What COVID-19 Is Versus What It Means to Us

Shin

An update on the basics after two years

It seems odd to ask this question at this point. But maybe it’s about time to ask again, given that it has been over two years since we discovered Covid-19 in Wuhan, China, in December 2019. So, maybe it’s about time to re-visit what Covid-19 truly is and what Covid-19 means to us.

Covid-19: The basics after two years of research

The coronavirus disease 2019 (COVID-19 or the less formal Covid-19) is an infectious disease caused by a coronavirus, specifically the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

SARS-CoV-2 uses its spike protein to bind to the ACE2 receptor on human cells. Upon binding, SARS-CoV-2 injects its genetic material to hijack the cell’s machinery to produce more virions, which go on to bind to and hijack other cells. We call this process an infection. So, an infected person means that SARS-CoV-2 has infected at least a cell.

Owing to its unique furin cleavage site in its spike protein, SARS-CoV-2 is remarkably competent at infecting cells — so much so that it has initiated a pandemic. Its capacity to transmit via aerosols — coupled with crowded civilization and unventilated indoor air — further aid its global success.

SARS-CoV-2 is a respiratory virus. It infects people through the respiratory tract, and it usually causes respiratory symptoms. So, the main description of Covid-19 is mild flu-like symptoms (e.g., fever, dry cough, malaise, and shortness of breath) and loss of smell, which may progress to severe pneumonia, acute respiratory distress syndrome, or respiratory failure, especially in people who are older or have pre-existing diseases.

But later, we found that SARS-CoV-2 or Covid-19 could harm other organ systems via two main mechanisms: cytokine storm and vascular dysfunction. Cytokine storm is the most supported one, characterized by excessive release of pro-inflammatory cytokines that cause widespread tissue damage, including blood vessels, causing vascular issues like blood clots. SARS-CoV-2 may also cause vascular problems via the bradykinin storm — a build-up of bradykinin from ACE2 overactivation, making blood vessels leaky.

But cytokine storm is likely the more crucial driver of severe Covid-19. Anti-inflammatory drugs like dexamethasone and other corticosteroids could treat severe Covid-19, but anti-bradykinin drugs don’t seem to work.

The third probable mechanism is a direct infection. Some cell culture (in vitro) and animal (in vivo) studies showed that SARS-CoV-2 could infect non-respiratory cells, such as brain neurons or blood vessel cells. But such findings are not always supported. Differences in experimental design and lab conditions probably explain those discrepant findings.

Autopsies — usually done on severe Covid-19 patients — could find evidence of SARS-CoV-2’s genes or proteins in the brain and blood vessels, but in some cases only, not all. Plus, we are unsure if such findings apply to non-fatal Covid-19. After all, we can’t just extract the brain or blood vessels from a living human to dissect and see if SARS-CoV-2 replication occurs.

So, Covid-19 is mainly a respiratory disease, which may come with other complications, especially in organ systems already burdened with pre-existing diseases or old age. Thus, people dying from Covid-19 may not necessarily be dying from respiratory diseases, but it could be blood vessel-related diseases (e.g., pulmonary embolism, brain or gastrointestinal bleeds, or stroke), heart failure, acute renal failure, sepsis, or multi-organ failure.

Lastly, Covid-19 is not just about ending up dead or alive. Some Covid-19 survivors will develop the long-Covid syndrome, characterized by persistent symptoms — usually fatigue, dyspnea, and cognitive impairments— lasting at least three months after Covid-19 is over. Long-Covid happens because the body may not fully heal from Covid-19 due to reasons such as residual tissue damage, immune system dysregulation, or virus persistence.

What Covid-19 means to us: The case definition

Now, what Covid-19 is may be different from what Covid-19 means to us. In fact, the case definition we give to Covid-19 — what counts as a Covid-19 case — has been highly controversial.

It’s globally accepted that a positive polymerase chain reaction (PCR) test for SARS-CoV-2 alone qualifies as a Covid-19 case, regardless of disease signs or symptoms. But this rule has been heavily critiqued for the following reasons:

  1. PCR tests detect SARS-CoV-2 genetic material, not virus replication. So, a positive PCR test indicates the presence of virus fragments, not active replication. By analogy, finding dog fur (without looking for the dog) in an area doesn’t mean that the dog is still there.
  2. An infection is different from a disease. SARS-CoV-2 is a virus; Covid-19 is a disease with signs and symptoms. An infection generally produces disease, but it can also fail to establish disease for reasons such as low virus dose or inability to overcome the host immunity. By definition, therefore, PCR tests serve to detect SARS-CoV-2 infection, not the Covid-19 disease.
  3. Using PCR tests alone, without symptomatic criteria, can’t tell if a person got hospitalized or died from or with Covid-19 or SARS-CoV-2. Dying from x means that x caused the death; dying with x doesn’t mean that x caused the death. And x could be a positive PCR test or vaccination.

Despite knowing these, the scientific and public health authorities still define a Covid-19 case as a positive PCR test for SARS-CoV-2. Why?

Let’s unpack the above points again, one by one, in order:

  1. The only reliable way to detect SARS-CoV-2 replication is to culture the virus from a nasal/throat sample in the lab, which is far too time-consuming. We can’t afford this time amidst a pandemic of a highly infectious virus. So, although a positive PCR test can either mean ongoing virus replication or dead virus fragments, at least it can rule out negative virus replication. In other words, a negative PCR test can guarantee the absence of virus replication, at least in the sampled area.
  2. Infection and disease are indeed different, but SARS-CoV-2 is so infectious that we can’t afford the workforce to distinguish them. Identifying Covid-19 based on disease symptoms or manifestations (like lung abnormalities via chest CT scan) needs medical expertise that is always in short supply. So, identifying Covid-19 based on PCR tests is more efficient and doesn’t require a high level of expertise. Plus, about 40% of Covid-19 cases are asymptomatic, with no symptoms but viral replication may be ongoing, allowing virus transmission. Relying on symptomatic criteria to define Covid-19 may, therefore, miss out on asymptomatic cases.
  3. This with vs. from problem is more relevant for Covid-19 deaths. After all, a patient can get hospitalized for heart failure but with Covid-19 (PCR positive for SARS-CoV-2) and later face Covid-19 disease progression. But dying with vs. from Covid-19 has been controversial as determining the cause of death is up to the doctor’s judgment. Sometimes, Covid-19 may have accelerated heart failure progression, leading to death, and the cause of death will include Covid-19. Is this fair? Yes, it is, as the person would have lived longer if not for Covid-19, for we know Covid-19 can initiate or contribute to heart failure via mechanisms such as cytokine storm, blood vessel dysfunction, or direct heart infection. In fact, official Covid-19 death counts are likely underestimated due to limited testing and the higher number of excess deaths. So, reasons for overcounted (if any) and undercounted Covid-19 deaths sort of balanced each other out.

The conundrum of what Covid is

So, it’s apparent that there are some limitations in how we define Covid-19. To define a Covid-19 case with only one criterion — positive PCR test for SARS-CoV-2 — seems negligent, not strict enough.

But it’s understandable given that we must act efficiently, albeit imperfectly, amidst a pandemic. We may need to compromise scientific accuracy a bit to practice both biomedical and public health sciences together effectively.

As Carl Heneghan, Ph.D., professor and director of the Centre for Evidence-Based Medicine at the University of Oxford, said:

“In any other disease we would have a clearly defined specification that would usually involve signs, symptoms, and a test result. We are moving into a biotech world where the norms of clinical reasoning are going out of the window. A PCR test does not equal covid-19; it should not, but in some definitions it does.”

Covid-19, therefore, has two meanings. The biomedical meaning — i.e., what it is — is that Covid-19 is a disease with its unique set of signs and symptoms caused by SARS-CoV-2 replication. The public health meaning — i.e., what it means to us — is that Covid-19 is PCR positive for SARS-CoV-2, irrespective of whether virus replication or symptoms are present or not.

Which one is true depends on the context. Clinical and epidemiological papers — randomized controlled trials and cohort studies involving humans— study Covid-19 as a PCR-positive case without verifying the presence of SARS-CoV-2 replication. In contrast, biological papers — cell culture and animal studies — study Covid-19 as SARS-CoV-2-induced disease.

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