More than a respiratory infection, Covid-19 wreaks havoc on many organs; inflammation and abnormal blood clotting are
Garvon Russell was having trouble breathing when he arrived sick with Covid-19 at a New York City emergency room. By the time he left the hospital two weeks later, he had battled the new coronavirus all over his body.
His lungs were inflamed, their tiny air sacs filled with fluid that made it hard for oxygen to get into his bloodstream. His kidneys failed with Mr. Russell in septic shock from his infection.
Then, when it looked like he had turned the corner, his bedside nurse noticed his left leg was swollen. Doctors found a blood clot in a deep vein.
Mr. Russell, a 67-year-old retiree, said he feels lucky to have survived: “It’s nothing to play with.”
As the number of Covid-19 grows, doctors are learning its damage can extend well beyond the lungs, where infection can lead to pneumonia and acute respiratory distress syndrome, the sometimes fatal condition Mr. Russell had. The disease can also affect the brain, kidneys, heart, vascular and digestive system. Some patients have sudden strokes, pulmonary embolisms or heart-attack symptoms. Others have kidney failure or inflammation of the gut.
Infection can affect the nervous system, causing seizures, hallucinations or a loss of smell and taste. It may affect pregnancies, though the science is nascent: The placenta of a patient who miscarried during her second trimester tested positive for the virus and showed signs of inflammation, according to a paper published April 30 in the Journal of the American Medical Association.
The virus’s strange effects go beyond anything doctors say they usually see with other viral infections. “It seems to strike so many systems,” said Maya Rao, a nephrologist at New York-Presbyterian/Columbia University Irving Medical Center in New York who is treating Covid-19 patients with acute kidney failure. “We don’t understand who gets it.”
Doctors are trying to understand what about the infection predisposes patients to so many complications. The number of confirmed Covid-19 cases world-wide topped 3.7 million as of Thursday morning with roughly 260,000 deaths, according to data compiled by Johns Hopkins University. The U.S. accounted for more than 1.2 million cases and over 73,000 deaths.
“Sometimes with very severe infections you can see things similar to this,” said Magdy Selim, a neurologist at Beth Israel Deaconess Medical Center in Boston, who is treating Covid-19 patients who have had strokes. “But not all this combination of things in one patient. These are really sick patients.”
Some patients are young and otherwise healthy. Some children, who generally don’t get very sick with Covid-19, have been hospitalized with symptoms similar to Kawasaki disease—an inflammatory condition typically affecting young children—with acute inflammation in their hearts and intestines.
The extreme inflammation that is a hallmark of the most severe Covid-19 cases is likely at play, doctors said. Inflammation can also cause blood clots, which doctors believe may be a common denominator spanning several complications. Physicians describe stunningly extensive and swift clotting leading to the strokes and pulmonary embolisms seen in even otherwise young, healthy patients.
The complications add to the mysteries of a virus that makes an estimated 10% to 20% of those who are infected severely ill, though more population-wide testing and studies are needed to know the true percentage. Most people who develop Covid-19 experience relatively mild symptoms—fevers, coughs, chills, fatigue, nausea, diarrhea, pinkeye—but for a minority, ailments can quickly escalate to a more serious stage.
Figuring out how to treat patients with Covid-19 is difficult because the virus is new, identified just at the beginning of this year, and its effects differ from those of other coronaviruses that infect humans. Patients are often admitted to the hospital when already very sick, significantly narrowing the window to save them, and there aren’t any medications approved to specifically treat infection with the new coronavirus. Some of these complications ultimately will be considered rare but appear more common now because so many people have gotten sick at once, doctors say.
Scientists are combing through piles of studies, and doctors are sharing experiences in real-time on Facebook and WhatsApp groups.
The inflammation at play in many complications is starting to come into focus. Immune-system cells rush in to kill infected cells. They also release molecules known as cytokines and chemokines that promote inflammation. The inflammation’s goal is to cordon off infected tissue, but too much can promote extra damage and create a “cytokine storm.”
Inflammation in the lungs can starve the blood of oxygen, depriving other organs, as it did with Mr. Russell, who spent eight days on a ventilator. Inflammation of the heart muscle, called myocarditis, can cause chest pain, shortness of breath and heart-rhythm disorders and scar the heart tissue.
Mark Gorelik, a pediatric rheumatologist and immunologist at New York-Presbyterian/Columbia University Irving Medical Center, has treated children and young adults with a condition resembling Kawasaki disease. While that condition involves artery inflammation, Dr. Gorelik said, these young patients have fevers, “a lot of cardiac inflammation” and sometimes a condition in their guts resembling colitis.
Genetic sequencing showed some patients have gene variants associated with a hyperactive immune response to viral infections, he said, yielding one possible clue into why some people develop serious complications, though such evidence is preliminary.
Doctors Tally Up the Ways Coronavirus Attacks the Body
Researchers are also studying complications possibly caused by a direct attack by the virus. A recent study in the journal The Lancet found evidence the virus attacks endothelial cells, which form a layer lining blood vessels and the heart. That makes Covid-19 a vascular disease as well as a lung disease, said Mandeep Mehra, executive director of the Center for Advanced Heart Disease at Brigham and Women’s Hospital in Boston, an author of the study.
“It might be that this is a disease that requires a combination of therapy that attacks the virus and that also stabilizes the vasculature,” he said.
STRANGE COMPLICATION
Among the strangest and most worrisome complications is how prone to clotting the blood of some Covid-19 patients seems to be. “Every time you have hyper-inflammation, you’re more prone to clotting,” said Andre Goy, a hematology oncologist and chair of the John Theurer Cancer Center at Hackensack University Medical Center. “This is not new…but what’s amazing is the extent of it.”
A study in the Netherlands found 49% of patients in intensive-care units developed clotting complications, mostly pulmonary embolisms but also some strokes. The risk of death for these patients with these complications was 5.4 times the risk for those without those complications, according to the study, published in the journal Thrombosis Research. “We were very much surprised by what we saw,” said Erik Klok, an internist and vascular-medicine specialist at Leiden University Medical Center, and lead author of the study. “We’re not used to this in patients with the normal flu.”
Doctors have seen some patients’ blood clot during dialysis, or while circulating in life-support machines, clogging the circuits. “They’re clotting off things that don’t usually clot,” said Lee Schwamm, executive vice chairman of neurology at Massachusetts General Hospital in Boston. “It’s as if you had sludge in your garden hose.”
At Mount Sinai Hospital in New York, a 44-year-old stroke patient’s blood started visibly clotting while surgeons were trying to remove a clot from his brain despite infusion with clot-busting drugs, according to Thomas Oxley, the interventional neurologist who treated the patient. The patient can’t speak or move his right side, he said.
Strokes happen when large clots in large blood vessels make their way to the brain, cutting off vital oxygen. About 5% of Covid-19 patients develop them, according to a study of 221 patients in China.
Patients are presenting not just with the more-common large clots that can lead to strokes and pulmonary embolisms, but also a constellation of small clots that block blood flow through the tiny blood vessels, known as capillaries, that deliver blood to all organs throughout the body. Some suffer from “Covid toe,” a painful, purplish swelling caused by clots in small blood vessels.
The International Society on Thrombosis and Haemostasis now recommends that any patient admitted to the hospital be evaluated for the risk of clotting and be given anticoagulants like heparin, according to Jeffrey Weitz, the organization’s president-elect. Thrombosis is the medical term for blood clots that form in blood vessels.
How Covid-19 infection makes blood more clot-prone isn’t entirely understood. But a growing body of studies suggests some patients have elevated levels of d-dimer, a protein produced when the body breaks down clots. D-dimer levels are a reliable indicator of Covid-19 severity, several doctors said. A study published by Chinese researchers in March in The Lancet found patients who died had higher d-dimer levels than survivors.
Clinicians think clots may be forming along walls of tiny and major blood vessels due to damage caused by inflammation or the virus itself. When the SARS-CoV-2 virus, as the new coronavirus is officially called, reaches the lung, it replicates rapidly, damaging cells of tiny air sacs called alveoli. That damage triggers inflammation, which leads the blood to coagulate, clinicians say. The damaged cells also release substances that activate coagulation.
A study of three patients who died from Covid-19 published in The Lancet showed evidence the virus can infect walls of capillaries that feed several organs, including the kidneys and small intestine. Pro-clotting proteins flood in to patch up the damage in a process similar to what happens when a scab forms—except the wounding persists internally, promoting more clotting.
“The high levels of d-dimer indicate the body is trying its darndest to break down the clot,” said Dr. Weitz. But “the forces to generate clots are overwhelming the capacity of the body to get rid of them.”
This runaway process wreaks havoc on the entire body. When micro-clots form in tiny blood vessels, they create a traffic jam. Blood can’t flow through the lungs’ alveoli, where blood picks up oxygen.
Clots can lead to heart problems, including reduced blood flow in coronary arteries. Some patients show signs of heart problems a week or so after developing blood clots that start in the lung, said Gian Paolo Rossi, chair of internal medicine at the University of Padua in Italy. The heart damage develops slowly, he said. “They do very badly.”
Clots are also one suspect in acute kidney failure, which is caused by inadequate blood flow and oxygen. Blood clots in capillaries may prevent blood from getting to the kidneys, said Dr. Rao, of Columbia. Other possible causes of acute kidney injury are shock or a direct attack by the virus, because the kidneys have the ACE2 receptor to which the SARS-CoV-2 virus binds to enter cells, she said. Patients include people who had healthy kidneys, she said.
As many as 30% of Covid-19 patients in the intensive-care unit at her hospital have required dialysis or consultation from a nephrologist, Dr. Rao said. That doesn’t include patients with kidney injuries that aren’t severe, she said. “We have seen an enormous amount of this in patients who are in the ICU with Covid-19,” she said.
Some people will fully recover. Others will need dialysis the rest of their lives, she said. “We’re not seeing a lot of recovery in the kidneys,” she said, “but we hope in the longer term people will get better.”
MR. RUSSELL’S CLOT
Other patients develop deep vein thrombosis, a life-threatening condition usually occurring deep in a leg vein. Mr. Russell, who has diabetes and high blood pressure, was improving in late March when doctors found the blood clot in his left leg. He had been on a prophylactic dose of a blood thinner, but it wasn’t enough, said Neha Dangayach, a neurocritical care specialist at Mount Sinai Hospital, where Mr. Russell was cared for.
He was put on a stronger dose of anticoagulants, Dr. Dangayach said. Given Mr. Russell’s health and the number of complications he suffered, she said, “he could have died.”
He is now at home in the Bronx. His kidneys recovered, but he is on blood thinners to prevent more clots.
A study published Wednesday by Mount Sinai researchers in the Journal of the American College of Cardiology found that treating hospitalized patients with blood-thinning drugs improved their chances of survival.
In a span of two weeks, Mount Sinai treated five Covid-19 patients under age 50 who had experienced a major stroke. None had clotting disorders, though one had a previous history of stroke. Normally, the hospital sees less than one such patient on average during that same period, according to a paper published in the New England Journal of Medicine in April.
Patients are often unsure when to call for help when they start experiencing symptoms such as numbness on one side of the body and trouble speaking, neurologists said. Some are waiting more than a day to call. The reason: Patients are being advised to call for help only if fevers or shortness of breath worsen.
Sagine Alexandre, 33, one of the patients described in the paper, had no history of stroke. She said she is slowly regaining movement in her left arm and learning how to walk again. She hasn’t seen her family in person since she went into the hospital on April 1.
“It’s hard to be going through something like this and not have any family or friends around,” she said. “I thank God for FaceTime. That’s all I have.”
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