Asymptomatic, Pre-Symptomatic, and Definitions

The phrase asymptomatic can mean many things and is sometimes misused.
With the goal of reducing ambiguity, possible [mis]-uses of the term asymptomatic include:

  • Pre-symptomatic
    Recently infected, is rapidly replicating the virus, and feels no symptoms yet, but will within a few days
  • Genuinely Infected Asymptomatic Carrier
    Rare. Feels no symptoms and never will but is internally rapidly replicating the virus at significant rates for many days
  • Non-Infected PCR Positive
    NOT replicating the virus in any significant manner but has multiple positive PCR test but other diagnostics negative
  • Immune Triggered Asymptomatic
    Minor infection from small viral-load exposure triggering immune response – seroconverting. May or may not test PCR Positive (probably will).
  • Immune Re-exposed Asymptomatic
    Minor or no replicating virus, has positive PCR test, has increasing IgM / IgG antibody titers
  • Cross-Reactive Immune Asymptomatic
    Similar to Immune Re-exposed Asymptomatic, but primary (first) infection was from another virus

The point of these clarifications is to better classify the various “types” of conditions that are often referred-to as asymptomatic. There are a few reasons why this is important.

Some studies and popular news articles have errantly linked COVID positive diagnosis to PCR positive indication. It is possible that a PCR positive indication is a genuine positive for the virus but the individual is not replicating the virus. If an individual is NOT replicating the virus, they do not have COVID and are not infectious. That said, a person could carry a virus on their clothes, hands, nose, mouth, skin, glasses, cell phone, etc. like any other inanimate surface, but that is not an infectious person – they are simply contaminated – like any contaminated object. So some people that are labeled asymptomatic are simply NOT Infected but they had one or more PCR positive for whatever reason. Perhaps they got a whiff or taste of the virus but did not become infected. Further, a positive PCR positive indication may not mean the virus detected is active; it may be an inactivated virus that fools the PCR test into a positive. Inactive / dead viruses can reliably fool PCR tests into a positive.

Another common misuse of the term asymptomatic is an individual that has been infected and will experience symptoms soon but is not yet doing so and is therefore Pre-Symptomatic or Incubatory Carrier which is a well defined term that should be applied but occasionally people use the term asymptomatic incorrectly when they should be using the term pre-symptomatic.

“The immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered”.

People who have been infected, recovered, and have antibodies that gradually diminish over some period (that may be months to decades) have some level of immunity during the time antibodies are diminishing. When these people are re-exposed to the virus from someone or something in their environment, their adapative / acquired immune system, including those virus-specific antibodies, will defend against the new infection.
The speed at which this occurs depends upon many things, including the amount of antibodies still present in their blood (again, they diminish over time). Having even small amounts of remaining antibodies (or B memory cells) is a huge “head-start” to rapidly defeating the new infection. The antibodies / B memory cells that do exist can be replicated very rapidly rather than having to be “built from scratch”. In some cases, almost no viral replication will occur because the adaptive immune system (and innate) defeat the new infection before it can infect any / many cells. In most cases, some cells will become infected but the virus will be defeated more rapidly than it multiplies in those cells and the person will never become “sick”. How many cells become infected and how rapidly the immune system responds depends on many things, but the response is MUCH faster than the response from someone who is being infected for the first time and has no antibodies for the virus yet. So, that is the Immune Re-exposed Asymptomatic definition. They will not get sick. They may replicate and may shed some very small amount of virus and possibly be very slightly infectious, but they will generally not shed very much virus and only for a very short period of time, if at all. Further, because their acquired immune system is rapidly at work, the virus that they do shed will likely be inactive, but may fool a PCR test. It becomes very confusing to call this type of person asymptomatic because they are really just a person who is recovered and has had a re-exposure that they usually defeat in minutes or hours. It is easy to mislabel this person as an asymptomatic because they may shed some virus and fool a PCR test. Some studies using PCR have created confusing results because the study did not properly account for this type of person and mislabeled them as a Genuinely Infected Asymptomatic Carrier because the PCR detected an inactive virus or very small localized viral load that was not shedding.

In the late stages of an outbreak, there can be many immune but re-infected people. However, the closer in time to their original infection, the less their antibodies will have had time to decay, and the shorter the window of time before they defeat the new exposure and the less likely they are to shed virus. Because of the decay of antibodies over time after recovering from an infection, in the case where a population is “slowing the spread” and “flattening the curve”, there is a larger the probability that it will take a re-infected person some additional time to to ramp back up to defeat any new infection. This makes them a little more likely to be slightly contagious as that ramp up occurs.

Perhaps the most interesting is the prospect of the Immune Triggered Asymptomatic. These individuals have a minor infection that likely resulted from small viral-load exposure triggering an immune response. Because of the minor nature of the infection, they are unlikely to shed large amounts of virus. They are seroconverting and developing antigen-specific B cells and corresponding antibodies. They may or may not test PCR Positive (probably will). When a small viral load exposure occurs, the immune systems often creates a response, yet symptoms may be minimal or non-existent. This immune response often creates some level of future immunity.

Children and younger adults may also often fall into the Immune Triggered Asymptomatic group because of children having a more active innate immune response, it may be that the innate response rapidly lowers the “effective” initial exposure viral load helping to create a more mild or asymptomatic infection in pre-adolescents / young adults. It has been shown that in humans, natural antibodies are produced by innate or IgM MBCs, a population of MBCs that is generated independently of the germinal centres and is most abundant in children.

The Cross-Reactive Immune Asymptomatic has characteristics similar to Immune Re-exposed Asymptomatic, but the primary (first) infection was from a different virus that had a similar enough epitope such that the paratope of antibodies / leukocytes developed from the first infection will have some ability to bind to the virus in the new exposure and thus provide some level of immunity as result of cross-reactive protective immunity.

Issues With Asymptomatic Studies

The study below related to asymptomatic cases uses PCR testing to determine “infection” status which is flawed. PCR detects RNA, not necessarily a viable virus. When COVID symptoms are present, it is generally reasonable to assume that a PCR positive result means the symptoms are due to COVID. When no symptoms are present a PCR positive might mean detection of the RNA of a non-viable virus or that the RNA detected has not infected the person tested. Other studies related to asymptomatic COVID positive status also make this error. Some comments that can be made about this study include:

It would seem 2 things would help after obtaining a PCR positive in a study like this. Culture to determine virus viability as inactivated virus / damaged envelope will most often still result in PCR RNA positive but the virus is not infectious. And perhaps antibody titers of IgM and IgG would be interesting to see in the PCR “asymptomatic”, never-symptomatic, patients. Seems like the antibody test would have added minimal cost / effort. – DV, EpGrp

“Viral shedding was longer than others but it doesn’t equate with infectivity…” – RS, EpGrp

We don’t really care if people shed viral RNA. We care if they shed viable virus at loads sufficient to cause infection in others. We’ve already learned that the two don’t correlate perfectly, so I believe that this study doesn’t prove what it’s trying to prove. – DG, EpGrp

“It is important to note that detection of viral RNA does not equate infectious virus being present and transmissible. For a better understanding of the viral shedding and potential transmissibility of asymptomatic infection, large rigorous epidemiologic and experimental studies are needed.” – excerpt from the study

The following study shows that PCR detection of virus in circulating blood is only found in patients trending toward a severe case. Why would the virus not be circulating in the blood of mild cases? If PCR could directly detect presence of virus in blood and the patient was asymptomatic, it would be a clear indication of an infection without symptoms.