Viruses are strictly intracellular and use the host cells for replication. Their structure is very basic and consists of a segment of nucleic acid surrounded by a protein shell. Even though they are structurally simple, they have efficiently utilised their nucleic acid in creative ways to increase their functionality and optimise their survival. Genetic mutations are a virus’s natural way to adapt quickly to pressure. Fundamentally, a “good” virus is one that survives.
Once a virus has entered a host cell, viral replication is underway. The process becomes a race between host survival and virus survival. If the host wins, the virus is cleared through innate and adaptive immune responses. If the virus wins, large-scale virus replication results in host tissue destruction and disease, and possibly death of the host. Clinically, the immune responses mediated by cytokines result in symptoms such as fever, headache and myalgia. However, some viruses can cause tissue damage in the absence of an inflammatory response. That leads to asymptomatic infection and shedding of the virus which complicates case detection and disease control but is a survival advantage for the virus (1).
Explanations as to why we see asymptomatic cases for SARS-CoV-2 are not available yet. It is conceivable that in some patients, locally produced neutralising antibodies are present due to cross protective immunity from previous seasonal coronaviruses, or their antiviral innate immune response is efficient enough to diminish but not fully stop viral replication. In either case, low numbers of infectious virus would be shed. Alternatively, the process of virus replication could be decoupled from the immune system. This phenomenon has been described in simian immunodeficiency virus (SIV) and local immune evasion but suppression of specific cytokines is known to occur in upper respiratory infection with human rhinovirus (2).
Very early in the pandemic, reports of potential asymptomatic transmission came to light. The studies were investigating family clusters and found that not every household member had symptoms even though they had detectable SARS-CoV-2 RNA in respiratory tract samples (3) (4).
To have asymptomatic transmission as a major driver of an outbreak, high viral loads and an ability to shed large numbers of infectious virus would have to be part of a manifold process. In seasonal coronaviruses, asymptomatic carriage has been described and viral loads have been low compared to symptomatic patients (5). In SARS-CoV-2, viral loads in asymptomatic patients can be as high as in symptomatic patients (6; 7). However, it is likely that a diverse range of viral loads exist in asymptomatic or pre-symptomatic individuals infected with SARS-CoV-2, and this may be linked to the individuals immune response.
Several reports on asymptomatic transmission in specific scenarios have been published. A long-term care facility in Washington found 13 residents (57 percent) to be asymptomatic at the time of first testing, all but three developed symptoms subsequently. It was highlighted in the article that accurate classification of “asymptomatic” can be influenced by subjective assessments and by cognitive impairment of residents (8). In another facility, 24 of 27 asymptomatic residents developed symptoms and were reclassified as pre-symptomatic (7). An analysis of COVID-19 cases on board the Diamond Princess ship revealed asymptomatic carriage of 17.9 percent (9), universal screening of 215 asymptomatic obstetric cases detected RNA in 33, of which 29 had no symptoms and only two of these developed symptoms later on (10). Some modelling suggests that 44 percent of secondary cases have been infected while the index case has been pre-symptomatic (11).
What determines infectivity?
Simplified, infectivity is influenced by the load of virus needed to predictably cause infection in a susceptible individual (the infective dose). This dose is yet to be determined for SARS-CoV-2. The closeness between “infector” and “infectee” as well as the length of exposure are also important, and so is the hosts physical health and immune system. For SARS-CoV and SARS-CoV-2, it is known that efficient transmission occurs under conditions of close contact (12). This is supported by the finding that clusters often occur in households, aged residential care and correctional facilities. It is yet to be determined if some strains of SARS-CoV-2 are more infectious or virulent than others.
While it is assumed that high viral loads equal a high infectivity, it is worth considering that early in the infection during the asymptomatic or pre-symptomatic phase the virus replicates in the nasopharyngeal epithelium and remains intracellular during that process. No inflammatory response is elicited yet. Once freshly replicated, the virus is released into the nasopharynx and inflammatory immune response induces symptoms. At that point a much larger quantity of “free” virus neatly suspended in saliva can be transported to the next host in addition to the virus still replicating within cells. In theory, this would make the symptomatic stage the more efficient one for transmitting virus. However, the exact pathophysiology and viral kinetics for SARS-CoV-2 in asymptomatic persons remain unknown.