Presymptomatic COVID-19

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The prodigious transmissibility of the emerging coronavirus we now call SARS-CoV-2 has raised questions about the period leading up to symptomatic infection. If a presymptomatic stage of COVID-19 is common, it could contribute to viral spread and explain its high transmissibility.  This is important for diagnosis and control of the infection.

The virus-infection-disease nexus. The laboratory tests used to confirm a diagnosis of viral respiratory infection are key to understanding the underlying cause, but are only part of the process used to diagnose the disease. The features that lead to you doctor’s diagnosis are the patient’s subjective symptoms and objectively observed clinical signs. Taken together, these clinical features may fit into a recognisable pattern that suggests a syndrome or disease. The COVID-19 tests performed to confirm infection detect RNA from SARS-CoV-2 present in nose or throat swabs, or in sputum.  The virus (SARS-CoV-2), its infection (upper and/or lower respiratory tract infection) and corresponding disease (COVID-19) overlap, but they are not the same thing. For now, detection of the virus is needed to confirm COVID-19, but that is obviously possible only in communities that widely test people with features of a respiratory infection. As different places have different public health criteria for testing, the results tell us different things, depending on why the tests were done. Which brings us to the issue of a presymptomatic state.

Test positive/disease negative. As the current definition of COVID-19 relies on a highly sensitive laboratory test, which can detect less than 10 copies of the target virus gene per microlitre, it is not that surprising that cases of SARS-CoV-2 infection can be detected before the onset of symptoms. The questions this level of sensitivity raise are (a) is that person a source of infection to those around them, and (b) does a positive test result predict progression to symptomatic disease? These issues were addressed by the public health specialists that investigated the outbreak of COVID-19 on the Diamond Princess cruise liner [1]. They found 320 asymptomatic cases, and estimated 17.9% cases were asymptomatic. As the Monte Carlo modelling they used to arrive at their conclusion used assumptions about the likely incubation period, a much wider range was possible, from 20.6-39.9%. Their cautious interpretation of data from the cruise liner noted possible sources of bias towards performing PCR assays on symptomatic patients, a non-random sample of passengers and crew, and underlying disease risks associated with symptoms.

How common is the presymptomatic state? The 17.9% asymptomatic infection rate differs from the World Health Organization’s assertion that asymptomatic infection was uncommon and usually progressed to symptomatic disease in their initial report [2]. Shortly afterwards reports began to emerge reporting asymptomatic cases. The language used to describe this was either presymptomatic or the terminal stages of the incubation period [3, 4] It has taken small countries like Iceland, or small, defined communities in larger countries, to achieve the high levels of test coverage to estimate the prevalence of asymptomatic infection on shore. In Iceland around half those with a positive test had no symptoms, and in the Italian town of Vo, most of those with positive SARS-CoV-2 tests were asymptomatic.

When does presymptomatic transmission occur? The extent of transmission from asymptomatic infection is uncertain except in the specific circumstances of vulnerable populations confined to a few cruise liners, and other highly defined, closed populations such as long term skilled care facilities [5]. In the wider population, its multiple social, recreational and occupational connections make attribution of asymptomatic viral spread quite difficult. A recent report from Singapore investigated several COVID-19 case clusters, finding that transmission from an asymptomatic source occurred 1-3 days before the onset of symptoms [6].  It is becoming clear that virus load and shedding are not necessarily lower in the presymptomatic period. Just because you haven’t developed COVID-19 symptoms doesn’t mean you won’t transmit it.

What can be done about it?

  1. General population. Few countries have the capacity to test their entire population. Scientific principles can be used to take representative cross sections of the population, and expand COVID-19 screening to asymptomatic people as is starting to happen.
  2. Those at risk. If the greatest concern is for the most COVID-19 vulnerable people, a more targeted screening plan can be used to expand the coccooning concept to include the surrounding community of carers, supporters and extended family. It is clear that front line health care workers need to be considered among the vulnerable.
  3. The vulnerable. Our elderly population needs to be singled out for special attention because they are over-represented among those who are dying with COVID-19. Can we be sure that there is no transmission from presymptomatic persons in residential aged care facilities?

Is it really infection? The distinction between permanently asymptomatic and presymptomatic SARS-CoV-2 infection may only be possible in retrospect, and assumes that COVID-19 screening will not be restricted to symptomatic individuals. Much more data is needed to predict the proportion of presymptomatic COVID-19 that progresses to disease. There is a pathological process under way, even in the absence of symptoms and objective signs of respiratory infection.  This can be considered an occult infection.

Does it matter? In some cases, asymptomatic SARS-CoV-2 infection could conceivably fizzle out as a result of effective immune defences; the desired result of a vaccine, and a theoretic possibility in some unvaccinated individuals. For the rest, infection without symptoms will either be on the way to clinically evident disease, or when persistent viral shedding occurs during convalescence. In both cases, the risk of transmission for longer than symptoms suggest may need test results to manage infection control.

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Reading:

  1. Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. 2020 Mar;25(10). doi: 10.2807/1560-7917.ES.2020.25.10.2000180.
  2. World Health Organization. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). Geneva, 16-24 February 2020.
  3. Tong ZD, Tang A, Li KF, Li P, Wang HL, et al. Potential Presymptomatic Transmission of SARS-CoV-2, Zhejiang Province, China, 2020. Emerg Infect Dis. 2020 May 17;26(5). doi: 10.3201/eid2605.200198.
  4. Li P, Fu JB, Li KF, Chen Y, Wang HL, et al. Transmission of COVID-19 in the terminal stage of incubation period: a familial cluster. Int J Infect Dis. 2020 Mar 16. pii: S1201-9712(20)30146-6. doi: 10.1016/j.ijid.2020.03.027.
  5. Kimball A, Hatfield KM, Arons M, James A, Taylor J, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility – King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020 Apr 3;69(13):377-381. doi: 10.15585/mmwr.mm6913e1.
  6. Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, et al. Presymptomatic Transmission of SARS-CoV-2 – Singapore, January 23-March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020 Apr 10;69(14):411-415. doi: 10.15585/mmwr.mm6914e1.