons not demonstrating symptoms.

Modeling Evidence
Two studies used models to estimate the serial interval (time between symptom onset in a primary patient and the secondary patient) (29,30) (Table 3).
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 7, July 2020 e3 They estimated the serial interval of COVID-19 to be 4 days, which is shorter than the estimated median incubation period for COVID-19 of 5 days (31). One report suggested that up to 13% of infections may be transmitted during the presymptomatic period of illness (29). These studies relied on reports of primary and secondary cases and may be limited by recall bias; secondary patients are more likely to remember proximal exposures, biasing results toward a shorter serial interval. Two models attempted to estimate the number of infections caused by asymptomatic, presymptomatic, or mildly symptomatic infected persons (30,32). These models varied widely; 1 model suggested that up to half of infections were transmitted from infected persons who were presymptomatic (33), and another suggested that up to four fifths of infections were transmitted by persons with no symptoms or mild symptoms (32). Both models suggested that a large number of persons with asymptomatic or mildly symptomatic infections were not detected by the health system and that these persons meaningfully contributed to ongoing community transmission (32,33). Although models are highly dependent on the assumptions built into them, these models suggest that the speed and extent of SARS-CoV-2 transmission cannot be accounted for solely by transmission from symptomatic persons.
Each of the epidemiologic, virologic, and modeling studies described has limitations. However, in the aggregate, these diverse studies suggest that SARS-CoV-2 can be transmitted by persons with presymptomatic or asymptomatic infection, which may meaningfully contribute to the propagation of the COVID-19 pandemic. This literature summation was conducted to support changes in CDC recommendations to reduce the risk for asymptomatic transmission and was not a systematic review. These conclusions are drawn from the literature available at the time and may change, given the rapidly evolving nature of the evidence base for asymptomatic transmission.

Public Health Implications of Transmission While Asymptomatic
The existence of persons with asymptomatic SARS-CoV-2 infection who are capable of transmitting the virus to others has several implications. First, the case-fatality rate for COVID-19 may be lower than currently estimated ratios if asymptomatic SARS-CoV-2 infections are included (34,35). Second, transmission while asymptomatic reinforces the value of community interventions to slow the transmission of COVID-19. Knowing that asymptomatic transmission was a possibility, CDC recommended key interventions including physical distancing (36), use of cloth face coverings in public (37), and universal masking in healthcare facilities (38) to prevent SARS-CoV-2 transmission by asymptomatic and symptomatic persons with SARS-CoV-2 infection. Third, asymptomatic transmission enhances the need to scale up the capacity for widespread testing and thorough contact tracing to detect asymptomatic infections, interrupt undetected transmission chains, and further bend the curve downward.

Science Questions to Inform Public Health Action
The existence of SARS-CoV-2 transmission while infected persons are presymptomatic and asymptomatic raises 3 key questions that need to be answered to inform public health action. First, the incidence of asymptomatic compared with symptomatic SARS-e4 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 7, July 2020 Data limited to reports of confirmed cases early in the outbreak; recall bias may attribute infection to recent exposures and falsely lower the serial interval. (30) Published articles and case investigation reports.
The median serial interval was 4-5 d, depending on the reports analyzed.
Recall bias may attribute infection to recent exposures and falsely lower the serial interval. (32) Spatiotemporal data and reports on infections of 375 persons during Spring Festival, China An estimated 86% of all infections were asymptomatic or mild and not reported; up to 79% of reported cases may have originated from these unreported asymptomatic or mild cases.
Data limited to China early in the outbreak; several assumptions built into a complex model. On the basis of generation times and serial intervals, the authors estimated that one third to one half of transmission occurred from presymptomatic persons.
Data limited for reports of confirmed cases early in the outbreak; recall bias may attribute infection to recent exposures and falsely lower the serial interval.
CoV-2 infection needs to be determined. The extent of presymptomatic or asymptomatic SARS-CoV-2 infection may be clarified by studies using serial virologic data, serologic data, or a combination of both in observational cohorts or surveillance systems. If a substantial proportion of infections are asymptomatic, enhanced testing strategies may be needed to detect these persons. Second, given that a large proportion of infections probably result from transmission from asymptomatic or presymptomatic persons (32,33,39), the effectiveness of public health interventions aimed at reducing their infectiousness needs to be quantified. If the COVID-19 pandemic is found to be driven by undetected asymptomatic or mildly symptomatic SARS-CoV-2 infections, new innovations in disease detection and prevention (beyond exhaustive contact tracing, mass testing, and isolation of asymptomatic contacts) may be needed. Last, knowledge of SARS-CoV-2 immunity among persons with asymptomatic or mild SARS-CoV-2 infection is needed; specifically, whether full or partial immunity develops in these persons, how long protective immunity lasts, and if it is possible to be immune from reinfection but still asymptomatically transmit SARS-CoV-2 while in a carrier state. This information will be crucial for projecting the anticipated course of the pandemic and the potential for SARS-CoV-2 resurgence if immunity wanes (40). Information about immunity is also valuable for healthcare and other critical infrastructure workers for whom rates of exposure, and thereby asymptomatic infection, may be higher and who therefore warrant data-informed guidance on how to safely return to work. The answers to these questions will be crucial for guiding the gradual relaxing of community interventions, resuming the normal functions of society, and recovering from the COVID-19 pandemic.

About the Author
Dr. Furukawa is a CDC Epidemic Intelligence Service Officer in the CDC National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, working on the CDC COVID-19 response clinical team. His research interests include HIV, sexually transmitted diseases, tuberculosis, hepatitis, and Ebola.