key: cord-340992-88t1c0zs
authors: Nikolai, Lea A; Meyer, Christian G.; Kremsner, Peter G.; Velavan, Thirumalaisamy P.
title: Asymptomatic SARS Coronavirus 2 infection: Invisible yet invincible
date: 2020-09-03
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.08.076
sha: 
doc_id: 340992
cord_uid: 88t1c0zs

While successful containment measures of COVID-19 in China and many European countries have led to flattened curves, case numbers are rising dramatically in other countries, with the emergence of a second wave expected. Asymptomatic individuals carrying SARS-CoV-2 are hidden drivers of the pandemic, and infectivity studies confirm the existence of transmission by asymptomatic individuals. The data addressed here show that characteristics of asymptomatic and presymptomatic infection are not identical. Younger age correlates strongly with asymptomatic and mild infections, and children as hidden drivers. The estimated proportion of asymptomatic infections ranges from 18% to 81%. The current perception of asymptomatic infections does not provide clear guidance for public-health measures. Asymptomatic infections will be a key contributor in COVID-19 spread. Asymptomatic cases should be reported in official COVID-19 statistics.

Transmission of the virus by infected, albeit asymptomatic individuals has been reported since the early stages of the outbreak 8, 9 posing substantial challenges to COVID-19 containment.

Spread of COVID-19 likely occurs to a large extent through asymptomatic individuals, as these do not present at health care or testing facilities. Uncertainty about the significance of asymptomatic infections is reinforced by the vagueness with which the term "asymptomatic" is used. WHO defines an asymptomatic case as a laboratory-confirmed infected person without overt symptoms 10 . It remains to be established how thoroughly such a person needs to be examined clinically. Moreover, a distinction between asymptomatic and presymptomatic individuals is often neglected in COVID-19 case definitions.

A distinction between asymptomatic and presymptomatic stages can currently only be made retrospectively, after the occurrence or non-occurrence of clinical symptoms. Recent evidence suggests that elevated serum/plasma lactate dehydrogenase levels may, already in early stages, be indicative of presymptomatic infections and, thus, facilitate early differentiation 11 . Diagnostic imaging cannot distinguish between the two infection stages, as, surprisingly, 30% of asymptomatic individuals showed ground-glass opacities and 27% had diffuse consolidations 12 .

The frequency and infectivity of asymptomatically infected persons is one of the main reasons why COVID-19 has become a pandemic. Evidence has pointed to the need for strict tracking and testing of all contacts, regardless of apparent symptoms 2, 11, 13, 14 . However, detection of COVID-19 has long been driven by testing patients only, a practice still recommended in the EU/EEA (except Germany) and UK 15 . Meanwhile, some countries have started to extend testing and Luxembourg and the state of Bavaria (Germany) have announced that the entire population of 600,000 and 13 million, respectively, shall be tested to prevent a second wave.

The Centre for Disease Control (CDC) of USA recommends diagnostic tests for both symptomatic and asymptomatic individuals with known or suspected exposure to COVID-19 16 , while the European Centre for Disease Control (ECDC) proposes tests mainly for asymptomatic healthcare workers when testing facilities are underutilized 17 .

Since 1 April, China has responded to the emerging significance of asymptomatic infections by establishing a separate category of "asymptomatic cases" in its daily COVID 19 statistics 2 . Mathematical modelling clearly supports broader test strategies. A simulation applying data from the Jiangsu Province, China, compared epidemiological data with an estimated asymptomatic proportion of 44% and found that asymptomatic individuals can cause faster and larger outbreaks compared to imported cases 18 . Another analysis indicated that 30% of asymptomatics and 50% of symptomatic patients must be isolated to achieve disease control 19 .

Asymptomatic infections have increasingly been recognized in family clusters with unknown index cases. The first study cluster comprised of five family members from Anyang, China, who developed COVID-19 symptoms and tested positive by RT-PCR after acquiring the infection from the index case, an asymptomatic visitor from Wuhan who later tested positive 20 .

Another study with five family members from Luzhou, China, described a patient who developed severe COVID-19 pneumonia after attending a family reunion. Apparently, he had acquired COVID-19 from an asymptomatic relative from Wuhan 21 .

Several studies have focused on determining the incidences of asymptomatic infections. On the cruise ship Diamond Princess with 3711 passengers, a major outbreak with 634 cases occurred after an infected asymptomatic passenger had boarded in Hong Kong.

Due to the dense living conditions and frequent passenger contacts the R0 value was initially four times higher than in Wuhan 22 . The true asymptomatic proportion, defined as those who never developed symptoms, among all infected passengers was 18% 23 . Similar to the Diamond Princess, another study of an Argentinian expedition cruise ship found that 59% of the 217 passengers tested positive for COVID-19; 81% of those infected were asymptomatic virus carriers 24 . In Vo, the first Italian city with a confirmed COVID-19 fatality, the 3711 was surveyed twice. 2.6 % of the population tested positive before the lockdown and 1.2 % tested positive after the lockdown. Of these, 41% and 45% were asymptomatic before and after the lockdown, respectively 25 . When screening individuals in Gangelt, Germany, 22% of individuals positive for COVID-19 remained asymptomatic 26 . In another study of individuals re-patriated from Wuhan to Japan, 13 of the of 565 (2%) evacuated tested positive and 31% of those evacuated remained asymptomatic after a sufficiently long time to complete the incubation period 27 . A first nationwide population-based study from Spain including 61000 participants from 35883 households concluded that one in three infections seems to be asymptomatic and emphasizes the need for maintaining public health measures, to avoid a second epidemic wave 28 .

As these findings differ greatly it is difficult to accurately determine the extent of asymptomatic infections. Discrepancies could result from imprecise definitions of the term "asymptomatic" or a differing understanding of "asymptomatic" in the various studies (Table1).

Extremely high incidences could result from unintended inclusion of presymptomatic and very mild cases. The true incidence of asymptomatic infections can only be determined if close surveillance is installed and continued at least over the estimated average incubation period of at least 5 days in order not to miss a possible onset of symptoms.

When assessing public health risks raised by asymptomatic COVID-19 cases it is important to determine whether the infectivity varies between asymptomatic, presymptomatic and symptomatic individuals. A study of the first 243 patients in Singapore revealed a proportion of 6% presymptomatic cases with transmission occurring 1-3 days before the onset of symptoms 14 . Data from three Chinese hospitals, including 24 asymptomatic subjects, showed whereas 9 remained asymptomatic. There was a statistically significant difference between asymptomatic and presymptomatic infection, with higher Ct values in asymptomatic individuals than in presymptomatics. However, there was no significant difference in viral shedding 34 . In addition, infectivity was found to be highest roughly a day before symptom onset and it was estimated that 44% of secondary cases were infected by a presymptomatic carrier 35 .

In order to ascertain an asymptomatic, who did not meet the case definition, the detection of SARS-CoV-2 by RT-PCR on nasopharyngeal and oropharyngeal swabs is the only currently available standard diagnosis 36 

When analysing common characteristics of patients, young age often correlated with asymptomatic or mild manifestations of COVID-19. Among 78 patients from Wuhan, China, asymptomatic individuals were younger than symptomatic patients (median age 37 vs. 56 years) 32 . In Nanjing, China, of 24 initially asymptomatic subjects, 29% who never showed symptoms were significantly younger than the presymptomatic group 40 . These results are supported by the data from the cruise liner Diamond Princess, where of 96 asymptomatic persons 11 later developed symptoms that made them presymptomatic. The probability of turning to a presymptomatic stage increased with age 41 .

In fact, a much lower prevalence of COVID-19 is observed in children than in adults, with people under 18 years accounting for 5% of cases only in the USA compared to 22% in the total population 42 . Of 1412 Chinese children with infection, 4% and 51% were categorized as asymptomatic and mild, respectively 43 .

Recent evidence suggests that the entry of SARS-CoV-2 via the ACE2 receptor is facilitated by the membrane-bound serine protease TMPRSS2, which primes the viral S protein for fusogenic activity 44, 45 . Since TMPRSS2 is a gene that associates with androgen levels, a higher expression occurs in males, which provides one explanation why they are more likely to develop severe COVID-19 46 . This association also applies to the distinction between preadolescents and adults and is in line with low incidences and rather mild disease courses in children 47 . Since this also indicates a higher incidence of asymptomatic infections in younger people, it needs to be examined whether this group, especially children, could silently, yet efficiently, contribute to the spread of COVID-19.

In Geneva, Switzerland, 79% of all RT-PCR-positive children under 16 years of age were infected in household clusters 48 and in Wuhan, China, as much as 90% of this group were infected by a family member 49 . A systematic review identified 31 household clusters, of which only 10% had paediatric index cases compared to 54% in H5N1 influenza 50 . These observations, together with evidence of lower viral loads and milder respiratory symptoms in children, have led to the conclusion that children are unlikely to be the main cause of the pandemic 51 . Consequently, re-opening of kindergartens and schools has been proposed. A low attack rate among children may yet be biased, because the risk of infection is lowest for children 52 . Current data from Berlin, Germany, did not show significant differences in viral loads between age groups, suggesting that children may be as infectious as adults 53 .

Neglecting the role of children in the spread of COVID-19 is precarious. It is important in modelling the pandemic to undertake careful surveillance, including asymptomatic children J o u r n a l P r e -p r o o f with rates of infections assessed by serology in order to better characterize childhood infection and the role of children in transmission networks 54 . Children need protection, as some become ill, although severely only in the very minority of cases. COVID-19 vaccination in children may provide protection for older, unvaccinated populations. Vaccination in childhood will lead to a great deal of immunity required for overall protection in any population 54, 55 .

Studies suggesting high incidences of transmission through asymptomatic individuals have raised hope that broad immunization of the population occurs unnoticeably. In general, about two thirds of a population must be immunized to achieve herd immunity. On 24 June 2020, the countries with highest incidences of COVID-19 were the USA, Brazil, Russia, India and the United Kingdom, with case numbers representing 0.71%, 0.54%, 0.43%, 0.03% and 0.47% of the population, respectively, thus being far from herd immunity 56 .

In Gangelt (Germany), an event linked to carnival celebrations caused SARS-CoV-2 spread throughout the city and resulted in 3% of the population with positive RT-PCR results.

Serological screening revealed later that 16% of the population were exposed 26 . Even in densely populated and severely affected areas the prevalence of anti-SARS-CoV-2 antibodies is still relatively low, e.g. 11% in Madrid, Spain 57 , 15% in London, UK 58 and 20% in New York City, USA 59 .

It is still unclear whether asymptomatic infections lead to protective immunity. It was observed that, although all patients with severe and mild COVID-19 experienced seroconversion during or after hospitalization, only 1 in 5 asymptomatic patients seroconverted 30 . Another comparison between an asymptomatic and a symptomatic cohort showed that IgG levels were significantly higher in symptomatic group 12 . However, data from two hospitals in Hong Kong suggest that the severity of the disease is not correlated with serum antibody levels 60 . It would not only be misleading, but dangerous to rely on silent immunization.

Apparently, so far only a small proportion of the population has been exposed to SARS-CoV-2.

The current perception of asymptomatic infections does not provide clear guidance for public health measures. As asymptomatic and presymptomatic infections are not distinguishable on a first sight, they may pose a significant threat to public health during the unlocking lockdown strategies currently implemented in many countries.

Therefore, public health measures need to further-mandatorily and for an unforeseeable period of timeinclude sound hygiene measures and personal protective equipment to prevent spread by asymptomatic individuals. Contacts of infected persons must test for COVID-19, regardless of symptoms. Asymptomatic cases should be reported separately in official COVID-19 statistics and shifts from asymptomatic to symptomatic stages must be reported to health authorities. Mass rallies and major events need further be postponed or cancelled.

Asymptomatic infections are an important aspect of SARS-CoV-2 infection and the data addressed here show that the characteristics of asymptomatic and presymptomatic infection are not identical. Asymptomatic infections will be a key contributor in COVID-19 spread.

Infectivity studies confirm the existence of transmission by asymptomatic individuals but are contradictory when comparing viral loads and virus shedding in symptomatic and asymptomatic infections. Younger age correlates strongly with asymptomatic and mild infections and therefore suggests children as hidden drivers of the pandemic. However, since childhood infections are usually far below the age average in COVID-19 infections, the role of children in transmission events is not yet clear.

While the public health measures might be practicable in wealthy countries with well-established and rather stable health care systems, the question on how the pandemic will affect low-and middle-income countries as observed in South America or on the African continent remains still unresponded 61, 62 . The international community is obliged to pay attention to the spread of COVID-19 to low-income countries, as health systems could become severely overburdened and the pandemic could continue to elude control, hitting those hardest with the least protection.

All authors disclose no conflict of interest. 

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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All authors disclose no conflict of interest. All authors have an academic interest and contributed equally. TPV is a member of the Pan African Network for Rapid Research, Response, and Preparedness for Infectious Diseases Epidemics consortium (PANDORA-ID-NET RIA2016E-1609).

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