We Thought It Was Just a Respiratory Virus

We were wrong.

By Ariel Bleicher and Katherine Conrad UCSF 
Magazine Summer 2020 Illustration: Anna & Elena Balbusso

In late January, when hospitals in the United 
States confirmed the presence of the novel 
coronavirus, health workers knew to watch for 
precisely three symptoms: fever, cough, and 
shortness of breath. But as the number of 
infections climbed, the symptom list began to 
grow. Some patients lost their sense of smell and 
taste. Some had nausea or diarrhea. Some had 
arrhythmias or even heart attacks. Some had 
damaged kidneys or livers. Some had headaches, 
blood clots, rashes, swelling, or strokes. Many had no symptoms at all.

By June, clinicians were swapping journal papers, 
news stories, and tweets describing more than 
three dozen ways that COVID-19, the disease the 
coronavirus causes, appears to manifest itself. 
Now researchers at UC San Francisco and around 
the world have begun taking a closer look at this 
dizzying array of symptoms to get at the 
disease’s root causes. They are learning from 
people inside the hospital and out; people on the 
brink of death and only mildly sick; people newly 
exposed and recovered; people young and old, 
Black, brown, and white. And they are beginning 
to piece together the story of a virus unlike any known before.

How infection sets in

Viruses lead a curious purgatorial existence of 
being neither fully alive nor dead. Enveloped in 
a protein cloak, a virus consists almost entirely 
of genetic material – DNA or RNA, the blueprints 
for all of life. But it can’t reproduce on its 
own. To survive, it must break into a cell and 
co-opt the cell’s gene-copying machinery.

The novel coronavirus, an RNA virus named 
SARS-CoV-2, has become notorious for its skill at 
breaking and entering human cells. Its tools of 
choice are the protein spikes protruding from its 
surface – a feature that distinguishes all 
coronaviruses. The spikes of SARS-CoV-2 are the 
crème de la crème: By the luck of the 
evolutionary draw, they are able to easily grab 
hold of protein gates on human cells known as 
ACE2 receptors and, like jackknives, pry these gates open.
Illustration of a coronavirus symbol.

Spikes on the virus’s surface act like jackknives 
to break and enter human cells.

“You can think of an ACE2 receptor like a docking 
site,” says 
Fattahi, PhD, a 
Sandler Fellow. When the coronavirus pandemic hit 
San Francisco, Fattahi repurposed her laboratory 
to study this key receptor, which normally plays 
a role in regulating blood pressure. “When the 
virus lands on it,” she says, “it initiates a 
molecular process that brings the virus inside the cell.”

If you’re exposed to SARS-CoV-2 – say, from a 
cough or sneeze – the virus will likely first 
encounter ACE2 receptors on cells in your nose or 
throat. But these receptors also populate your 
heart, gut, and other organs. Fattahi’s team has 
found evidence suggesting that male sex hormones 
such as testosterone may increase the number of 
ACE2 receptors that cells produce, which could 
help explain 
SARS-CoV-2 seems to wreak greater havoc on men 
than on women and why kids rarely get sick. “The 
fewer ACE2 receptors, the less risk of infection 
– that’s the idea,” she says, adding that this 
hypothesis for the disease’s gender gap is only one of several.

Once inside a few initial host cells, the virus 
sets them to work churning out copies of itself. 
Within hours, thousands of new virus particles 
begin bursting forth, ready to infect more cells. 
Although SARS-CoV-2 is less deadly than the 
original SARS virus, which emerged in 2002, it 
replicates more rapidly. Also unlike SARS, which 
primarily infects the lungs, SARS-CoV-2 
replicates throughout the airway, including in 
the nose and throat, making it highly contagious – like the common cold.

Illustration of the inside of a head, with coronavirus cells th

SARS-CoV-2 replicates throughout the airway, 
making it highly contagious, like the common cold.

However, infection with SARS-CoV-2 usually 
doesn’t feel like a cold. Fewer than 20% of 
infected people who eventually show up at a 
hospital report having had a sore throat or runny 
nose. During the first few days of being 
infected, you’re more likely to have a fever, dry 
cough or, peculiarly, lose your sense of smell or taste.

Most likely, though, you won’t feel sick at all. 
When UCSF researchers tested people for 
SARS-CoV-2 in San Francisco’s Mission District, 
of those infected never had any symptoms. “That’s 
much higher than expected,” says 
Gandhi, MD, MPH, a UCSF professor of medicine 
with expertise in HIV. Surveys of outbreaks in 
nursing homes and prisons show similar or even 
higher numbers. “If we did a mass testing 
campaign on 300 million Americans right now, I 
think the rate of asymptomatic infection would be 
somewhere between 50% and 80% of cases,” Gandhi 
says. Millions of people may be spreading the 
virus without knowing it, she points out, making 
asymptomatic transmission the 
heel of efforts to control the pandemic – and 
highlighting the 
of universal masking.

“The majority of people who have COVID-19 are out 
in the community, and they are either 
asymptomatic or only mildly ill,” says 
<>Sulggi Lee, 
MD, PhD, a UCSF assistant professor of medicine. 
When the coronavirus pandemic hit San Francisco 
in early March, Lee conceived a study to 
investigate why. She scrambled to assemble a team 
funding and equipment. She borrowed a colleague’s 
clinic – a van outfitted with an exam table and a 
phlebotomy chair – so that her team could drive 
around the city, collecting samples from infected 
people. Lee hopes data from the study, called 
CHIRP (COVID-19 Host Immune Response 
Pathogenesis), will show how people’s immune 
systems respond as SARS-CoV-2 starts to gain a foothold in their bodies.

“A lot is riding on that initial response,” she 
says. If Lee and her collaborators can figure out 
the biological processes that allow some infected 
people to stay relatively well, they can perhaps 
use that knowledge to prevent others from falling severely ill.

Battling in the lungs

True to its name, SARS-CoV-2 (which stands for 
severe acute respiratory syndrome coronavirus 2) 
is first and foremost a bad respiratory virus. If 
your immune system doesn’t defeat it at its 
landing site in your nose or throat, it will 
advance down your windpipe, infiltrating the 
cells lining your lungs’ branching air tubes. At 
the tubes’ ends, tiny air sacs called alveoli 
pass oxygen to your blood. As the virus 
multiplies, the alveoli may fill with fluid, 
shutting down this critical gas exchange. Your 
blood-oxygen level may drop and, typically about 
six days into an infection, you may start feeling short of breath.

What causes this mayhem? “Some of it is 
definitely caused by the virus itself,” says 
Matthay, MD, a UCSF professor of medicine who has 
studied acute respiratory diseases for more than 
30 years. Inevitably, a fast-replicating virus 
will kill or injure many of the lung cells it 
infects; the more cells it infects, the more ruin it will leave in its wake.
Illustration of a coronavirus symbol.

The virus’s fatality rate seems to be roughly 10 times that of the flu.

But SARS-CoV-2 doesn’t appear to be a savage 
destroyer of cells. Although it’s too early to 
know for sure, the virus’s fatality rate seems to 
be roughly 10 times that of the flu. “You would 
think that’s because it’s just a killing 
machine,” says 
Krummel, PhD, UCSF’s Smith Professor of 
Experimental Pathology and chair of the Bakar 
ImmunoX initiative. So far, however, the science suggests otherwise.

“One of the weirder things about this new 
coronavirus is it doesn’t seem to be incredibly 
cytopathic, by which we mean cell-killing,” 
Krummel says. “Flu is really cytopathic; if you 
add it to human cells in a petri dish, the cells 
burst within 18 hours.” But when UCSF researchers 
subjected human cells to SARS-CoV-2, many of the 
infected cells never perished. “It’s pretty 
compelling data that maybe we’re not dealing with 
a hugely aggressive virus,” Krummel says.

The bigger provocation, he suspects, may be your 
own immune system. Like any pathogen, SARS-CoV-2 
will trigger an immune attack within minutes of 
entering your body. This counterstrike is 
extraordinarily complex, involving many tactics, 
cells, and molecules. In a 
<>UCSF study called 
COMET (COVID-19 Multi-Phenotyping for Effective 
Therapies), Krummel and other scientists have 
been observing this immune warfare in more than 
30 people admitted to UCSF hospitals with 
COVID-19 and other respiratory infections. “What 
we’re doing is looking at patients’ blood, their 
genes, and the secretions from their noses and 
lungs, and we’re asking, ‘What’s your army? What’s your response strategy?’”

An early analysis of COMET data, Krummel says, 
suggests that the immune systems of many 
hospitalized patients mobilize differently – and 
more aggressively – against SARS-CoV-2 than 
against influenza viruses, which cause the flu. 
Their lungs are ravaged, these data suggest, not 
by the virus alone but by the detritus of an 
immunological battle gone awry. This rogue immune 
response could explain why, around day 11 of a 
COVID-19 infection, patients often develop a 
severe pneumonia known as acute respiratory distress syndrome, or ARDS.

Ultimately, COMET seeks to find COVID-19 
therapies that can rein in an overeager immune 
system in order to prevent or treat ARDS. But 
that feat won’t be easy, says 
Calfee, MD, MAS ’09, an ARDS expert, UCSF 
professor of medicine, and co-leader of the 
study. Too much or the wrong kind of 
intervention, she explains, could cripple a 
person’s immune system to the point where it 
can’t clear an infection. “It’s a fine line 
between therapeutic and deleterious,” Calfee 
says. “We’re trying to find that balance.”

Typically, people who die from COVID-19 ARDS die 
around day 19. Reported rates of mortality have 
varied widely, with the highest rates being where 
the pandemic has hit hardest, overwhelming 
hospital resources and staff. At UCSF hospitals – 
likely due to the city’s early shelter-in-place 
orders, which prevented an initial surge of 
COVID-19 cases – so far only 10 of 85 critically ill patients have died.

“The good news is that we’ve been doing clinical 
trials of best-care practices for ARDS since 
1998,” Matthay says. Thanks to 
<>research by 
him and others, for example, clinicians have long 
known which ventilator settings result in the 
fewest deaths and how to flip patients onto their 
stomachs – a technique known as proning – to best 
help them breathe. If public health measures can 
keep hospital admissions low so that frontline 
providers can make good use of the skills and 
knowledge they already have, we may find that we 
have less to fear from SARS-CoV-2 than we thought.

On the other hand, the virus behaves in ways that are still mysterious.



Text upper left: From Head to “COVID Toes” 
underlined. Text below underline: People with 
COVID-19 exhibit from none to many of these 
symptoms. Some symptoms (such as fever, cough, 
and loss of smell) are common, while others (such 
as sore throat, pink eye, and stroke) are rare. 
Middle of page: Illustration of human body. From 
the top: Brain with one plus sign that opens to 
text reading: Headaches, brain fog, dizziness, 
delirium, stroke, and another plus sign that 
opens to text reading: Pink eye. Throat area with 
plus sign that opens to text reading: Loss of 
smell or taste, runny nose, sneezing, sore 
throat. Heart with plus sign that opens to box 
reading: Arrhythmia, weakened cardiac muscle, 
heart attack. Lower left lung with plus sign that 
opens to text reading: Cough, shortness of 
breath, lung injury. Kidney with plus sign that 
opens to text reading: Kidney injury, elevated 
liver enzymes. Intestines with plus sign that 
opens to text reading: Nausea, stomachache, 
vomiting, diarrhea. Upper thigh with plus sign 
that opens to text reading: Fever, fatigue, 
muscle aches, inflammation, blood clots, vascular 
injury. Toe with with plus sign that opens to 
text reading: Skin rash, numbness or swelling in 
feet or hands. Bottom of illustration: rectangle 
filled with faded-back coronaviruses and text at 
far right reading: illustration Stephanie Koch. 
Left of body illustration: small illustration of 
coronavirus. Top and right of illustration: small illustration of coronavirus.

Concept credit: Jennifer Babik, MD, PhD

Heart failure

In April, Susan Parson, MD, a Bay Area medical 
examiner, made a startling discovery. For nearly 
two months, officials had believed that the first 
people in the U.S. to die from COVID-19 had died 
of respiratory failure in Washington state in 
late February. At the time, the U.S. Centers for 
Disease Control and Prevention limited testing to 
people who had respiratory symptoms and had 
recently traveled to China or otherwise been 
exposed to the virus. Those restrictions, however, turned out to be misguided.

As a medical examiner for California’s Santa 
Clara County, Parson had done a routine autopsy 
on a 57-year-old woman named Patricia Dowd, who 
had died suddenly at home on February 6. In 
Dowd’s tissues, Parson found the cause of her 
death: SARS-CoV-2. But the virus hadn’t wrecked 
Dowd’s lungs. In fact, she had only mild 
pneumonia. Instead, SARS-CoV-2 had ruptured her heart.

Meanwhile, epidemiologists began learning that 
preexisting heart disease and related conditions 
put people at greater risk of suffering and dying 
from COVID-19. “We’re finding that many patients 
who have more severe forms of the illness are 
obese, they are diabetic, they are hypertensive,” 
says cardiologist 
Parikh, MD, a UCSF associate professor who 
specializes in population health research. Such 
risk factors, she says, are unusual. “They’re not 
ones that really stood out in prior epidemics.”

Clinicians, too, were seeing surprising numbers 
of COVID-19 patients develop heart problems – 
muscle weakness, inflammation, arrhythmias, even 
heart attacks. “We’re not used to respiratory 
viruses having such dire consequences on the 
heart in such apparently high numbers,” says 
Marcus, MD, MAS ’08, UCSF’s Endowed Professor of 
Atrial Fibrillation Research. Many patients whose 
hearts acted up also had failing lungs. But 
others had no other symptoms or, like Dowd, only mild ones.

Since March, Marcus has co-led one of the largest 
community surveys to better understand the spread 
of SARS-CoV-2 and its myriad effects. The study, 
dubbed COVID-19 Citizen Science, has so far 
enrolled more than 27,000 people; anyone with a 
smartphone <>can 
participate. Marcus plans to also start 
collecting data from wearable devices, including 
Fitbits and Zio patches, which wirelessly monitor 
heart rhythms. “There may be large numbers of 
people who are suffering from cardiovascular 
effects of COVID-19 in the absence of other 
symptoms,” Marcus says. “I’m worried we’re missing those cases.”

It stands to reason that SARS-CoV-2 affects the 
heart. After all, heart cells are flush with ACE2 
receptors, the virus’s vital port of entry. And, 
indeed, laboratory experiments suggest that the 
virus can enter and replicate in cultured human 
heart cells, says 
Conklin, MD, a professor of medicine and an 
expert in heart-disease genetics at UCSF and the Gladstone Institutes.

But Conklin doesn’t think SARS-CoV-2 necessarily 
kills heart cells outright. Rather, in the 
process of copying itself, the virus steals 
pieces of the genetic instructions that tell the 
heart cells how to do their job. “It’s hauling 
away and hijacking stuff that’s necessary for the 
heart to beat,” he says. He is currently testing 
this hypothesis using human heart cells grown in 
cup-sized vessels in the lab of 
McDevitt, PhD, a bioengineer at UCSF and the Gladstone Institutes.

It’s also possible, however, that an infected 
person’s own immune system may do the majority of 
the damage in the heart, as it appears to do in 
the lungs. “The heart probably gets infected by a 
lot of other viruses, and they don’t have a 
lethal effect,” Conklin says. “What makes this one different?”

Graph with three bars. Bar at left has 80% at top 
and Non-Severe at bottom. Bar in middle has 15% 
at top and Severe at bottom Bar at right has 5% 
at top and Critical at bottom. Text below graph 
reads: Most symptomatic cases of COVID-19 are 
mild. To left of graph, small circle with the 
letter “i” in the middle opens to text reading: 
Graph Data: Wu et al., JAMA 2020. Livingston et 
al., JAMA 2020. Garg et al, MMWR 2020. Stoke et 
al., MMWR 2020. Left of graph: illustration of a coronavirus.

Most symptomatic cases of COVID-19 are mild.

Stranger things

Toward the end of March, as San Francisco began 
to warm up, Sonia got cold feet. She put on wool 
socks and turned up her heater. Still, her feet 
felt frozen. Three days later, her soles turned 
splotchy purple. Red dots appeared on her toes. 
At night, her cold feet itched and burned. 
Walking hurt. And she was exhausted, napping 
through afternoon Zoom meetings. “It was so 
bizarre,” says Sonia, a San Francisco resident. A 
week later, her symptoms were gone.

“Yes, COVID,” wrote 
<>Lindy Fox, 
MD, a UCSF professor of dermatology, replying to 
an email describing Sonia’s case. Sonia wasn’t 
surprised. Anyone, like her, who’s been following 
news of the pandemic has probably heard about 
“COVID toes,” a painful or itchy skin rash that 
sometimes pops up in young adults with otherwise 
mild or asymptomatic cases of COVID-19. “It looks 
like what we call pernio, or chilblains,” Fox 
says, “which is a pretty common phenomenon when 
somebody goes out in cold weather – they start to 
get purple or pink bumps on their fingers or toes.”

Many people with rashes like Sonia’s don’t test 
positive for COVID-19, Fox says, which has made 
some clinicians skeptical of the connection; when 
patients have both, it’s just a coincidence, they 
believe. But Fox doesn’t think so. For one thing, 
“the time of year is wrong,” she says. “Pernio 
usually shows up in the dead of winter.” Even 
more compelling, dermatologists around the world 
are “getting crazy numbers of calls about it,” 
Fox says. “In the last three weeks, I’ve had 
somewhere between 10 and 12 patients.
Normally, I have four a year.”
Illustration of a coronavirus symbol.

20%-40% of people with COVID-19 experience 
diarrhea, nausea, or vomiting before other symptoms.

And it’s not just dermatologists who are adding 
their observations to COVID-19’s ever-expanding 
symptom list. Gut specialists are finding that 
20% to 40% of people with the disease experience 
diarrhea, nausea, or vomiting before other 
symptoms, says gastroenterologist 
Kattah, MD, PhD, a UCSF assistant professor. If 
you swallow virus particles, he says, there’s a 
good chance they will infect cells lining your 
stomach, small intestine, or colon. As in the 
lungs and heart, these cells are studded with vulnerable ACE2 portals.

Especially disconcerting, Kattah says, is how 
long the virus seems to persist in the gut. About 
50% of patients with COVID-19 have virus 
particles in their stools, often for weeks after 
their nose swabs test negative, he points out. 
Laboratory studies show that these particles are 
often still alive and can infect cells in a petri 
dish. Whether fecal transmission occurs between 
people, however, is an open question. If the 
answer is yes, people recovering from COVID-19 
may need to stay quarantined even after they feel 
well, and the rest of us will need to be as 
meticulous about bathroom hygiene as we’ve become 
about handwashing and mask-wearing.

Other specialists are also raising flags. 
Neurologists worry about reports of COVID-19 
patients with headaches, “brain fog,” loss of the 
sense of smell, dizziness, delirium, and, in rare 
cases, stroke. Nephrologists worry about kidney 
stress and failure. Hepatologists worry about 
liver injuries. Ophthalmologists worry about pink 
eye. Pediatricians, meanwhile, worry about a 
inflammatory syndrome that’s showing up in kids and young adults.

Researchers are still sorting out the causes for 
this constellation of effects. If you come down 
with a particular symptom, is it because the 
virus is attacking your cells? Because your 
immune system is overreacting? Or just because 
you’re very sick? In any severe illness, for 
example, the kidneys must work extra hard to 
filter waste and control nutrients and fluid; if 
overtaxed, they may begin to fail. Similarly, 
cognitive problems can result from increased 
blood toxins due to stressed kidneys or from low 
oxygen due to respiratory distress. “There’s a 
lot of smoke,” says 
Wilson, MD ’07, MAS ’16, the Rachleff 
Distinguished Professor at UCSF’s Weill Institute 
for Neurosciences. “We need to figure out where the fire is coming from.”

Recently, there’s been speculation that some of 
COVID-19’s seemingly disparate symptoms may stem 
from trouble in the blood. Blood clots, for 
example, are showing up in cases of COVID-19 
frequently enough for clinicians to take notice. 
“There’s something unique about the coagulation 
system in these patients,” says nephrologist 
Liu, MD ’99, PhD ’97, MAS ’07, a UCSF professor 
of medicine. In caring for COVID-19 patients on 
dialysis machines, she’s been surprised to see 
blood clots block dialysis tubes more than usual. 
Clotted tubes are common, she says, “but this is extreme.”
Illustration of a coronavirus symbol.

Evidence suggests SARS-CoV-2 can infect cells in 
the walls of blood vessels that help regulate clotting.

That may be because, as growing evidence 
suggests, SARS-CoV-2 can infect cells in the 
walls of blood vessels that help regulate blood 
flow and coagulation, or clotting. If true, this 
behavior could explain some of the virus’s 
weirder (and rarer) manifestations, such as heart 
attacks, strokes, and even “COVID toes.”

“Our vasculature is a contiguous system,” says 
cardiologist Parikh. “Thus injury in one area, 
such as blood vessels in the lungs, can set off 
clotting cascades that affect multiple organs.” 
Some of that trouble likely results from 
inflammation triggered by the immune system, she 
points out, although another culprit may be the 
body’s RAAS, or renin-angiotensin-aldosterone 
system, a hormone system that controls blood 
pressure and fluid balance. Because RAAS involves 
ACE2 receptors, Parikh suspects it may become 
disrupted when the virus infects cells through 
these receptors, thus triggering coagulation and 
other downstream effects. Her lab is now studying 
this system in COVID-19 patients to better 
understand how SARS-CoV-2 infection affects it.

Inevitably, some ailments may turn out to be red 
herrings. During a pandemic, when people are 
flocking to hospitals with infections, clinicians 
will also see a rise in other health problems, 
simply by the rules of statistics, points out 
Andrew Josephson, MD, the Francheschi-Mitchell 
Professor, chair of UCSF’s neurology department, 
and a member of the Weill Institute for 
Neurosciences. “If the prevalence of infection is 
high, then almost any condition – a broken leg, 
if you will – you might conclude is associated with COVID-19.”

“As clinicians, we want to get information to our 
medical community and to the public as quickly as 
possible,” Josephson says, “but we have to be 
cautious about not making too big a deal of a little blip.”

The long tail

As with any infection, how long a bout of 
COVID-19 lasts 
from person to person. If you’re ill enough to 
need critical care, you can expect the disease to 
take at least a few weeks to run its course. In 
some cases, symptoms persist for months. For a 
typical milder case, though, you should feel better within a couple weeks.

At that point, the question foremost on your mind 
will be: Am I immune? There are now more than a 
dozen antibody tests on the market, but most are 
to UCSF research. And even the best tests can’t 
tell you whether you have enough of the right 
kinds of antibodies to protect you against 
reinfection. “There is a lot of hope and belief 
that we’ll have an antibody test that actually 
informs us of immunity, but we’re not quite there 
yet,” says 
Langelier, MD, PhD, a UCSF assistant professor of 
medicine who is working to improve diagnostic tools for COVID-19.

What we have in the meantime are a lot of 
unknowns: If you do become immune to SARS-CoV-2, 
when and how does that occur? Will you gain 
immunity from a mild or asymptomatic case, as 
well as a severe one? How long will that immunity last?

“The answers will have huge implications for 
social distancing and masking and for getting the 
economy back up and running,” says 
Peluso, MD, a clinical fellow who came to UCSF 
three years ago to help fight HIV. Now he’s 
co-leading <>a new 
study called LIINC (Long-term Impact of Infection 
with Novel Coronavirus), which is enrolling 
people who have been infected with SARS-CoV-2 and 
will follow them for two years. Besides 
illuminating changes in immunity over time, LIINC 
is investigating chronic effects of infection on 
the immune system, lungs, heart, brain, blood, and other parts of the body.

“I hope people will recover and immunity will be 
protective and long-lasting, and that will be that,” Peluso says.

It’s what we all hope. We hope we will beat an 
infection swiftly – or, better yet, avoid the 
virus until there is a vaccine. We hope that if 
we do fall gravely ill, we will be cared for by 
the best providers and tended to by people we 
love. The reality, as we already know, is more 
complicated. And even if COVID-19 doesn’t batter 
our bodies, the pandemic will surely leave scars 
– on our psyches, our livelihoods, our 
institutions, and our health – that we are only 
beginning to fathom. In truth, we don’t know how 
our cards will fall, as individuals or as a 
people. Only time – and data – will tell.