Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

Manifestations of COVID-19, an illness caused by infection of SARS-CoV-2, are highly varied. The spectrum of cases may include asymptomatic COVID-19 patients, who do not manifest with any signs and symptoms but are confirmed positive by viral nucleic acid tests (RT-PCR). Asymptomatic cases may be carriers of the disease.1

Pre-symptomatic cases refer to individuals who are in their incubation period, which is the interval between exposure to the virus and symptom onset. The incubation period for COVID-19 is between 5-6 days on the average but may be up to 14 days. Hence pre-symptomatic cases do not exhibit symptoms yet but would eventually develop symptoms.1

The true prevalence of asymptomatic and pre- symptomatic infections is unknown. Based on a retrospective review of 2,143 pediatric patients with COVID-19, asymptomatic infections were at 13%.2 The estimated asymptomatic proportion among all infected cases on the

Diamond Princess Cruise ship was 17.9% (95%CrI: 15.5– 20.2%) but this may be underreported due to testing priority given to symptomatic patients.3 A review on the prevalence of asymptomatic infections reported it may be as high as 40% to 45% based on 3 cohorts with representative sample in Iceland, USA and Italy.4 In the Philippines, as of June 2020, only 586 (2.8%) of the 20,990 active cases were classified as asymptomatic. It is not clear, however, if these cases are carriers (asymptomatic) or still in the incubation period of the disease (pre-symptomatic).5

The true burden of COVID-19 remains underestimated because both asymptomatic and pre-symptomatic patients may not seek healthcare and are not routinely tested unless they are part of a high-risk group. In addition, the extent and magnitude of transmission from asymptomatic COVID-19 patients and patients in their pre-symptomatic period are uncertain. Asymptomatic and pre-asymptomatic transmission can be an important but neglected area for epidemic prevention.6

This rapid review summarized the available evidence on asymptomatic and pre-symptomatic transmission of COVID-19.

METHODS

An electronic search of Medline, Central and Google scholar was done for published and unpublished studies on asymptomatic or pre-symptomatic transmission of SARS- CoV-2.We also searched for ongoing trials from Clinicaltrials. gov and the Chinese Clinical Trial Registry. The reference lists of retrieved articles were also checked for additional studies. The search terms used included asymptomatic transmission, asymptomatic carrier, COVID-19, SARS- CoV-2 in MeSH and free text. The search strategy is summarized in Appendix 1.

Screening and selection of studies were done by two independent reviewers based on the following inclusion criteria:

•Population: COVID-19 patients of any age, with any co-morbidities, any severity

•Exposure: asymptomatic transmission, pre-symptomatic transmission

•Outcomes: COVID-19 infection, viral shedding

•Study designs: observational studies (e.g. cohort, case- control, cross-sectional, case report, case series)

The quality of the included studies was assessed by two reviewers. The Newcastle-Ottawa scale was used for cohort studies and is detailed in Appendix 2. Any disagreements were resolved by a third reviewer.

The following data were extracted from the included studies: title, author, study design, country, population and key findings.

RESULTS

Characteristics of Included Studies

Forty-eight studies were included in the review composed of 39 observational studies (4 case reports, 27 case series, 1 cross-sectional study, 3 retrospective single cohorts, 4 prospective cohorts) and 9 statistical modeling analysis. The observational studies included 15 studies on pre-symptomatic transmission, 11 studies on transmission from an asymptomatic index case, 2 studies on both pre- symptomatic and asymptomatic transmission and 11 studies on viral shedding. These studies involved reports from China, Japan, Singapore, Vietnam, USA, Germany, South Korea, Brunei, Vietnam, India, Italy and Taiwan. Case reports and case series were from contact tracing of known COVID-19 patients. COVID-19 was confirmed via RT-PCR testing in all studies.Description of the included studies are summarized in Appendix 3.

Pre-symptomatic Transmission (15 studies)

A study done in Singapore investigated all COVID-19 cases in the country from January 23 to March 16, 2020. A total of 243 cases, 157 of which were locally acquired, were reviewed to determine if pre-symptomatic transmission occurred. Seven clusters with two to five patients each were identified in which pre-symptomatic transmission may have occurred. Ten cases (4.1%) from these clusters were attributed to pre-symptomatic transmission. These cases also accounted for 6.4% of all locally acquired cases. In four clusters, pre-symptomatic transmission occurred 1-3 days before symptom onset of the index case. However, the exact exposure could not be determined for the rest of the clusters due to continuous exposure to the index case.7

A study in China on a cluster of young people (aged 16 to 23 years old) in January 2020 reported 7 COVID-19 cases (31.8%) from 22 close contacts of a 22-year-old male from Wuhan. One of the close contacts that tested positive was a cousin he met 3 days before symptom onset. He also attended a 2-hour get-together with 15 previous classmates a day before he presented with symptoms. Six of the 15 young people were positive for COVID-19 with an attack rate of 40%. Transmission by the primary case occurred 1-3 days before onset of symptoms with duration of contact of 1-7 hours. The median incubation period of secondary cases was 2 days. Median serial interval was 1 day with 2 patients developing symptoms on the same day as the index case.8 A family cluster from India involving a family of four with a history of travel to Saudi Arabia. These 4 index cases transmitted the infection to 26 of 43 (60%) family members they had close contact with during the pre-symptomatic period of 6 days.9 In a group involving 4 clusters in China, infection was transmitted from one cluster to another during the pre-symptomatic periods of each infected case ranging from 2-9 days before symptom onset.10

Eleven other different cluster studies in separate publications (9 in China, 1 in Taiwan, 1 in Germany) of COVID-19 cases from January to February 2020 reported possible pre-symptomatic transmission because exposure of secondary COVID-19 cases to the index case happened prior to the index patient’s symptom onset. 11-21  Index cases of these studies had history of travel to Wuhan except for three clusters with travel to cities outside Wuhan12,19-20 and travel of a Shanghai resident to Germany.18 One to seven secondary cases were documented per cluster. Transmission of the infection by pre-symptomatic index case were documented in all 11 clusters. The shortest interval between close contact with the index case prior to symptom onset of index case was 1-2 days13,18 while the longest interval was 12- 14 days.11 Exposure of the other clusters was also reported before symptom onset, but it was difficult to determine exact timing of disease transmission because of continued exposure of household contacts. No computed transmission rates were reported in the 10 studies and only 5 studies reported COVID-19 negative contacts within their clusters.12,14,19-21 Apart from the index case, patients from all clusters did not have travel to Wuhan and had no other known potential exposure to COVID-19.11-21

Asymptomatic Transmission (11 observational studies and 2 statistical models)

Five case series in China suggested that asymptomatic COVID-19 cases or carriers may transmit the virus. Each study reported 2-6 symptomatic COVID-19 secondary cases who were exposed to asymptomatic index cases.22-26 The primary case or index case tested positive for COVID-19 but remained asymptomatic with normal CT scan findings.22,24-26 One study was not able to identify an index case suggesting an asymptomatic carrier may have transmitted the virus.23 Only the study of Bai et al., reported an incubation period of 4-13 days.25 The clusters did not identify any other possible source of COVID-19 infection and presumed asymptomatic COVID-19 cases with travel to Hubei as the primary source of infection.22-26 In Brunei, local asymptomatic transmission associated with a religious super-spreader event in Malaysia was documented in two clusters (1 household cluster and 1 school cluster). The index case of both clusters remained asymptomatic. In the household cluster, 3 of the 7 household contacts of the index case tested positive for SARS-CoV-2 with attack rate of 25.7%. Only 1 of 29 school contacts in the school cluster tested positive for SARS-CoV-2 with attack rate of 3.4%. Exposure to the index case ranged from 9-10 days in both clusters.27

A study by Chen et al. reported surveillance data from January 20 to March 6, 2020 in Ningbo City, China out of 191 cases identified, 30 (15.7%) were asymptomatic. For the asymptomatic cases, six out of the 146 (4.11%) close contacts tested positive for SARS-CoV-2 while for symptomatic cases 126 out of 2001 close contacts (6.3%) tested positive. There was no significant difference between the two groups

for the risk of infection (p = 0.288). Exclusion of index cases with very high transmission rates also showed no significant difference in the transmission rates of the symptomatic and asymptomatic cases (p = 0.84). Timing of contact with symptomatic cases to determine if pre-symptomatic transmission occurred was not investigated.28-29 This data was used to quantify transmissibility of asymptomatic cases by calculating the reproduction number (R0) and estimating the probability of transmission per contact (ρ) based on the SEIR model. The risk ratio (RR) of the infectivity (R0) of the symptomatic group versus that of the asymptomatic group was 3.9 (95% CI:1.5-11.8) while the RR of ρ was estimated at 1.5 (95% CI: 0.7-3.4).These results show that symptomatic cases were likely more infectious than asymptomatic cases.30

Of the 279 COVID-positive contacts of COVID-19 cases identified in Chongqing, China between January to March 2020, sixty three (23%) were asymptomatic. Among the asymptomatic cases, there were 18 cases of familial clustering in which 9 cases transmitted the virus to others.31 On the other hand, in a cluster of 1,143 individuals tested in a building in South Korea, 97 COVID-19 cases were identified with four (4.1%) pre-symptomatic cases and four (4.1%) asymptomatic cases. Symptomatic cases had a household secondary attack rate of 16.2% but the exact timing of exposure was not reported. However, there were no documented transmission from pre-symptomatic and asymptomatic cases.32 An asymptomatic case admitted at an emergency department in China and another asymptomatic case that underwent an orthopedic surgery in Missouri, USA had no documented transmission to 455 contacts and 11 contacts respectively. 33-34

Pre-symptomatic and Asymptomatic Transmission within cluster (2 studies)

One study reported on pre-symptomatic and asymptomatic transmission within the same cluster. In a cluster of three families in China, a pre-symptomatic patient had 88 close contacts from which two contacts (2.27%) became positive for SARS-CoV-2. One of which was his mother-in-law who remained asymptomatic. She had 73 close contacts and only her son (1.37%) became infected with SARS-CoV-2.35 In a study in Vo, Italy, 29 of 2,343 people tested were positive for SARS-CoV-2 with 13 asymptomatic cases. Extensive contact tracing showed that exposure to asymptomatic COVID-19 individuals was reported in 4 of 8 newly identified cases. Pre-symptomatic transmission was also reported in a family cluster where an index case transmitted the disease to 3 family members living in the same household and 4 family members in a gathering four days prior to onset of symptoms.36

Viral Shedding in Asymptomatic cases (11 studies)

Although asymptomatic transmission was not documented in 4 case series, SARS-CoV-2 was detected with RT-PCR low cycle thresholds in the nasopharyngeal

and/or throat swabs of asymptomatic cases which suggests the potential of these patients to transmit the virus.37-40 A study on an asymptomatic COVID-19 infant identified in Singapore showed high viral load.38 A study in Vietnam identified an asymptomatic COVID-19 positive patient that demonstrated viral shedding up to 9 days after initial exposure.39

A nursing facility in Washington, USA reported that 23 residents were positive for COVID-19 of which 10 (43%) were pre-symptomatic and 3 (13%) were asymptomatic. There was no significant difference (p = 0.3) in the real- time RT-PCR cycle threshold (Ct) values among residents with positive test results among the four symptom groups: symptomatic with atypical symptoms, typical symptoms, pre- symptomatic and asymptomatic.41 A follow-up surveillance conducted after one week (March 19-20, 2020) revealed that of the 89 residents in the facility, 48 tested positive of which 17 (35%) had typical symptoms, 4 (8%) had atypical symptoms, and 27 (56%) had no new symptoms. Eighty nine percent (24/27) who were initially asymptomatic developed symptoms within the next 7 days (median 4 days, IQR 3-5 days) and were reclassified as pre-symptomatic. The median RT-PCR cycle threshold (Ct) values for the four symptom status groups were similar (asymptomatic residents, 25.5; pre-symptomatic residents, 23.1; residents with atypical symptoms, 24.2; and residents with typical symptoms, 24.8). Viral growth was observed for specimens obtained from 62.5% (10/16) of residents with typical symptoms, 75% (3/4) with atypical symptoms, 71% (17/24) of pre-symptomatic residents, and 33% (1/3) of asymptomatic residents. Viable virus was isolated from specimens collected 6 days before to 9 days after symptom onset. The transmission of infection from asymptomatic and pre-symptomatic residents was not quantified but evidence suggests potential for substantial viral shedding.42

In contrast, a study in China among 31 virologically- confirmed COVID-19 patients included 22 (71%) pre- symptomatic cases and 9 (29%) asymptomatic cases. The cycle threshold (Ct) values for asymptomatic patients (39.0, IQR 37.5-39.5) was significantly higher than those of pre-symptomatic patients (34.5, IQR 32.2-37.0), which indicated a lower viral load in asymptomatic patients.43 A study of 71 hospitalized patients in South Korea reported very high viral titers (Ct value <20) in two of the three pre-symptomatic patients, which suggest infectious state even without symptoms.44 In Vietnam, a study among 30 confirmed COVID-19 patients which included 17 (57%) mildly symptomatic cases and 13 asymptomatic cases reported viral detection in nasopharyngeal swab (NPS) samples on enrollment were more likely in the symptomatic group (62% in asymptomatic vs 100% in symptomatic, p = 0.02). Among those who tested positive on enrollment, viral loads were similar in symptomatic and asymptomatic patients (p = 0.223). During follow-up, asymptomatic patients were found to have lower viral loads than symptomatic patients

(p = 0.027 for difference over first 19 days) and were less likely to test positive for the RT-PCR test (p < 0.001 for difference over first 19 days) with the difference most pronounced during the first week of follow-up. Asymptomatic transmission to up to four people was documented in 2 cases.45

In a cohort of 199 COVID-19 patients in a residential treatment center in South Korea with 53 asymptomatic cases (26.6%), the duration of viral shedding was significantly longer for symptomatic patients compared to asymptomatic patients (25.2 days versus 22.6 days, p < 0.01).46 Comparing asymptomatic and pre-symptomatic groups, the duration of viral shedding was similar (7 days IQR 5-14 vs. 8 days IQR 5-16) which suggests the possibility of disease transmission during the asymptomatic period.47

SARS-CoV-2 was also detected on anal swab of an asymptomatic 8-year-old girl with exposure to her father who was a confirmed COVID-19 case. She had negative nasopharyngeal results but was positive for SARS-CoV-2 on anal swab for 42 days (February 9 – March 31, 2020). It is unknown whether asymptomatic patients positive on anal swab only can transmit the infection but her mother, with whom she had constant close contact with never became infected.48

Serial interval from modelling studies (7 studies)

From four modelling studies conducted in China, Japan, Germany, Singapore and Brunei, the estimated mean serial interval from onset of symptoms of the index case to onset of symptoms of the secondary case were shorter than the reported incubation period of 5-9 days which suggest pre- symptomatic transmission may occur. 49-52 Negative serial interval was documented by Du et al. and Wong et al. in 59 of 468 reports (12.6%) and 6 of 53 reports (11.3%) respectively suggesting the possibility of asymptomatic transmission.50,52 The estimated pre-symptomatic transmission rate was

37% (95% CI: 16-52%) for South Korea, 48% (95% CI:

32-67%) for Singapore and 62% (95% CI: 50-76) for Tianjin, China.53-54

Critical Appraisal

Available evidence included 4 case reports, 27 case series and 7 cohort studies with small sample size. Because studies were contact tracing from known COVID-19 patients, the studies were retrospective in nature, hence it was difficult to ascertain exposure and duration of exposure with index case prior to symptom development. Studies were also prone to recall bias especially in the older population with comorbid conditions since it was heavily dependent on patients’ recollection of events. It is also uncertain if all contacts of the index case were identified on contact tracing and other unidentified contacts may have been responsible for other clusters of infection.The variations in contact tracing schemes and isolation measures among different countries may have influenced the rate of transmission reported. Mass testing and stringent isolation measures in South Korea may have

decreased the transmission of infection from asymptomatic and pre-symptomatic individuals.32 The cohort studies were appraised using the Newcastle-Ottawa scale and were of poor quality. In some cohorts, testing was done among the older population hence results may not apply to the general population (Appendix 4).

In one Chinese study, the risk ratio for infectivity and probability of transmission was higher for symptomatic cases compared to asymptomatic cases, however the results were imprecise due to a wide confidence interval.The symptomatic cases had 1.6-fold higher close contacts per index case compared to the asymptomatic cases.30

Although the modelling studies had larger sample size, these estimates may be affected by healthcare systems, recall bias, travel-related delays in transmission and other unaccounted possible sources of transmission. Serial interval estimates may also vary as the outbreak progresses.

Ongoing studies

There are seven ongoing clinical trials on asymptomatic transmission of COVID-19 being conducted in the USA, UK, Norway, France, Hong Kong and China. The studies are mostly observational cohorts of asymptomatic healthy individuals with known COVID-19 patient contacts who are followed up for development of COVID-19 infections. There are three studies which include healthcare workers. There are two trials which already completed recruitment, but results are not yet available. For the other trials, results are expected between June 2020 to March 2022. The details of the clinical trials are presented in Appendix 4.

Recommendations from other guidelines

The CDC and WHO report that current evidence has documented COVID-19 pre-symptomatic transmission in the incubation period. Asymptomatic transmission of carriers was suggested by reports. The risk of transmission of symptomatic cases is still believed to be highest on symptom onset when viral shedding is highest. WHO, however, maintains that most transmission occurs from close contact with symptomatic cases and reports suggest asymptomatic cases are less likely to transmit the virus than those with symptoms. However, transmission rate of pre-symptomatic or asymptomatic cases compared to symptomatic cases is unclear.1,55-56

CONCLUSION

Asymptomatic and pre-symptomatic transmission of SARS-CoV-2 may occur.Studies that compared the viral load of pre-symptomatic, asymptomatic and symptomatic cases reported contradicting results. The duration of viral shedding was significantly longer for symptomatic patients compared to asymptomatic patients but similar for asymptomatic and pre-symptomatic patients. The transmission rate of pre-symptomatic or asymptomatic cases compared to

symptomatic cases is unclear with conflicting results reported by different studies. Hence, more high quality studies are needed to validate these findings and determine the extent of asymptomatic and pre-symptomatic transmission.

Declaration of conflict of interest

No conflict of interest.

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Key findings

The index case presented with fever and myalgia 5 days after her arrival from China. At the same time, her husband presented with rhinorrhea and both sought medical consult. Both tested positive for COVID-19. The study suggests transmission of the disease while the index case was asymptomatic.

Patient 1 (Index case): 52/F, travelled from Wuhan, China, had fever and myalgia on Jan 25

Patient 2: 50/M, husband of index case, had contact with index case on Jan 21, 4 days before index case had symptoms, presented with rhinorrhea on Jan 25