GINA FERAZZI / LOS ANGELES TIMES Riverside County medical personnel administer a coronavirus test to a motorist at a drive-thru testing facility at Diamond Stadium in Lake Elsinore, California, on March 21. Those tested have symptoms or have had a risk of exposure.

SAN JOSE, Calif. Monica and Adrian Arima both were infected by COVID-19 at the same time on the same Nile River cruise, probably during a shared dinner buffet between the Egyptian cities of Aswan and Luxor. As they traveled home to Palo Alto, California, the couples early symptoms body aches and low-grade fever were identical.

But then, mysteriously, their experiences suddenly diverged. Monica spent 13 days at Stanford Hospital; Adrian was there for just three days. She needed extra oxygen and an experimental drug; he didnt.

Now, weeks later, she still has a cough. He is fully recovered, healthy enough to go food shopping and do other errands. Meanwhile, two of their traveling companions in their 70s and 80s tested positive but never suffered symptoms.

Their experience illustrates one of the many puzzling questions raised by the lethal new disease: Why is COVID-19 so inexplicably and dreadfully selective? The difference between life and death can depend on the patients health and age but not always.

To understand, scientists are scrutinizing patients medical histories, genomes and recoveries for any clues to explain this mystery.

Why are some people completely asymptomatic, some have mild disease, others have severe disease but recover and others have fatal disease? We are still trying to figure this out, said Dr. Brian Schwartz, vice chief for clinical affairs in UC San Franciscos Division of Infectious Diseases.

For most, not severe

It is a small subset of people that will go on to develop serious disease. Most will not, he said. We want to learn how to prevent people from developing serious disease and if they do, figure out how to treat it the right way.

Its well-known that death rates are higher among older people. Only 0.2% of people younger than 19 die. But for people between the ages of 60 and 69, the death rate is 3.6%. It jumps to 8% to 12.5% for those between ages 70 and 79, and 14.8% to 20% for those older than 80.

But theres more to it than that. Monica Arima is age 64; her husband, Adrian, is 70. But she has asthma and diabetes, while his underlying health is good.

Emerging U.S. data confirms trends seen in China and Italy: Rates of serious COVID-related symptoms are higher in those with other medical problems and risk factors, such as diabetes, hypertension, chronic obstructive pulmonary disease, coronary artery disease, cerebrovascular disease, chronic renal disease and smoking. In a U.S. Centers for Disease Control report released Tuesday, higher percentages of patients with underlying conditions were admitted to the hospital and to an ICU than patients without other health issues.

There may also be a genetic influence.

One of the things that weve learned from human genetics is that there are extremes at the human phenotype distribution, and pathogen susceptibility is no different, Stanford geneticist Carlos Bustamante told the journal Science. Stanford is part of a COVID-19 Host Genetics Initiative, a Finnish effort to link genetic variants associated with COVID-19 susceptibility and severity.

There are going to be people who are particularly susceptible, and there are going to be those who are particularly resistant, he said.

At the cellular level

Biologically, whats going on?

One leading theory is focused on the doors of a cell that permit the virus to enter. We know that the virus enters the body through epithelial cells in the respiratory tract. To get inside the cell, the virus uses a door a receptor called ACE-2 (angiotensin converting enzyme 2) on the cells surface.

Individual variations in this receptor could make it harder or easier for the virus to enter, cause infection and burrow deep into the lungs. In some of us, the cell door may open easily; in others, it may stay closed.

Or perhaps some people simply have more of these receptors on their cells. With more doors, the virus may enter more readily, so patients suffer worse infection and more serious disease, said Schwartz.

Theres an abundance of this ACE-2 receptor in cells in the lower lung, which may explain the high incidence of pneumonia and bronchitis in those with severe COVID-19 infection.

Once someone is infected, their immune systems response to that infection is likely the next big decider of their fate.

Doctors are discovering that nine or 10 days into the illness, theres a fork in the road. In most people, the immune system launches a carefully calibrated and effective response, so they recover. But in others, the immune response is too aggressive, triggering massive inflammation in whats called a cytokine storm. Immune cells are overproduced and flood into the lungs, making it hard to breathe and leading to often fatal acute respiratory distress syndrome. Those people develop sepsis, then acute kidney and heart damage. By day 20, they may be dead.

Why does the immune system misbehave? One reason may be age. As we get older, our immune response grows less accurate. It doesnt respond as effectively, and it is not as well-regulated. Genetics may also play a role.

Finally, other preexisting illnesses seem to elevate our risk, although the precise mechanisms arent known.

There may be something about these illnesses that causes them to have an abundance of ACE-2 open doors on the cell surface, Schwartz speculated.

Or perhaps the viral infection worsens the underlying diseases.

Not just the lungs

While typically considered a threat to the lungs, the virus also presents a significant threat to heart health, according to recently published research.

Cardiovascular disease, for example, is an inflammatory condition; so is COVID-19, said cardiologist Dr. Michelle A. Albert of UC San Francisco and president of the Bay Area American Heart Associations board of directors.

New research shows that the inflammatory response of a cytokine storm can lead to heart failure.

The circulating cytokines released during a severe systemic inflammatory stress can lead to atherosclerotic plaque instability and rupture. And infections can trigger an increase in myocardial demand.

Against the backdrop of existing inflammation, it could set off a cascade that results in a worsened underlying biological system, she said.

Some cancer treatments including chemotherapy, targeted therapies, immunotherapy and radiation can weaken the immune system, making a patient more vulnerable.

And if the airways of the lungs already are impaired by illnesses such as cystic fibrosis, asthma, emphysema or surgery, that person is much more susceptible to a pathogen that enters and infects the injured tissue.

People living with cystic fibrosis particularly need to be cautious because they already have compromised lung function and are susceptible to chronic infections, said Ashley Mahoney of the Cystic Fibrosis Foundation.

That likely explains the different courses of illness experienced by singer songwriter John Prine and his wife, Fiona, both infected during a recent tour in Europe. Fiona has recovered. But Prine, a survivor of lung cancer surgery, is hospitalized and critically ill.

Also at risk is anyone who must take medication to suppress their immune systems, such as organ transplant recipients.

Viral infections are always hard on people with diabetes, according to the American Diabetes Association. Thats because infection can cause the body to produce higher levels of certain hormones, such as adrenaline or cortisol, which counter the effects of insulin. Patients may develop a dangerous condition called diabetic ketoacidosis.

Patients come in all different kinds, said Monica Arima.

Some, like my husband, recover at home, without much help, she said. But I got knocked down.

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