When the first wave of the pandemic hit the US East Coast last spring, clinicians expected to see patients suffering primarily from a respiratory ailment that, in severe cases, left people needing mechanical ventilators to breathe. But Harvard Medical School’s Haytham Kaafarani, a trauma surgeon and critical-care physician at Massachusetts General Hospital, and his colleagues noticed an unexpected surge in patients with complications in another part of the body—the gut—ranging from nausea and a loss of appetite to severe intestinal obstruction. According to Kaafarani, gastrointestinal surgeons were consulted frequently for “many, many symptoms that showed up.”
Now, with SARS-CoV-2 having infected more than 100 million people and counting, it’s clear that the virus can indeed lead to extensive damage outside of the lungs—damage that has contributed to a total of more than 3 million deaths to date. Over the past year and a half, investigators around the world have documented a wide range of symptoms in the blood, heart, kidney, gut, brain, and many other parts of the body. Some studies suggest that nearly a third of all COVID patients experience such symptoms—and this proportion rises to more than two-thirds of those who are critically ill, Kaafarani says. “The one thing we know for sure that we did not know a year ago is that COVID-19 certainly has extra-pulmonary manifestations.”
In addition to revealing where COVID-19 leaves its trail of damage in the body, patient assessments, postmortem investigations, and experiments with human cells and tissues have provided hints of the mechanisms through which many of these complications may arise. Single-cell sequencing analyses have revealed that cell surface receptors called ACE2 and TMPRSS2, which are used by SARS-CoV-2 to enter our cells, are widespread. And PCR has revealed the presence of viral RNA in various tissues, hinting at the possibility that SARS-CoV-2 can infect cells outside the respiratory system, though direct evidence of such infection is still limited. Another possibility is that the runaway immune response and blood clotting that SARS-CoV-2 infections can trigger may be to blame for the complications seen around the body. (See illustration.)
Mapping the Effects of SARS-CoV-2
When COVID-19 first emerged more than a year and a half ago in Wuhan, China, experts, seeing hospital beds filling up with patients in need of ventilators, initially thought it was a lung disease. But after more than 100 million confirmed infections, it’s clear that SARS-CoV-2, the virus behind the disease, is capable of causing damage far beyond the respiratory system. COVID-19 sparks symptoms around the body, such as headaches, diarrhea, etc. And researchers have identified viral RNA and receptors that SARS-CoV-2 uses to enter cells in various tissues and organs. This raises the possibility that the virus is capable of infecting multiple systems, though in few cases has actual infection been confirmed outside of the respiratory tract. Moreover, even if the virus does infect cells outside of the lungs, inflammation or blood clotting caused by the body’s immune reaction to infection likely also play a role in tissue-specific symptoms.
© TERESE WINSLOW
“We’ve learned part of the story,” says Stanley Perlman, a microbiologist and immunologist at the University of Iowa. “We’re moving forward—there’s just always more questions, particularly with [COVID-19], which, at least [for] now, hasn’t gone away.”
Blood clots, both large and small, are some of the most common complications of COVID-19. Early in the pandemic, reports from patients who ended up in the ICU in countries such as China, France, and Italy indicated that physicians were seeing blockages of large vessels in the lungs and in the legs. Some studies suggested that close to half of all critically ill patients ended up with these clots. Later studies revealed that many COVID-19 patients also ended up with clots in the small arteries and capillaries of the lungs, as well as in the vessels of other organs, such as the heart, kidneys, brain, and liver. Researchers have also found high levels of D-dimer, fragments of proteins that signal the presence of blood clots, in individuals severely ill with COVID-19.
It’s unclear why the clots are happening. Using patient samples, researchers have pinpointed some evidence that the virus, via ACE2, may directly infect vascular endothelial cells and platelets, components of blood that aggregate to form clots, but the clotting process could also be set off by the maladaptive, runaway immune response, says Hanny Al-Samkari, a hematologist at Massachusetts General Hospital and an assistant professor at Harvard Medical School. “It’s probably, like most things this bad, a component of both.”
Al-Samkari also points out that a major feature of SARS-CoV-2 infection is damage to the vasculature and that the resulting dysfunction of the blood vessels, called endotheliopathy, can lead to clotting regardless of whether it is caused by direct viral effects or inflammation. Investigations of various organs affected by COVID-19 support the notion that endotheliopathy is a key manifestation of the disease. In the heart, for example, main features of SARS-CoV-2 infection include inflammation of the blood vessels (vasculitis) as well as injury and dysfunction of the endothelial cells, says Erica Spatz, a cardiologist at Yale University.
We started getting more and more convinced that there might be something specific to COVID-19 resulting in the presentation of the disease in the gastrointestinal tract.—Haytham Kaafarani
As clotting problems emerged in a growing number of COVID-19 patients, investigators launched clinical trials to evaluate the use of blood thinners as a therapeutic. An international collaboration launched three such trials, REMAP-CAP, ACTIV-4, and ATTACC. Interim results, which include data from more than 1,000 patients at 300 hospitals around the world and have not yet been peer reviewed, point to the possibility that blood thinners lead to worse outcomes in people with severe COVID-19 by increasing the probability of major bleeding, while reducing complications in moderately ill patients who were hospitalized but not yet admitted to the ICU. This suggests that in milder COVID-19 cases, preventing clots from forming can help head off more-severe problems, but that there is a threshold at which a patient’s blood vessels are already damaged and filled with clots, making blood thinners more likely to cause dangerous levels of bleeding.
“I think this took everybody by surprise,” says Al-Samkari, who is involved in that ongoing research. “People like to think of bleeding and clotting as being on a spectrum, and they are really not. . . . You can be at increased risk of bleeding and at increased risk of clotting at the same time.”
Al-Samkari adds that the observation that blood thinners can stymie the worsening of disease in milder COVID-19 cases indicates that “a significant component of how COVID-19 makes people sick is probably related to blood clotting.”
As was the case with many of COVID-19’s effects on other organs, a link between the disease and kidney function came into focus early in the pandemic. When ICUs across the globe started to fill up with patients, reports from various countries quickly revealed that people with chronic kidney disease and those who required dialysis or a kidney transplant were at high risk of severe disease and death due to COVID-19.
Clinicians also saw acute kidney injury emerge as a key complication of severe COVID-19, even in those without a history of kidney disease. Some early observational studies reported that up to two-thirds of hospitalized COVID-19 patients experienced kidney-related complications. Most problems were mild to moderate: blood or high levels of protein in the urine signaled kidney damage. In some cases, however, patients experienced more severe kidney injuries that led to dialysis and, for some, a higher likelihood of death.
How the virus exerts its influence on the gut is an open question, but several lines of evidence suggest that it may at least partly be due to direct effects of the virus.
Scientists are still unraveling the mechanisms underlying COVID-19’s effects on the kidneys. Patient autopsies have revealed signs of blood clotting and inflammation as well as viral RNA in the tubules—kidney structures that remove excess fluids, salts and other waste products from the body. Researchers have also reported signs of the SARS-CoV-2 spike protein in urine, pointing to the possibility that the virus directly infects cells of the urinary tract. According to Annette Bruchfeld, a nephrologist and professor at Linköping University and the Karolinska Institutet in Sweden, such evidence is still preliminary, and it is likely that both direct and indirect effects of the virus—in addition to the role of predisposing factors such as genetics—are likely at play.
Whether such kidney complications associated with COVID-19 can lead to chronic disease remains unknown. “I think it’s fair to say that acute kidney injury in connection with COVID is a really bad thing and it drives mortality,” says Bruchfeld. “But it doesn’t mean that if you survive that you will end up being a chronic dialysis patient. We still don’t know the long-term effects.”
Clinicians observed the first signs that COVID-19 could damage the gut during the initial months of the pandemic. An early meta-analysis that included data from more than 4,000 patients, mostly from China, found that the overall prevalence of gastrointestinal symptoms, including loss of appetite, diarrhea, and nausea, was approximately 17 percent, and that GI problems seem to be much more common among COVID-19 patients with severe illness.
Last spring, when Kaafarani and his colleagues at Mass General first noticed an uptick in the numbers of COVID-19 patients with such complications, they launched an investigation to assess whether this trend was a unique manifestation of the viral disease, or if it was a general response to critical illness. To do so, they compared the prevalence of gut issues in patients admitted to the ICU in March and May 2020 to those admitted to the hospital for acute respiratory distress syndrome (ARDS), the type of respiratory failure found in COVID-19 patients, prior to the pandemic. The findings were striking: the prevalence of gastrointestinal complications in severe COVID-19 patients was 74 percent, almost double the 37 percent prevalence seen in the group of people with ARDS but no infection. The researchers recorded symptoms such as bowel blockages and ileus, problems with movement in the intestines. “We started getting more and more convinced that there might be something specific to COVID-19 resulting in the presentation of the disease in the gastrointestinal tract,” Kaafarani says.
How the virus exerts its influence on the gut is an open question, but several lines of evidence suggest that it may at least partly be due to direct effects of the virus. For one, there are often high levels of the ACE2 receptor in the cells of the GI tract in COVID-19 patients. In addition, scientists have detected SARS-CoV-2 RNA in patients’ stool and GI tissue samples. Whether SARS-CoV-2 replicates in the gastrointestinal tract has yet to be confirmed. It’s conceivable that these viral particles are simply fragments of ingested virus. However, Kaafarani notes that scientists have also detected in the gut pieces of the viral messenger RNA, strings of genetic sequences containing the instructions for building proteins—evidence the virus is in fact replicating there.
Preliminary examinations of GI tissues from COVID-19 patients have also revealed some signs of clotting, particularly in the small vessels found below the bowel, that can obscure the flow of blood into the intestinal arteries, according to Kaafarani. Both blood clotting and direct viral effects are plausible explanations for COVID-19’s effects in the GI tract, he adds. “I believe in the next few years we will find out exactly which causes what.”
A multi-organ disease
COVID-19’s effects have also been documented elsewhere in the body—such as in the heart, where the virus has been linked to heart injury and failure, and in the brain, where issues include stroke, seizures, and sensory impairments. Investigators have also identified damage to the eyes, ears, and pancreas, among other organs in COVID-19 patients.
As with the vasculature, kidney, and GI tract, it’s not yet known whether these symptoms come directly from the virus infecting the cells of these organs, or if indirect effects, such as inflammation or blood clotting, may be responsible. In general, the evidence to date of direct viral infection in most parts of the body outside the lungs is limited, says Perlman, so it is likely that much of the damage that occurs in those with COVID-19 “results from the infection rather than what the [virus] itself is doing.”
Spatz notes that as research into these various pathologies continues, the findings should help lead the way to treatments for the broad-ranging symptoms of COVID-19—both in the acute phase of infection and for the still-mysterious long COVID. Some of these findings have already led to more-informed treatments, as in the case of blood thinners, for which expert guidelines changed in response to the research, according to Al-Samkari. Still, Spatz says, many open questions remain, especially when it comes to the long-term effects. “A frustrating aspect of where we are is that what we’re learning hasn’t yet fully impacted our ability to help patients in the long-hauler phase. . . . There’s so much that we don’t know.”