Testing studies from around the world confirm that up to 45% of people infected with COVID-19 were asymptomatic

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An extraordinary percentage of people infected by the virus behind the ongoing deadly COVID-19 pandemic – up to 45 percent – are people who never show symptoms of the disease, according to the results of a Scripps Research analysis of public datasets on asymptomatic infections.

The findings, recently published in Annals of Internal Medicine, suggest that asymptomatic infections may have played a significant role in the early and ongoing spread of COVID-19 and highlight the need for expansive testing and contact tracing to mitigate the pandemic.

“The silent spread of the virus makes it all the more challenging to control,” says Eric Topol, MD, founder and director of the Scripps Research Translational Institute and professor of Molecular Medicine at Scripps Research.

“Our review really highlights the importance of testing. It’s clear that with such a high asymptomatic rate, we need to cast a very wide net, otherwise the virus will continue to evade us.”

Together with behavioral scientist Daniel Oran, Topol collected information from testing studies on 16 diverse cohorts from around the world.

These datasets – gathered via keyword searches of PubMed, bioRxiv and medRxiv, as well as Google searches of relevant news reports – included data on nursing home residents, cruise ship passengers, prison inmates and various other groups.

“What virtually all of them had in common was that a very large proportion of infected individuals had no symptoms,” says Oran. “Among more than 3,000 prison inmates in four states who tested positive for the coronavirus, the figure was astronomical: 96 percent asymptomatic.”

The review further suggests that asymptomatic individuals are able to transmit the virus for an extended period of time, perhaps longer than 14 days. The viral loads are very similar in people with or without symptoms, but it remains unclear whether their infectiousness is of the same magnitude. To resolve that issue, we’ll need large-scale studies that include sufficient numbers of asymptomatic people.

The authors also conclude that the absence of symptoms may not imply an absence of harm. CT scans conducted on 54 percent of 76 asymptomatic individuals on the Diamond Princess cruise ship, appear to show significant subclinical lung abnormalities raising the possibility of SARS-CoV-2 infection impacting lung function that might not be immediately apparent. The scientists say further research is needed to confirm the potential significance of this finding.

The authors also acknowledge that the lack of longitudinal data makes distinguishing between asymptomatic and presymptomatic individuals difficult. An asymptomatic individual is someone who is infected with SARS-CoV-2, but never develops symptoms of COVID-19, while a presymptomatic person is similarly infected, but will eventually develop symptoms.

Longitudinal testing, which refers to repeated testing of individuals over time, would help differentiate between the two.

“Our estimate of 40 to 45 percent asymptomatic means that, if you’re unlucky enough to get infected, the probability is almost a flip of a coin on whether you’re going to have symptoms. So to protect others, we think that wearing a mask makes a lot of sense,” Oran concludes.


COVID-19 initially has been divided into four types: mild, moderate, severe, and critical cases.3 However, with the global outbreak of coronavirus, there is increasing evidence that many infections of COVID-19 are asymptomatic, but they can transmit the virus to others.

Asymptomatic infections refer to the positive detection of nucleic acid of SARS-CoV-2 in patient samples by reverse transcriptase-polymerase chain reaction (RT-PCR), but have no typical clinical symptoms or signs, and no apparent abnormalities in images, including lung computed tomography (CT).4

The clinical characteristics of asymptomatic infections and other types of COVID-19 are shown in Table 1 . Early recognition of an infected person and cutting off the route of transmission are key points to control COVID-19. However, most asymptomatic infections do not seek medical assistance due to no obvious clinical signs and poor prevention awareness, which contribute to the rapid spread of COVID-19.

Therefore, it is a great challenge to prevent and control this specific type of patient globally, which requires more attention worldwide.

Table 1

Clinical characteristics of asymptomatic infections and other types of COVID-19.23

TypeClinical characteristicsRT-PCR test for COVID-19
AsymptomaticNo clinical symptoms and chest imaging findings.Positive
MildMild clinical symptoms, such as fever, fatigue, cough, anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, headache.
No abnormal chest imaging findings.
Positive
ModerateMild or moderate clinical features.
Chest imaging showed mild pneumonia manifestation.
Positive
SevereSuspected respiratory infection symptoms, plus any of the following:  Shortness of breath, RR ≥ 30 breaths/min;  At rest, oxygen saturation ≤93%;  Pa02/Fi02 ≤ 300 mmHg (1 mmHg = 0.133 kPa). Chest imaging showed the lesions significantly progressed > 50% within 24–48 h was a severe disease.Positive
CriticalRapid progress of disease, plus any of the following: Respiratory failure, and need mechanical ventilation; Shock; Combined with other organ failure requires ICU monitoring treatment.Positive
RT-PCR, reverse transcriptase-polymerase chain reaction; RR, respiratory rate; Pa02, arterial partial pressure of oxygen; Fi02, oxygen concentration; ICU, intensive care unit.

Infectivity
Asymptomatic infections have the same infectivity as symptomatic infections.5 It has been reported that a 53-year-old UK patient with an asymptomatic COVID-19 infection may cause 11 infections.6

A report pointed out that one asymptomatic person who experienced 19 days from contact with the source of infection to RT-PCR confirmation may have infected 5 people.7

These asymptomatic cases may play a role in the transmission and therefore pose a significant challenge to infection control.

Estimates of the incidence of asymptomatic infections will clarify the epidemiological potential of COVID-19 transmission and understanding of the true universality of the disease.

There are many studies on the incidence of asymptomatic infections (Table 2 ), but each study has its limitations. First of all, due to insufficient awareness of asymptomatic infections and limited detection capabilities in the early stage of the outbreak, China’s 1.6% may be underestimated.8

On the contrary, another study investigated 565 Japanese citizens evacuated from Wuhan at the end of January and found that the incidence of asymptomatic infections was 30.8%.9

Another example is the “Diamond Princess” cruise ship, which was isolated in Japanese waters in early February due to COVID-19 infection found that the incidence of asymptomatic infections was 51.7%.10

Some researchers suggested that the above two studies overestimated the incidence, but in fact, a person truly has a higher risk if he has close contact with diagnosed or suspected infected persons in a relatively confined space.

Incidence of asymptomatic infections from other studies had some shortcomings, such as those in Korea11 and Washington,12 which showed inaccurate results due to the small sample size.

One case in Wuhan tracked the prevalence of 1391 children under 15 years old who had been in close contact with infected or suspected cases.13 The incidence of asymptomatic infections in the children is lower than that of the whole population, we propose that it is related to the special immune response and ACE2 level in the children’s bodies.14

According to these studies, the ability of asymptomatic infections to spread the virus is not low, and these patients are likely to cause a new round of outbreaks. Therefore, finding asymptomatic infections is the key point for early prevention and control of COVID-19 worldwide.

Table 2

The incidence of asymptomatic infections with COVID-19 in different studies.

China8 (n = 72,314)Japan9 (n = 565)Diamond Princess10 (n = 3711)Korea11 (n = 28)Washington12 (n = 76)Wuhan Children13 (n = 1391)
RT-PCR positive cases56,128136342823171
Asymptomatic cases889432831327
Incidence rate (%)a1.630.851.710.756.515.8
aAs of the data published in the literature, the proportion of asymptomatic infections in the population with positive nucleic acid test.

The incubation period is the approximate time from the first exposure to the virus until the clinical symptoms or signs onset, and patients can also transmit the virus in this period.15

Asymptomatic infections have no special incubation due to no clinical signs. However, a recent research found that the viral load detected in asymptomatic populations were similar to that in symptomatic patients, indicating that asymptomatic infections have the potential for transmission, which may occur early in the course of infection.16

Since the viral nucleic acid positivity refers to that the virus load in samples reaches a certain limit, but the infectivity mainly depends on whether the virus is in a reproductive state.17

That is, sometimes, despite ongoing high viral loads, no live virus can be isolated, which means that viral nucleic acid positivity does not indicate infectivity.18 It is also proved by a clinical study in which the recovered COVID-19 patients who had no obvious clinical symptoms were detected to be positive for SARS-CoV-2 by hyper-sensitive viral nucleic acid re-examination methods, but these patients had not caused new infections.19

Due to the limited data from current studies, we think that it is necessary for us to be highly vigilant to asymptomatic infections. Moreover, viral nucleic acid positivity has been reported not to be always considered, and more clinical studies are still needed to verify that.

A previous study found that the median period of asymptomatic patients from viral nucleic acid positive to negative was 9.5 days, the longest was up to 21 days among the 24 asymptomatic cases.20 Then in another study found that the median period from contact to diagnosis and the last positive nucleic acid test was 19 days (8–24 days) and 21.5 days (10–36 days), respectively.21

The median period from diagnosis to negative nucleic acid test was 7.5 days (2–20 days) with normal or atypical chest CT infections and 12.5 days (8–22 days) with typical CT findings.21

However, an asymptomatic infection should be quarantined for 14 days until now,22 more studies are still needed to assess the infectivity duration of asymptomatic cases. And if necessary, more attention should be paid to some special infectious individuals who need longer segregation due to the result of nucleic acid test.

Distribution
The most likely source of asymptomatic infections is close contacts of patients who have been diagnosed or suspected, and family clusters have been presented before. Also, colleagues, friends, and people who coincide with the trajectories of diagnosed or suspected patients are all regarded as high-risk populations.

Familial cluster has made the epidemic challenging to prevent and control. Some family members do not have any clinical manifestations, but the nucleic acid test result is positive, and this has become a major difficulty in the prevention and treatment of COVID-19.

In one case report, all three of the family members were diagnosed with COVID-19, and only one family member had clinical symptoms.23 Another family cluster report showed that the first patient was in good health without clinical manifestations, including fever and cough, and denied having primary diseases.

He went to the local hospital for treatment only because of urticaria. The patient stated that he had lived in the local area for a long time and had not been to the epidemic area. However, the investigation of the disease control experts found that the patient had close contact with his relatives in Hubei Province one week before the onset of symptoms.

Finally, by investigating the family members and close contacts of the patient, three pulmonary CT scans were normal, but the nucleic acid test results were positive.24 Family members of COVID-19 patients, even without any symptoms, should be closely monitored and examined to rule out infection.

These cases also highlight the need for a close epidemiological investigation to prevent the omission of possible sources of contamination.

Different individuals may have different clinical signs. Studies have shown that asymptomatic infections are more common in populations of young and middle-aged individuals with functional performance status without underlying diseases.

It was reported that asymptomatic cases were more common in middle-aged people in Shenzhen (median age:49 years, 30.9% between 30 and 49 years)25 and a few younger people in Nanjing (median age:32.5 years).20

Above all, age and body condition may play an important role in the severity of COVID-19, and this is related to different immune responses and other potential pathogenesis.

Pathogenesis
Similar to SARS-CoV, SARS-CoV-2 invades cells by using angiotensin-converting enzyme 2 (ACE2) as its receptor.26 Because ACE2-mediated angiotensin II (Ang ll) degradation plays an important role in the pathogenesis of severe lung failure after a viral infection, the severity of the virus infection is closely related to the maturity and binding capacity of ACE2.27

Therefore, we supposed that a lower level of ACE2 and weaker binding capacity with SARS-CoV-2 should be a major factor that leads to the absence of any clinical manifestations for asymptomatic infections.

It has been reported that only a specific mild immune response is caused by the SARS-CoV-2 invasion in asymptomatic patients.28 However, more clinical samples should be collected, and a relative examination of ACE2 should be performed and compared for different types of COVID-19 cases, as this would be helpful to explain its pathogenesis.

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Source: Scripps Research Institute

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