PHILADELPHIA — In mid-February, when the coronavirus was well on its way in the United States but almost no one was on the lookout, two employees at a northern California hospital struggled to help a woman who was feverish and gasping for breath.
They gave her a nebulizer. They put her on a type of breathing machine sometimes used for sleep apnea. After several days, one of the health-care providers stuck a tube down the woman's throat and hooked her up to a ventilator.
Eleven days later, she tested positive for the virus. Sure enough, the two hospital workers did, too.
But how to explain 15 other nurses and therapists _ each involved in procedures that would have filled the air with the patient's infectious particles _ who did not?
Four months into this worldwide affliction, these kinds of puzzles continue to defy easy answers.
As a rule, the greater a person's exposure to a virus, the higher the chance of infection and the worse the symptoms _ up to a point. With this virus, witness the more than 9,000 U.S. nurses, paramedics, doctors, and other health professionals who had tested positive as of April 9, including at least 700 who had to be hospitalized.
But mounting evidence suggests the "dose" of the coronavirus is just a small part of the story, researchers say. In many of the patients with severe symptoms, the immune system has somehow gone haywire, overwhelming the lungs with inflammation so that the body's response is worse than the virus itself.
That older people would be more likely to get very sick is no surprise, as their immune systems tend to be weaker. People with preexisting heart or lung disease, sure. But some combination of other factors seems to be at work, determining why many suffer mild symptoms or none at all.
Patients' genes almost certainly play a role. Perhaps so does their microbiome, or what infections they have encountered in the past, said Arturo Casadevall, chairman of microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health.
"Everybody wants a simple answer," he said. "When it comes to infectious disease, the most important message you can convey is that many variables combine to produce unpredictable outcomes."
Here is a crash course on where scientists are looking for clues:
The front lines
A key defense against the coronavirus, and any respiratory virus, is not the immune system at all, but mucus. Countless infectious particles are trapped in this gunk; we swallow more than a quart every day. Once the mucus reaches the stomach, the viruses within are safely dissolved in acid.
But the more viruses a person inhales, the greater chance some will bypass this barrier, latch onto cells in the airways, and get inside to start multiplying _ the definition of an infection.
"It's like playing the lottery," said Matthias Schnell, a professor of microbiology at Thomas Jefferson University.
With the coronavirus, the number of particles, the way they are transmitted, and the type of human cell they encounter all are likely to be key. Smaller "aerosol" particles _ the kind produced more often by ventilators _ travel deeper into the airways, potentially leading to more severe illness, said Richard Webby, a flu specialist at St. Jude Children's Research Hospital in Memphis.
A description of the episode at VacaValley Hospital in Vacaville, Calif., contained in a study by local and federal health officials, does not include how sick the workers became after operating ventilators and other aerosol-generating devices _ only that two tested positive and 15 did not.
Scientists test different exposures to other viruses, such as those that cause common colds and the flu, by placing microbe-laden droplets in the noses of human volunteers. The coronavirus is too dangerous for that, but researchers have started doing such experiments in ferrets. The animals do not seem to get as sick as humans, yet their response is similar enough that they could be used as a model for how humans might respond to drugs.
Learning to fight
Once a virus gets inside a target cell, the immune system kicks into gear. The cell releases chemical warning signals to its neighbors. It tries to self-destruct before the virus can make copies of itself. Should any of these copies escape, specialized killer cells stand by to engulf them.
These early "innate" responses to infection ramp up almost immediately. A second, "adaptive" response generally takes a few days. It is set in motion by white blood cells that carry pieces of viruses to the lymph nodes, where other immune-system cells learn various customized strategies to fight back.
A diagram of all this looks like a plateful of intertwined spaghetti noodles, illustrating one reason that developing drugs against viruses can be difficult. Treat someone with a drug that affects one strand, and you may produce an unintended consequence in another, giving the virus a boost.
Another good analogy is a symphony, with all sorts of molecules and cells entering and leaving the fray at various times, said Glenn Rall, a Fox Chase Cancer Center professor who studies viruses that infect the brain.
Usually the players get the job done, despite the fact that there is no overall conductor. But in some people infected with the coronavirus, the music spins out of control, and no one is sure why.
Among the possible culprits:
Chemicals called cytokines, normally essential to the body's immune response, can provoke an inflammatory "storm." University of Pennsylvania researcher Carl June has proposed treating that problem with an immune-suppressing drug called cyclosporine.
A gauzy "web" formed by overactive white blood cells called neutrophils may cause lung damage. That topic is being studied by 11 research institutions including Cold Spring Harbor Laboratory.
Deficiency in an enzyme called G6PD interferes with the ability of red blood cells to clean up toxic by-products of metabolism. This condition ordinarily causes no symptoms, but it affects millions worldwide, especially those of Mediterranean descent. Among those infected with the coronavirus, the added stress from this deficiency could make them sicker, said Dan J. Vick, a pathologist at Central Michigan University. Could that explain the high death rate in Italy?
Bahaa Elzein, 30, who is starting a residency at Detroit Medical Center this year, is intrigued. Young and otherwise healthy, he is of Lebanese descent and has the enzyme deficiency. He became infected with the coronavirus in March, though he is not sure how, and it left him bedridden more than a week.
"It hit me," he said, "like a bus."
Still others have investigated patients' blood type. A Columbia University study suggests those with type A-positive may be at greater risk of infection, but there is no plausible explanation for why that might be, coauthor Nicholas Tatonetti said. Men seem more likely to be hit hard, suggesting that hormones may play a role.
More answers may come soon. On April 14, the leaders of the UK Biobank _ one of the world's largest databases of human genetic and health records, with more than 500,000 people enrolled _ announced that data on those infected with the coronavirus would be available to other researchers.
For those who recover, another unanswered question is how long they are immune.
Infection with a specific strain of virus generally makes the person immune to future infections with that strain for a year or more. This immunity also may offer some protection against similar strains, as seems to happen with the flu.
But for some viruses, the opposite is true, said Casadevall, the Hopkins researcher. A prime example is dengue, a viral disease that causes such severe joint pain that it is nicknamed "breakbone fever."
People infected with one type of dengue become resistant to that type. But if they are then infected with another type, they can become even sicker, Casadevall said. Antibodies that were developed to fight the one type somehow enable the second type to wreak havoc.
"You are the product of every immunologic experience you have had since you were a baby," he said.
Who can tell the answers to such questions for the coronavirus? As the pandemic rages on, the hunt has only just begun.
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