Four Different Family Members. Four Different Covid-19 Outcomes.


The Ruspini family in Sunnyvale, Calif., went down like dominoes. One by one, they all got the coronavirus in early April, but with different symptoms and recovery trajectories.

Diego Ruspini, a 53-year-old computer scientist with a history of asthma, was hospitalized for a week in early April, and coped with respiratory issues and fatigue until August.

His wife, Connie Lares, a 48-year-old medical interpreter at Stanford Children’s Hospital, had a couple of weeks of low-grade fever, body aches, diarrhea and hot flashes. By June she felt well enough to hike a 14,500-foot mountain.

Severe reaction: Diego Ruspini was hospitalized for Covid-19 back in April and was on supplemental oxygen for a week. His cough lasted several months, and fatigue for longer.

Their 17-year-old daughter, Natalia, was hardly able to eat for months, and dealt with brain fog and fatigue. And their 12-year-old son, Santiago, had no symptoms except for an increased appetite and low-grade fever for a few days, despite a congenital heart condition.

One of the biggest mysteries of the virus that causes Covid-19 is why it leads to such different experiences for the people it strikes. While some severe outcomes can be explained by people more at risk of serious illness—such as the elderly and those with chronic conditions—other outcomes have left doctors and researchers stumped, particularly the subset of Covid-19 patients with persistent symptoms, who often refer to themselves as long-haulers or long-Covid patients.

Several studies—including at Columbia University, Stanford University School of Medicine, and the University of California, San Francisco—are trying to better understand the different reactions to the same virus.

Faster recovery: Connie Lares was sick with a low-grade fever, body aches, diarrhea, and hot flashes for a couple of months. She felt completely recovered by mid-June.

“The thing that has really stood out to me the most about this viral infection is that it’s really remarkable how much variability there is on the recovery end,” says Michael Peluso, a clinical fellow in the division of HIV, infectious diseases, and global medicine at UCSF, and a member of a team working on the LIINC (Long-term Impact of Infection with Novel Coronavirus) study.

The Ruspini family is part of a Stanford Medicine study—called The Long Term Immunity (LTI) study—looking at the immune response and post-Covid health of about 200 participants. The study includes 40 children, 20 pregnant women, as well as couples and families. About 30% of participants were hospitalized due to Covid-19.

The participants’ symptoms are varied and can’t all be explained by genetics, says Kari Nadeau, a professor of medicine and pediatrics at Stanford University and director of its Sean N. Parker Center for Allergy and Asthma Research, who is overseeing the study. “Even within one family who get the same strain of the virus at the same time and have the same underlying genetics, the symptoms that people are showing can be different,” says Dr. Nadeau.

Prolonged symptoms: Natalia Ruspini, now a 17-year-old high school senior, was confined to bed for two weeks. She had a lack of appetite, fatigue and brain fog for several months.

The study was originally slated to be three months, says Dr. Nadeau, but was extended to four years when researchers found that for a subset of patients—about 10%—the symptoms from Covid-19 persisted more than three months.

“We’re trying to understand what biomarkers could have preceded the ability to know whether someone is going to have a more chronic form of the disease or not,” says Dr. Nadeau.

The most common persistent symptoms include arthritis, fatigue, cognitive dysfunction, and vasculature issues such as atrial fibrillation, cardiomyopathies and blood clotting. Kidney issues are also frequent.

“These are all new symptoms that they didn’t have before Covid,” says Dr. Nadeau. “What happens in the immune system is that as the inflammation takes shape and misfires, you start to see additive diseases.”

Mildest case: Santiago Ruspini, who recently started seventh grade, was the one Ms. Lares was the most worried about because he has a congenital heart condition. “I was relieved, his symptoms were the mildest of all,” she says.

Among early findings: Pregnant women with Covid-19 appear to shed virus cells for a longer time—as many as 100 days for some. (It is unclear if the virus is dead or infectious.) Nearly 10% of participants developed antibodies often associated with autoimmune diseases. Also, Covid-19 may reactivate dormant viruses in the body.

“Covid might have a higher rate of causing those reactivations because of the intense exhaustion of the immune system,” says Dr. Nadeau.

Researchers are also following immune reaction markers associated with blood clotting issues, as well as lung scarring and remnants of pneumonia in patients who didn’t experience pulmonary symptoms.

Other researchers are making similar discoveries.

Lawrence J. Purpura, a researcher and physician with New York-Presbyterian/Columbia University Irving Medical Center’s division of infectious diseases, is working on a post-Covid study following about 160 patients over six months to see if they develop antibodies, how long those antibodies last, and the duration of patients’ symptoms, among other things. About half the patients were hospitalized for Covid-19.

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Dr. Purpura’s study is reviewing data from the last three months and finding a much higher rate of symptoms than expected. “Over 60% of patients are reporting at least one symptom at every visit, with weakness, shortness of breath, headaches, muscle aches, joint pain, and psychiatric symptoms being among the most common,” he says.

“It is not surprising that patients who were in the ICU or intubated are having long-term health complications and longer recoveries,” he adds. “Most of these complications have nothing to do with ongoing effects of the virus itself and are due to prolonged hospitalization and general deconditioning.” But they are seeing similar rates of persistent symptoms in the patients not hospitalized for Covid.

Dr. Kari Nadeau is overseeing a study at Stanford University that the Ruspini family is participating in. The study was originally slated for three months, but was extended to accommodate patients suffering from prolonged symptoms.



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Stanford School of Medicine

“You don’t see that with flu or most other viral infections,” Dr. Purpura says. “This virus is acting differently, and these long-term sequelae may be due to underlying inflammation or dysregulation of the immune system.”

Dr. Purpura says he is helping launch a Covid-19 clinic at NYP/Columbia that will specialize in providing care to Covid-19 patients with long-term symptoms.

Dr. Peluso says UCSF’s LIINC study has enrolled about 150 Covid-19 patients—one-third of whom were hospitalized—with the hopes of having up to 300. The study compares about 40 people who experienced prolonged symptoms for up to four months with the remainder of the group for whom the illness has resolved.

“We are trying to find out what’s going on biologically and immunologically—what’s causing those symptoms and can we identify biologic targets for them,” says Dr. Peluso. “It’s hard to know at this point whether there’s a single biological mechanism that underlies every possible symptom presentation. Or is this a post-viral syndrome?”

Meanwhile, the Ruspini family says it is happy to contribute to Stanford’s research. “We are committed in any possible way our experience can be useful to anyone,” Ms. Lares says.

Researchers collect blood, saliva, nasal swabs and questionnaires from participants every month, and are focused on how the immune system responds to the virus. Different immune cells and pathways are activated during the various phases of the infection, says Dr. Nadeau.

“We need to be able to find these biomarkers when these immune changes are still at the molecular level, before they become troublesome clinical symptoms, so that we can intervene early,” Dr. Nadeau says.

“We really need to figure this out,” she says. “Fast.”

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