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Saved Stories – None: The Complex Pathogenesis Of Covid-19

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A health worker checks a patient at the COVID-19 area of the 32nd Zone General Hospital of the … [+] Mexican Social Security Institute (IMSS) in Mexico City, on July 20, 2020, amid the new coronavirus pandemic. (Photo by PEDRO PARDO / AFP) (Photo by PEDRO PARDO/AFP via Getty Images)

AFP via Getty Images

Our understanding of Covid-19 as a disease has evolved rapidly over the course of the pandemic. While many aspects of Covid-19—from its symptoms to its duration to its short- and long-term aftereffects—remain difficult to pin down, we now have enough data to identify four broad stages of infection that can guide us going forward.

To grasp the complete picture, it helps to look back on how each individual piece of the puzzle fell into place. The story began, like most mysteries, with an emerging problem and a complete lack of knowledge. In the first few weeks of the outbreak, Covid-19 appeared to be nothing more than a serious pneumonia. Symptom-wise, it seemed similar enough to what some people experience when they contract a severe case of the flu.

A month went by. Researchers in China, and soon enough elsewhere, began to realize that the lung damage associated with the disease was more complex than previously thought. This was due in large part to an overreaction of the immune system known as a cytokine storm. Not only was the pathology of autospied lungs atypical for viral-induced pneumonia, but high levels of inflammatory chemokine and cytokines were present as well.

About two months into the pandemic, physicians around the world began noticing hypercoagulation—rampant blood clots, in other words. Heart attacks, ischemic strokes, and lung emboli were noted, as well as the incidence of blood clot-related kidney disease.

More recently, evidence has emerged that suggests the existence of a late hyperinflammatory phase. When Covid-19 patients enter this stage, the lining of the blood vessels—arteries and veins alike—becomes inflamed. Skin rashes, Covid toe, and other markers of hyperinflammation appear.


What’s curious about the disease progression is that most of it occurs after the immune system begins to clear the replication-competent virus. What’s more, viral RNA has been found lingering in the body long after the infectious virus has disappeared.

This raises the possibility that much of the late—and highly lethal, I might add—aspects of the disease don’t occur because the virus is continuing to propagate itself, but because replication-competent sub-genomic fragments persist that are partially sequestered from immune recognition. Such pathology would be unusual, but not unprecedented.

The chart below, created by infectious disease specialist Dr. Daniel Griffin, represents our current knowledge of how Covid-19 progresses, from the moment of infection to no certain end. The pathologies described above can be summed up in four phases: the viral phase, cytokine storm phase, coagulation phase, and late hyperinflammatory phase.

Phases of Covid-19

The four phases of Covid-19

“COVID-19 Testing: How Long Is Someone Infectious Enough To Be Able to Spread The Virus? How to Limit Undetected Infectious Days?”, Dr. Daniel Griffin, Columbia University’s Zuckerman Institute, July 17, 2020,

Aspects of the infection not depicted in this chart include damage to insulin-producing islet cells, which leads to diabetes; damage to the splenium of the corpus callosum, which leads to neurological complications; and damage to cells of the liver and heart. More pathologies are to come, I’m sure, as the number of Covid-19 patients increases.

That so many Covid-19 patients go on to develop such a diverse array of adverse health outcomes is troubling, to say the least. But the more we learn about this disease, the more capable we become of developing tools to mitigate it. My hope is that those come to fruition sooner rather than later.

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I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard Medical School and Harvard School of Public Health where I

I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard Medical School and Harvard School of Public Health where I founded two academic research departments, the Division of Biochemical Pharmacology and the Division of Human Retrovirology. I am perhaps most well known for my work on cancer, HIV/AIDS, and genomics. My work now also includes efforts to improve access to high quality, affordable healthcare for people in low, middle, and high income countries alike. I am chair and president of ACCESS Health International, a nonprofit organization I founded that fosters innovative solutions to the greatest health challenges of our day. Each of my articles at will focus on a specific healthcare challenge and offer best practices and innovative solutions to overcome those challenges for the benefit of all.

Saved Stories – None