The reports seemed to take doctors by surprise: The “respiratory” virus that causes Covid-19 made some patients nauseous. It left others unable to smell. In some, it caused acute kidney injury.
As the pandemic grew from an outbreak affecting thousands in Wuhan, China, to some 10 million cases and 500,000 deaths globally as of late June, the list of symptoms has also exploded. The Centers for Disease Control and Prevention constantly scrambled to update its list in an effort to help clinicians identify likely cases, a crucial diagnostic aid at a time when swab tests were in short supply and typically took (and still take) days to return results. The loss of a sense of smell made the list only in late April.
“For many diseases, it can take years before we fully characterize the different ways that it affects people,” said nephrologist Dan Negoianu of Penn Medicine. “Even now, we are still very early in the process of understanding this disease.”
What they are understanding is that this coronavirus “has such a diversity of effects on so many different organs, it keeps us up at night,” said Thomas McGinn, deputy physician in chief at Northwell Health and director of the Feinstein Institutes for Medical Research. “It’s amazing how many different ways it affects the body.”
One early hint that that would be the case came in late January, when scientists in China identified one of the two receptors by which the coronavirus, SARS-CoV-2, enters cells. It was the same gateway, called the ACE2 receptor, that the original SARS virus used. Studies going back some two decades had mapped the body’s ACE2 receptors, showing that they’re in cells that line the insides of blood vessels — in what are called vascular endothelial cells — in cells of the kidney’s tubules, in the gastrointestinal tract, and even in the testes.
Given that, it’s not clear why the new coronavirus’ ability to wreak havoc from head to toe came as a surprise to clinicians. Since “ACE2 is also the receptor for SARS, its expression in other organs and cell types has been well-known,” said Anirban Maitra of MD Anderson Cancer Center, who led a study mapping the receptor in cells of the GI tract. (Maitra is an expert in pancreatic cancer and, like many scientists this year, added Covid-19 to his research.)
Infecting cells is only the first way SARS-CoV-2 wreaks havoc. Patients with severe Covid-19 also suffer a runaway inflammatory response and, often, clot formation, said infectious disease physician Rochelle Walensky of Massachusetts General Hospital. That can cause symptoms as different as a lack of blood flow to the intestines and the red, inflamed “Covid toe.”
“We’ve had five cases of patients who’ve had to have their gut removed,” Walensky said. “You see these cases and you say, wait a minute; the virus is doing this, too? It has definitely been keeping us on our toes.”
Venky Soundararajan had a hunch that the extent of ACE2 distribution throughout the body was lying in plain sight. The co-founder and chief scientific officer of nference, which uses artificial intelligence to mine existing knowledge, he and his colleagues turned their system into a hunt for ACE2 knowledge. Combing 100 million biomedical documents from published papers to genomic and other -omics databases, they uncovered multiple tissues and cell types with ACE2 receptors, they reported last month in the journal eLife.
They also calculated what percent of each cell type expresses “reasonable amounts” of ACE2, Soundararajan said. On average, about 40% of kidney tubule cells do, and in a surprise for a “respiratory” virus, cells in the GI tract were “the strongest expressors of ACE2 receptors,” he said.
The data mining found that ACE2 is also expressed in the nose’s olfactory cells. That’s not a new finding per se — the inference system found it in existing databases, after all — but it hadn’t been appreciated by scientists or clinicians. It explains the loss or altered sense of smell that Covid-19 patients experience. Its importance became clear earlier this month when scientists at the Mayo Clinic and inference reported that loss of a sense of smell is “the earliest signature of Covid-19,” appearing days before a positive swab test.
That study, using health records of 77,167 people tested for Covid-19, showed how the assumption that infection would first and foremost cause respiratory symptoms was misplaced. In the week before they were diagnosed, Covid-19 patients were 27 times more likely than people who tested negative for the virus to have lost their sense of smell. They were only 2.6 times more likely to have fever or chills, 2.2 times more likely to have trouble breathing or to be coughing, and twice as likely to have muscle aches. For months, government guidelines kept people not experiencing such typical signs of a respiratory infection from getting tested.
Faced with a disease the world had never seen before, physicians are learning as they go. By following the trail of ACE2 receptors, they are more and more prepared to look for, and treat, consequences of SARS-CoV-2 infection well beyond the obvious:
Gut: The coronavirus infects cells that line the inside of the large and small intestine, called gut enterocytes. That likely accounts for the diarrhea, nausea, and abdominal pain that about one-third of Covid-19 patients experience, said MD Anderson’s Maitra: “The GI symptoms reflect physiological [dysfunction] of cells of the lower GI tract.”
Why don’t all patients have GI symptoms — or indeed, the whole panoply of symptoms suggested by the near ubiquity of ACE2 receptors? For those with mild to moderate Covid-19, “the infectious load in the GI tract may simply not be sufficient to cause symptoms,” Maitra said.
Kidney: The cells lining the tubules that filter out toxic compounds from the blood are rife with ACE2 receptors. Last month, scientists studying 1,000 Covid-19 patients at a New York City hospital reported that 78% of those in intensive care developed acute kidney injury.
Smell: An analysis of 24 studies with data from 8,438 Covid-19 patients from 13 countries found this month that 41% had lost their sense of taste or smell, or both. That shouldn’t be surprising, said Fabio Ferreli of Humanitas University in Milan: “Perhaps the highest levels of ACE2 receptors are expressed in cells in the nasal epithelium.” The sensory loss isn’t due to nasal inflammation, swelling, or congestion, he said, “but to direct damage” to these epithelial cells. Loss of smell also impacts taste, but the virus may also have a direct effect on taste: The nference analysis found high levels of the ACE2 gene in tongue cells called keratinocytes, which contribute to the sense of taste.
There is another implication of the high expression of ACE2 in olfactory epithelium cells, scientists at Johns Hopkins concluded in a paper posted to the preprint site bioRxiv last month: ACE2 levels in the olfactory epithelium of the upper airways that are 200 to 700 times higher than in the lower airways might explain the virus’s high transmissibility. It was weeks before experts recognized that the virus could spread from person to person.
Lungs: This is where a respiratory virus should strike, and SARS-CoV-2 does. The lungs’ type II alveolar cells — among other jobs, they release a compound that allows the lungs to pass oxygen to the blood and take carbon dioxide from it — are studded with ACE2 receptors. Once infected with the coronavirus, they become dysfunctional or die, and are so swarmed by immune cells that this inflammatory response can explode into the acute respiratory distress syndrome (ARDS) that strikes many patients with severe Covid-19, Walensky said.
There is new evidence that the virus also attacks platelet-producing cells, called megakaryocytes, in the lungs. In a study published on Thursday, pathologist Amy Rapkiewicz of NYU Winthrop Hospital found something she had “never seen before”: extensive clotting in the veins and other small blood vessels of patients’ hearts, kidneys, liver, and lungs. She suspects that the platelets produced by infected megakaryocytes travel through the bloodstream to multiple organs, damaging their vasculature and producing potentially fatal clots. “You see that and you say, wow, this is not just a ‘respiratory’ virus,’” Rapkiewicz said.
Pancreas: In April, scientists in China reported that there was higher expression of the gene for ACE2 in the pancreas than in the lungs. Genetic data are an indirect measure of ACE2 receptors themselves, but could have been a tip-off to physicians to monitor patients for symptoms there. As it happens, the Chinese researchers also found blood markers for pancreas damage in Covid-19 patients, including in about 17% of those with severe disease.
Heart: Patients with severe Covid-19 have a high incidence of cardiac arrests and arrhythmias, scientists at the Perelman School of Medicine at the University of Pennsylvania recently found. That’s likely due to an extreme inflammatory response, but there might be more direct effects of the coronavirus, too. A large team of European researchers reported in April that arrhythmia (including atrial fibrillation), heart injury, and even heart failure and pulmonary embolism might reflect the fact that ACE2 receptors are highly expressed in cells along the inside walls of capillaries. When these “vascular endothelial” cells become infected, the resulting damage can cause clots, MGH’s Walensky said, which in turn can cause Covid toe, strokes, and ischemic bowel (too little blood flow to the gut). Studies from around the world suggest that 7% to 31% of Covid-19 patients experience some sort of cardiac injury.
Gallbladder: Specialized cells in this organ, too, have high levels of ACE2 receptors. Damage to the gallbladder (like the pancreas) can cause digestive symptoms.
With the number of Covid-19 patients closing in on 10 million, physicians fervently hope the virus has no more surprises in store. But they’re not counting on it.
“I’ve seen patients every day during this crisis,” said Northwell’s McGinn. “There have been times when I’ve said, wait, the virus can’t do anything new — and then there’s a young woman with a stroke or an older man with myocarditis,” inflammation of the heart muscle. “I keep thinking I’m going to run out of material” for the teaching videos he does on Covid-19, “but it hasn’t happened.”