Are Patients Dying 'From' COVID or 'With' COVID?

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Death is usually fairly easy to diagnose; cause of death, not so much. In fact, death certificates in the United States and around the world are notoriously wrong.

How does this happen? Death certificates are supposed to be completed by the "attending physician," who is expected to know the most about the patient's medical conditions. In a hospital setting, however, the physician who pronounces death may never have seen the patient before. Deaths that were unobserved or sudden often are referred to a medical examiner or coroner and may prompt an autopsy.

States must submit all death certificate information to the National Death Index for compilation into national vital statistics that guide public health and health policy decisions, and are the foundation of many vital statistics, such as the leading causes of death.

The Centers for Disease Control and Prevention (CDC) provides instructions for completing a death certificate online that are intended to make the process clear and relatively easy to do. Still, generations of American physicians have found it not at all easy to do this well.

One or Many Causes of Death

The death certificate form requires that an immediate cause of death be listed first. This is followed by a list of underlying (also referred to as predisposing) conditions that were contributory.

Take the example of influenza. The CDC notes a range of predisposing factors that could increase the risk for a serious complication from influenza, including death. These include an age of 65 years or older, pregnancy, chronic lung disease, heart disease, diabetes, and cancer.

We're still learning about COVID-19, but similar factors seem to predispose to a more serious outcome: older age, chronic lung disease, serious heart conditions, being immunocompromised, and living in a long-term care facility.

Early on, there was confusion about whether this novel coronavirus was truly different or simply another form of the influenza virus. Emergency use ICD-10 codes were assigned by the World Health Organization for the COVID-19 outbreak, one for identified and one for suspected disease. Data on the use of those codes suggest that confusion may still linger.

The CDC website reports a provisional COVID-19 death count. This tally includes thousands of deaths attributed solely to COVID-19. A second category of deaths from both pneumonia and COVID-19 includes thousands more persons. A third category of deaths lists three causes: pneumonia, influenza, and COVID-19. There are separate categories for deaths due to pneumonia or influenza alone.

Have you got that straight? I am more confused than ever.

What we are seeing in the data is the long-standing practice of lumping influenza and pneumonia into a single category of death. COVID-19, it appears, has now been added to create a single, catch-all category.

Comparing Annual Causes of Deaths

The 1968 H3N2 pandemic was reported to have resulted in a million deaths worldwide, with over 100,000 of them in the United States. I studied autopsies conducted in the Los Angeles area during a period that included that pandemic and compared year-over-year pneumonia diagnoses. I found no real differences. As a result, I have been a long-term skeptic of numbers of annual deaths reported to be due to influenza.

As a pathologist with decades of autopsies under my belt, I have never examined an individual with proven influenza who did not also have a superimposed, likely fatal, bacterial infection. I queried 25 other pathologists to see if their experience was different, and most simply said "no." One noted that H1N1 flu could cause diffuse alveolar damage and thus could be lethal all by itself. One responded with a "maybe." Two described influenza patients with acute respiratory distress syndrome.

From 2010 to 2019, the CDC reported annual death rates from influenza that ranged from 12,000 to 61,000. These numbers are derived from a mathematical calculation of "influenza-associated deaths"; they do not rely on death certificate information.

Why such huge numbers? I would argue that it is the result of lumping influenza with bacterial pneumonia. Most patients are not dying from influenza but rather with influenza that is comorbid with something else lethal.

We all know that association is not causation. Maybe this would be a good time to return to the drawing board to look at how the United States determines its death counts from influenza and try to ensure that the same mistake is not repeated with COVID-19.

What Are the Real Risk Factors?

It is unclear whether the simple fact of being 65 or older is a risk factor for death from COVID-19. Instead, are people in this age group just more likely to have a comorbidity that increases their risk for death with COVID-19? Do these predisposing conditions make it more likely that the individual will contract the illness? Or is it that they are more likely to suffer serious harm if infected?

A high, though unknown, percentage of us who are exposed to the virus appear to repulse it and may not even realize that an encounter occurred. Others are symptomatic but recover after a variable period of time. Many others (we don't know why) become seriously ill, sometimes with startlingly rapid progression. Large numbers die, often with multiorgan failure. For some, an overzealous immune response may become the problem, not the solution. Widespread coagulopathy can occur. Because we are uncertain about the exact number of infections, the true infection fatality rate is still unknown.

Reports of comprehensive autopsies for SARS-CoV-2 have been slow in arriving, due to several contributing factors. Hospital autopsies in the United States have nearly disappeared. Autopsies of COVID-19 patients are dangerous to perform and require special protective facilities, such as negative-pressure rooms. Coroners and medical examiners may be overwhelmed by the sheer volume of dead bodies. Of note, all of that work has left little time for writing papers to share knowledge. Reports from many well-performed autopsies, when they do arrive, will go a long way toward helping us to understand the pathophysiology of this disease.

Meanwhile, it seems obvious that when influenza kills, it does so "with a little help from its (deadly, complicating) friends." COVID-19 often "don't need no help." It can kill by direct viral tissue destruction, disseminated intravascular coagulation, and frequently strange "immune" responses. There is still so much to be learned.

George Lundberg, MD, is sheltering in place without access to his usual video studio. He is editor-in-chief at Cancer Commons and a clinical professor of pathology at Northwestern University. Previously, Dr Lundberg served as editor-in-chief of JAMA (including 10 specialty journals), AMA News, and Medscape.

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