key: cord-0962048-1shd9vt5
authors: Almadhi, Marwa Ali; Abdulrahman, Abdulkarim; Sharaf, Sayed Ali; AlSaad, Dana; Stevenson, Nigel J.; Atkin, Stephen L.; AlQahtani, Manaf M.
title: The high prevalence of asymptomatic SARS-CoV-2 infection reveals the silent spread of COVID-19
date: 2021-02-26
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.02.100
sha: c62c00e44be858dd71dc58520a66777c9c52220a
doc_id: 962048
cord_uid: 1shd9vt5

Purpose The COVID-19 pandemic has led to over 92 million cases and 1.9 million deaths worldwide since its outbreak. Public health responses have focused on identifying symptomatic individuals to halt spread. However, evidence is accruing that asymptomatic individuals are infectious and contributing to this global pandemic. Methods Observational data of 320 index cases and their 1289 positive contacts from the National COVID-19 Database in Bahrain were used to analyse symptoms, infectivity rate and PCR Ct-values. Results No significant difference (p = 1.0) in proportions of symptomatic (n = 160; 50.0%) and asymptomatic index cases (n = 160; 50.0%) were seen; however, SARS-CoV-2 positive contact cases were predominantly asymptomatic (n = 1127, 87.4%). Individuals aged 0-19 constituted a larger proportion of positive contact cases (20.8%), than index cases (4.7%; p < 0.001). 22% of the positive contacts were infected by symptomatic male index cases aged between 30-39 years. The total number of exposed contacts (p = 0.33), infected contacts (p = 0.81) and hence infectivity rate (p = 0.72) were not different between symptomatic and asymptomatic index cases. PCR Ct-values were higher in asymptomatic compared to symptomatic index cases (p < 0.001), and higher in asymptomatic compared to symptomatic positive contacts (p < 0.001). No difference between the infectivity rates of index cases with Ct-values <30 and values ≥ 30 was observed (p = 0.13). Conclusion These data reveal that the high asymptomatic incidence of SARS-CoV-2 infection in Bahrain, and subsequent positive contacts from an index case are more likely to be asymptomatic showing the high “silent” risk of transmission and the need for comprehensive screening for each positive infection to help halt the ongoing pandemic.

SARS-CoV-2, the virus causing Coronavirus disease 2019 (COVID- 19) , has infected more than 92 million people and lead to the death of more than 1.9 million people worldwide since its outbreak in December 2019 (1). The disease has a wide range of presentations, from asymptomatic infection to fever, cough, shortness of breath and the loss of taste and smell.

Symptoms normally appear 2-14 days following exposure to the virus and may develop into mild upper respiratory tract infections or progress to severe pneumonia, which can progress to acute respiratory distress, shock, multi-organ failure and death (2, 3) .

The virus is thought to be mainly transmitted through person-to-person contact, with evidence that SARS-CoV-2 transmits through the inhalation of large droplets exhaled by infected individuals (4, 5). Interventions have been taken accordingly to identify, test and isolate infected people with the aim of containing the spread of the disease. To date, international testing has mostly been carried out on symptomatic patients seeking diagnosis.

However, whilst there is increased evidence of asymptomatic infections (6) (7) (8) (9) (10) , testing has been prioritized to the more "pressing" symptomatic individuals. This is not surprising, as early in the pandemic, identification COVID-19 was extremely dependent on symptomatic diagnosis and management of symptoms is an essential treatment of care. Indeed, both the World Health Organisation (WHO) and the Center for Disease Control and Prevention (CDC) issued guidance for the identification of COVID-19 based on symptoms (11) . In agreement with the classical belief that viral infection normally stimulates a symptomatic response in its host, the WHO commented that transmission of COVID-19 by asymptomatic individuals is "very rare" (12) , although this has now been retracted. The CDC estimates that 35% of COVID-19 cases are asymptomatic and 40% of transmission occurs before symptom onset (13) . These statements were supported by reports showing that transmission between J o u r n a l P r e -p r o o f the asymptomatic index cases and contact cases occurred mostly within households or during hospital visits (6) (7) (8) (9) . A recent study by Arons et al., describes a COVID-19 outbreak in a Washington nursing facility. After a symptomatic healthcare worker tested positive for the virus, a facility-wide SARS-CoV-2 screen was carried out, which showed over half (56%) of workers that tested positive for SARS-CoV-2 were asymptomatic, of which 71% had viable virus by culture (10) . This study demonstrates the need to take this reservoir of asymptomatic infections as a serious threat to the community spread of SARS-CoV-2.

Although reports of these silent transmitters are limited in number, models simulating the spread of infection through China show that undocumented asymptomatic cases contributed largely (14, 15) . These reports reveal that undocumented cases, most of which are asymptomatic, were overlooked when evaluating the magnitude of the pandemic. This means that infectivity and hence identification and management of these asymptomatic cases was consequently "missed", but appears to be vital in controlling the pandemic. However, since currently available data on asymptomatic transmission is scarce and geographically limited, there is much controversy surrounding its real impact. As a result, current public health guidelines are not adapted to asymptomatic transmission, but with predictions of an imminent second SARS-CoV-2 wave approaching, we must increase our understanding of this key factor in this ongoing global pandemic.

Bahrain has recorded over 26,000 confirmed COVID-19 cases at the time this paper was written. The kingdom has been praised for its response to the pandemic, implementing goldstandard testing, and contact tracing procedures to identify, test and quarantine all potential cases. As well as developing a vaccine and therapeutic cure, disease control depends on developing a better understanding of the viral infection and spread in our national and international populations. This study aimed to compare the differences in characteristics Biosystems (Foster City, CA) 7500 Fast Dx RealTime PCR Instrument. The assay followed the WHO protocol and measured the viral E gene. If the E gene was detected, the sample was subsequently analysed for the SARS-CoV-2 RdRP and N genes. When measuring the initial E gene a Cycle threshold (Ct) value of >40 was considered negative. All confirmed cases were immediately admitted to a government isolation and treatment facility irrespective of being symptomatic or asymptomatic and discharged after two consecutive negative PCR tests.

"Index cases" were defined as individuals with a confirmed SARS-CoV-2 infection that had transmitted the infection to at least 1 close contact. Symptomatic index cases were identified on their presentation to the medical services whilst asymptomatic index cases were identified by the program of community screening targeting close contacts, travelers and random testing in areas with outbreaks. Screening for close contacts was carried out by the contact tracing J o u r n a l P r e -p r o o f team to identify all close contacts of a positive index case and arrange testing and quarantine of the close contacts. Close contacts who tested positive are termed "Positive contacts".

These two samples (index cases and all their positive contacts) were compared based on demographics (gender, age group, nationality) and clinical features (symptomatic or asymptomatic). Symptomatic individuals were those that presented with symptoms at testing, or developed symptoms in the period prior to or on admission to isolation or treatment facilities. Asymptomatic individuals were individuals that had no symptoms at testing and did not develop symptoms up to their isolation or admission to health facilities. Symptom status was not followed up after isolation of cases because these cases were no longer a public health risk. 

A total of 320 randomly selected index cases, and their 1289 positive contacts, were included in this study and their demographic characteristics are presented in Table 1 . There were significantly more males amongst both index cases (74.1%, z=8.6, p<0.001) and positive contacts (69.2%, z= 13.8, p<0.001). Bahraini nationals represented a significant proportion of both the index cases sample (59.7%, z=3.5, p<0.001) and positive contacts sample (54.5%, z=3.3, p=0.0011). There was no difference in the proportion of symptomatic versus asymptomatic index cases (50%, z=0.0, p=1.0). However, asymptomatic presentation was significantly greater among the positive contacts (87.4%, z=26.9, p<0.001). The age group J o u r n a l P r e -p r o o f with the highest proportion of index cases (40.3%) and positive contacts (28.3%) was 30-39 years. The least common age group for index cases was 0-9 years (0.3%), and 60+ years for positive contacts (4.1%).

When conducting further analysis of age group distributions, the age groups 0-9 and 10-19

were merged to account for the small sample sizes. To visualize the overall infected cases and determine the transmission levels of each age group, we compared the percentage (Figure 2) .

Of all 1289 positive contacts, 656 (50.9%) were contacts of symptomatic index cases and 633 (49.1%) were contacts of asymptomatic index cases and the difference between the number of people infected by a symptomatic or asymptomatic index case did not differ (z=0.6, p=0.52),. The mean number of close contacts from symptomatic index cases was 12.4±1.2 contacts, which did not differ to the mean number of close contacts from asymptomatic index cases was 14.0±1.1 contacts (p=0.33).

The majority of positive contacts were asymptomatic (87.4%).

To evaluate the effect of the presence or absence of symptoms upon rate of infection, we compared the mean number of positive contacts infected by either symptomatic cases (4.1±0.5 infected/case) or asymptomatic index cases (4.0±0.3 infected/case). No association between clinical symptoms and the number of cases infected was observed (t=0.2, p=0.81).

Second, to adjust for number of exposed contacts, we calculated infectivity rates. Infectivity rate for each index case was calculated using total positive contacts as a proportion of all exposed contacts.

(%) = ℎ ℎ 100

The mean infectivity rate for symptomatic index cases was 39.3%±2.0% that did not differ to asymptomatic index cases was 38.3%+2.0% (p=0.72). 

These data showed that 320 index cases transmitted the infection to 1289 positive contacts and on average, each positive contact infected 4 individuals, showing the high infectivity and reflecting in the SARS-C0V-2 pandemic that has resulted. This study has shown that the risk of transmission by asymptomatic individuals may be higher than previously expected. In this study we selected a random sample of 320 index cases that had documented links to exposed J o u r n a l P r e -p r o o f contacts who tested positive. We found that asymptomatic individuals constituted a larger proportion of index cases than expected (50.0%). This finding was even greater amongst positive contacts (87.4%). This may be due to early diagnosis of close contacts. In Bahrain and during the pandemic all close contacts were identified, tested and quarantined within 48hrs. This has led to the detection of a significant number of positive contacts early during their infection course. Bahrain has been praised globally for the excellent response and infrastructure setup early during the pandemic to identify, test and isolate infected individuals. Contact tracing was rapidly and strictly implemented to control spread. In addition, random community testing allows identification of cases before they escalate and hence limit transmission. These measures have led to increased diagnosis of cases of asymptomatic infection and may explain these findings. Moreover, several studies have suggested that children are less likely to develop severe COVID-19, and more likely to be asymptomatic (16) (17) (18) . The significantly higher rates of children we observed amongst positive contacts compared to index cases may also be a contributor to this increased asymptomatic presentation amongst positive contacts. These data are higher than those that have been previously reported where that 30-40% of all COVID-19 infections were suggested to be asymptomatic (19) , with higher estimates being suggested (15) , whilst in a cruise ship outbreak it was estimated that 81% of COVID-19 may be asymptomatic (20) ; however, the data are in accord with our previous data on international arrivals into Bahrain where asymptomatic patients were greater than those that were symptomatic (21) . In addition, a recent study using a model to assess SARS-CoV-2 transmission showed that asymptomatic transmission may account for at least 50% of all SARS-CoV-2 infections. Our results support these projections, in that 50% of index cases (i.e transmitters) in our sample were asymptomatic (22) .

Our data also showed a higher proportion of positive contacts aged 0-19 than index cases. This is consistent with reports from several studies, stating that transmission from children is less common than from adults (23, 24) . In addition, a recent prospective cohort study also showed lower rates of ages 0-17 amongst index cases compared to positive contacts (25) .

With current public health measures in Bahrain comprising the suspension of face-to-face teaching at schools and closures of youth socializing spaces, restaurants, cinemas and arcades, young people are more likely to remain at home and less likely to transmit in the community. This may clarify why this age group is over-represented in positive contacts compared to index cases; however, this study does not quantify transmission or infectivity by we believe these results are most likely due to behavioral tendencies as susceptibility of this age group to infection is extensively documented (28) (29) (30) .

We found no difference in numbers of symptomatic and asymptomatic index cases and their respective infectivity rates. We believe this shows that asymptomatic individuals play a larger role in the spread of the disease, and hence impose a higher public health risk, than currently believed. In addition, we found no significant difference in the numbers of contacts infected by a symptomatic and asymptomatic index cases. One hypothesis is that symptomatic individuals are more cautious and aware of the probability of being COVID-19 positive, and hence take precautions to reduce the transmission from what it would normally be for a symptomatic index case (31) . Simultaneously, asymptomatic individuals would be unaware of asymptomatic transmission, and hence interact normally with others and spread the disease. However, if this were the case and similarities in findings were entirely behavioral, then we would be expected to observe a larger average number of exposed contacts for asymptomatic index cases than symptomatic; however, this was not seen and we observed no difference in average exposed contacts or positive contact between symptomatic and asymptomatic index cases. This study suggests that globally asymptomatic transmission should be addressed imperatively in addition to that of symptomatic transmission.

It has been widely adopted that viral load can be quantified as an inverse relation to PCR Ct values (32, 33) , and this hypothesis has been applied in this study. Current identification measures of positive contacts are prioritized by symptomatic rather than asymptomatic patients, because until the SARS-CoV-2 outbreak asymptomatic infection and transmission was believed to be unlikely (12) . However, our results show that symptomatic presentation of COVID-19 may not be the only contributor to its spread. Indeed, temperature and symptom-based detection are not effective at surveilling asymptomatic individuals for COVID-19. The magnitude of asymptomatic transmission revealed in this study may explain the difficulty experienced worldwide in controlling the pandemic.

A strength of this study was that all individuals were admitted to health facilities on confirmation of infection and their symptoms determined so that we could distinguish between those that were symptomatic or asymptomatic. There are a number of limitations of this work including that this study population of index cases were collected from the contact tracing databases and only included index cases who transmitted the virus. This is an 

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