Although SARS-CoV-2, the virus that causes COVID-19, has been present in the United States for more than 18 months, most media coverage has coalesced around case counts, mask policy disagreements, the percentage of Americans who have received all the recommended doses of a COVID-19 vaccine, and “variants of concern,” such as Delta.

One topic receiving little coverage, however, is how the SARS-CoV-2 virus makes people sick, and why some people die. The Press spoke with clinical neurologist and autoimmune researcher Dr. Philip McMillan to learn about one theory for the mechanism of disease in COVID-19. Dr. McMillan has published two papers on the subject, in partnership with Dr. Bruce Uhal of Michigan State University.

These papers describe the unusual etiology of illness in COVID-19, including “a severe inflammatory response in the lungs with involvement of the liver and kidneys.” Noting that “the pattern of severe inflammation does not seem to follow that of any other similar viral infection,” Drs. McMillan and Uhal suggest that inflammation is an indication that autoimmunity is involved in severe COVID-19 cases. (Papers available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351250/ and https://www.frontiersin.org/articles/10.3389/fimmu.2021.582166/full)

Researchers investigating the SARS virus in 2004 knew that angiotensin-converting enzyme 2 (ACE2) binds to the S1 domain of the SARS-CoV protein (DOI: 10.1002/path.1570). Early in the current pandemic, researchers noted that SARS-CoV-2 also binds to ACE2.

Most people know ACE2 as a protein involved in regulating blood pressure. However, it is widely distributed in the body, attached to the membranes of cells in the heart, the kidneys, the gastrointestinal (GI) tract, and other organs. In addition to membrane-bound ACE2, ACE2 also floats freely in the serum (blood plasma). Drs. McMillan and Uhal observe that certain individuals, notably those with high blood pressure and heart failure, have elevated levels of ACE2 in their serum.

Explaining a possible mechanism for autoimmune damage – the body attacking itself in the presence of a protein or other “invader” – the researchers suggest the following pathway: First, SARS-CoV-2 binds to ACE2 that is floating freely in the serum. Then, white blood cells encounter the virus-bound ACE2. The body makes antibodies not only to the virus, but also to the ACE2. These antibodies to ACE2 attack tissues in the body containing this protein, including those of the heart and kidneys.

One piece of evidence supporting the autoimmune theory is the successful use of steroids in treating some coronavirus patients. Steroids dampen the body’s immune response, making their use in fighting a virus counterintuitive. Indeed, researchers did not turn to drugs such as dexamethasone until several months into the pandemic (https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04575-w).

Autoimmunity is also consistent with “long COVID,” persistent symptoms after the virus has been cleared from the body. After the virus is gone, antibodies to both SARS-CoV-2 and to ACE2 remain, Dr. McMillan theorizes, causing heart rhythm irregularities and other symptoms.

Autoimmune involvement in COVID-19 also explains the unusual side effects of both mRNA vaccines and adenovirus-vectored vaccines, Dr. McMillan says. “The recombinant ACE-2 is similar to serum ACE2 in that it is floating freely in the blood and binds very tightly to the spike proteins.” Unfortunately, he notes, “This whole process can trigger an autoimmune response. ACE-2 is located in the lungs, the heart, the kidney, and on platelets, which are involved in blood clotting.”

Next-generation vaccines

Dr. McMillan asserts that the greatest benefit of vaccination is to reduce the severity of disease in high-risk individuals, and contends that the use of mass vaccination campaigns to produce “herd immunity” is a well-intentioned error.

“The greatest benefit from vaccination is to those who are high-risk for severe COVID,” he notes, “and that’s where all of our focus should have been, not just in the first-world countries, but across the world.”

None of the manufacturers (Pfizer, Moderna and Johnson & Johnson) of COVID-19 vaccines distributed in the United States have claimed that their products reduce transmission of the virus. Rather, manufacturers asserted that their trial data showed reduced symptomatic infection, compared with control (unvaccinated) groups.

Although the federal government, which continues to control distribution of COVID-19 shots, staged its rollout to begin with vulnerable groups such as nursing home residents, the messaging changed from “protect the vulnerable” to “vaccinate the entire country.” The drive for mass vaccination may stem from conjectures about vaccine-derived herd immunity, and seems to have begun in earnest in the United States with President Joe Biden’s May 4, pronouncement of a “national goal” of 70 percent of adults having received at least one coronavirus shot by Independence Day. Among human diseases, only variola major (smallpox) has been eradicated by a mass-vaccination campaign.

Dr. McMillan anticipates improved vaccine-based protection as researchers develop different modalities. In particular, he sees promise in inhaled vaccines. Oxford University and AstraZeneca researchers currently have one such product in trials. He echoes other researchers’ calls for further research and development of vaccines to stimulate mucosal immunity, rather than only serum antibodies. (For more information, see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445431/)

Tissue pathology

examinations needed

In addition to studying the timing and types of steroids that help patients with severe COVID-19, Dr. McMillan calls for more research into the etiology of severe COVID-19 disease.

“Over 2.4 million [COVID-19 patients] have died across the world, and the number of autopsies is just over 1,000,” he laments. “The fundamental basis of medicine is pathology. We need to look at the tissue. What we have not done is look at enough tissue to fully delineate the mechanism of the disease. Until we have absolute clarity on the mechanism, every patient who dies should have an autopsy: samples of lungs, kidneys [other organs]. You can’t solve a disease that you don’t understand.”

Specifically, he believes that autopsies of people who died with, rather than from, COVID-19 will help unravel the mechanism of the disease. Referring to them as “asymptomatic autopsies,” he explains, “Imagine somebody who got hit by a bus, and you swab that person’s nose and it’s positive for COVID. What you want to know is what is happening in their lungs. It has been assumed that the person gets symptoms on Day 1 [after infection], but in reality, someone infected with coronavirus gets symptoms on Day 3. What happens in the body is critical to understand, to see how autoimmunity happens.”