Ask an Infectious Disease Expert: What Causes a Severe Case of COVID-19?

Makeda Robinson, MD, PhD, is an infectious disease specialist currently studying virus-host interactions in emerging viruses at Stanford University. Each week, Dr. Robinson breaks down complicated COVID-19 topics and addresses pressing public health concerns.

One of the most perplexing issues surrounding COVID-19 is why it manifests itself so differently in different people. Why is the disease mild for so many and extremely deadly for others?

While preexisting chronic diseases can make a person more vulnerable to COVID-19, they're not enough to explain the wide discrepancy in symptoms. Dr. Robinson spoke with Verywell Health about how certain genetic factors and immune responses play a role in the severity of the disease. 

Verywell Health: Why do some patients develop such severe COVID-19 symptoms, while others experience mild symptoms or no symptoms at all? 

Dr. Robinson: There are some known factors like age, gender, current health status, and the state of the immune system that play a role in symptom severity. But recently, we’ve learned that previous exposure to viruses and other pathogens can prime our immune systems to either react more or less quickly to different triggers.

Some people who have had exposure to related coronaviruses—which include versions of the common cold—have antibodies in their system that can help them fight SARS-CoV-2. However, this isn’t the case for everyone who has been exposed to the common cold, because our immune systems are so different.

For a person who has never been exposed to a coronavirus, SARS-Cov-2 will be completely new to their immune system. Their immune system is basically starting from scratch, so they may potentially have a worse outcome.  

Verywell Health: How does gender influence COVID-19 symptoms?

Dr. Robinson: Men are at higher risk than women for developing severe COVID-19 because of the way the immune system works. It’s possible that women’s immune systems are more reactive and mount a more robust early response after infection. This allows them to clear the virus more quickly, which leads to less severe symptoms.

Additionally, exposure to sex hormones can change the response of immune cells. While both men and women are exposed to sex hormones, estrogen, which is more common in women, can reduce the expression of something called ACE2. ACE2 is the protein receptor for SARS-CoV-2. By reducing the expression of ACE2, estrogen potentially reduces the ability of the virus to infect cells. This impacts both the chances of infection and symptom development. 

Studies have also shown that women may have a more robust cytotoxic T cell response. The function of T cells is to find and kill infected cells. So women may be able to control the infection more quickly before it gets out of control.

The immune response in men may be slower, allowing the initial flames of infection to develop into a fire.

Verywell Health: Why are older adults more at risk for severe COVID-19?

Dr. Robinson: We know that older people are at higher risk for severe disease. As we get older, our immune responses can become less effective. Once we hit 50, we start to see differences in the number of our immune cells and how reactive they are to different triggers. This phenomenon is called “immunosenescence.”

During immunosenescence, two things happen: immune cell function begins to decrease and cells become locked in an inflammatory state. These two aging processes mean older adults may be unable to control the initial infection, and then may develop an overly-aggressive inflammatory response. This response can lead to severe COVID-19 symptoms.

Verywell Health: Can people spread COVID-19 even if they don’t have symptoms?

Dr. Robinson: Earlier on [in the pandemic], researchers were thinking that symptomatic people likely "shed" the virus for longer periods of time, but newer research shows that asymptomatic people are likely shedding for the same—if not longer—period of time than symptomatic people.

What this means is that asymptomatic people are contributing to the spread of this virus. We've been looking at the tip of the iceberg, which is symptomatic people or severely affected people. But there’s all of this iceberg below the surface that we can’t see: asymptomatic infected people who have no warning signs. 

The problem here is that they may not necessarily incorporate the behavioral changes that symptomatic people would. If you’re symptomatic and you’re coughing or sneezing or not feeling well, you’re more likely to cover your mouth, get tested, and be cautious with who you see and where you go. If you’re asymptomatic and you feel fine, you may not. That may lead to infecting many other people.

Asymptomatic spread is becoming increasingly dangerous. For example, while children appear to have better outcomes than older adults, they can get infected and spread the virus to people who are much more vulnerable.

Verywell Health: What's an example of an underlying health condition that can make someone's COVID-19 symptoms even worse?

Dr. Robinson: Lung disease is an example. If you're already not oxygenating well and then you contract a respiratory viral infection which leads to increased inflammation, it's going to be more and more difficult for you to breathe. You don't have the lung reserve to fight it off.

Diabetes is also a risk factor for many things, because you have a higher state of inflammation to begin with. Basically, because your body is inflamed prior to infection, it won't inhibit the pro-inflammatory response seen in severe COVID-19 cases. This inflammation is what leads to the need for increased ventilation.

Verywell Health: We've seen several studies regarding vitamin D deficiency and COVID-19 severity. What do you think about the link?

Dr. Robinson: While vitamin D deficiency is a potential risk factor for developing severe symptoms of COVID-19, it often overlaps with other risk factors like older age, obesity, and ethnicity. Therefore, it's difficult to identify vitamin D deficiency as a risk factor on its own. However, it appears that active form of vitamin D, calcitriol, could have an antiviral effect both early during infection and in the later pro-inflammatory stages.

Human clinical trials are underway to study the effects of vitamin D as a standalone treatment. This would be an ideal low-risk, high reward therapy, even as a supplement to current treatment regimens. 

Verywell Health: Is it possible to prevent severe COVID-19 symptoms?

Dr. Robinson: No one is immune to this virus and we don’t know how anybody is going to respond to it, so we have to take as many precautions as we can. As we enter into fall, we should be thinking about how we are going to interact as safely as possible in our work environments and how to keep our children safe in their learning environments.

We know that people with no symptoms can carry and transmit SARS-CoV-2, so we shouldn’t assume that we are protected from infection simply because we don’t see anyone who “looks sick.” We all now know the tenants of social distancing, mask-wearing, and hand washing. Implementing these interventions and setting up guidelines early may prevent outbreaks and reduce anxiety as we continue to learn, work, and live in the new normal.

The information in this article is current as of the date listed, which means newer information may be available when you read this. For the most recent updates on COVID-19, visit our coronavirus news page.