COVID-19: A Tale of Two Diseases

COVID-19 has now stolen over 115,000 lives throughout the United States. The race to find a vaccine or an effective treatment continues. However, to win this race, doctors must understand that COVID-19 consists of two diseases: a known viral infection, but also a subsequent immune-mediated syndrome in a subset of critically-ill patients. The latter can be treated with early and aggressive therapy.

Much of the current search for effective COVID treatments focuses on follow the typical infection course any virus takes. This involves a virus being inhaled or consumed, incorporating itself into the cells that line the respiratory and gastro-intestinal tract, and then taking over those cells to replicate the virus’ genetic material and spread it throughout the body. This is what causes respiratory or abdominal symptoms.

Treatment of viruses, including influenza, typically involves early initiation of anti-viral therapies, which act to inhibit this replication and can help the patient’s own immune system fight off the virus from spreading further. Some people have antibodies to specific viruses; these antibodies signal the immune system that a foreign invader is present and cause the immune system to activate and stop the virus before it progresses into a full-scale disease.

The SARS-CoV-2 virus causes an infectious disease known as COVID-19, which in many ways may appear similar to the flu. A patient’s symptoms during the first week of COVID-19 illness are due to this process.

The vast array of symptom severity seen in COVID-19 beyond the second week of illness is likely due to a secondary immune-mediated response triggered by the viral infection: an immune-mediated syndrome. The immune system is designed to protect patients from contagions. This syndrome, occurring in a subset of patients, consists of the virus triggering the patient’s immune system to target their vital organs instead of its expected coordinated attack against the virus. It is a delayed reaction and usually manifests itself after the first 7-10 days of initial symptom presentation.

It is not uncommon for this process to occur with other viruses, however, the SARS-CoV-2 virus appears exceedingly proficient at this hyper-activation of the patient’s immune system and subsequent widespread destruction throughout the patient’s own body. Typical viruses do not cause the wide range and degrees of symptoms that have been associated with COVID-19. Therefore, it is not unreasonable to postulate that reported findings of cytokine storms, hypercoaguable states, vasculitis, Guillain- Barré syndrome, and Kawasaki like-disease seen in children with COVID-19 are the direct result of that patient’s individual immune system going awry, rather than a consequence of an initial viral infection itself.

It makes sense then, that the staggering number of deaths surrounding COVID-19 is likely caused by the patient’s own immune system wreaking havoc on the body.

Current treatments of COVID-19 target slowing the viral spread throughout the body, which is generally effective very early in the viral disease course. The majority of critically-ill COVID-19 patients are hospitalized after the first week of symptom onset, which is usually after a typical virus has run its course. This suggests that critically-ill COVID-19 patients are deteriorating as a result of their delayed individual immune response, and thus, treatment should be individualized toward that patient’s immune-mediated presentation.

One perplexing variable in treating these critically-ill COVID-19 patients involves using medications that suppress their immune system. Initially, the notion of suppressing an immune system during a life-threatening infection seems counter-intuitive. However, if this immune-mediated syndrome is properly diagnosed by the doctor, this treatment approach does show promise.

The methods of uncovering the immune-mediated response can be challenging: doctors must assess their patients as individuals, holistically and continuously evaluating other possible causes of clinical deterioration. Once a doctor can be assured that there is no other cause, they can make this diagnosis of exclusion. However, the choice to treat can literally be life or death. It is this dilemma which has made the disease so evasive. There is no one test that can help doctors make this difficult decision. Instead, they must rely on a combination of critical thinking and extensive medical training to guide them.

The decision to treat this subset of critically-ill patients with medications to suppress their immune system is excruciating. I frequently spend hours agonizing over whether or not I have made the correct choice. Will the immune suppressant I give cause harm or kill my patient? One of my earliest recollections of medical school is the solemnity involved with vowing the Hippocratic Oath: above all, do no harm.

Understanding that COVID-19 is comprised of two diseases—a systemic viral response and an individualized, inappropriate immune response—doctors and researchers can help treat patients more effectively. By checking a variety of laboratory tests, it is entirely possible to detect that this immune-mediated process may be occurring.

With early recognition and subsequent early initiation of therapy with immune suppressing medication, patients should require shorter hospitalizations, less intensive care unit utilizations, and decrease unnecessary loss of life. Crucial to this approach is the conception that each COVID-19 patient must be examined by their doctor as an individual. There is no one-size-fits-all approach to diagnosing and treating COVID-19 patients.

It is imperative that we as doctors assess our patients holistically, rather than becoming fixated on scattered components of their overall clinical picture. With this approach, the battle against COVID-19 can be de-mystified, allowing a clearer picture to emerge in a seemingly everlasting cloud of fear and uncertainty.

Dr. Thomas Yadegar is a critical care physician who has been practicing in Los Angeles, California for 20 years. He oversees two intensive care units and supervises 20 physicians