Paul Garner knew he was sick.
A professor of infectious disease at the Liverpool School of Tropical Medicine in the UK, Dr. Garner initially developed “a bit of a cough” back in mid-March. He felt “a little off,” but that was it—at first.
He was diagnosed with COVID 19 after his symptoms worsened. Over the next several weeks, Garner proceeded to catalog a constellation of far-ranging symptoms that he termed “weird as hell.” Among the things he described were the loss of a sense of smell (now known to be one of the early signs of COVID 19 infection in some people), extreme fatigue, tightness in the chest, a racing heart, ringing in his ears, arthritis in his hands, an upset stomach and various aches and pains all over his body. Even gentle exercise made him feel profoundly worse. The coronavirus infection, which he knew usually lasted about two to three weeks, dragged on in his case for nearly two months. He chronicled his experience in a blog for the British Medical Journal (https://blogs.bmj.com/bmj/2020/05/05/paul-garner-people-who-have-a-more-protracted-illness-need-help-to-understand-and-cope-with-the-constantly-shifting-bizarre-symptoms/).
There is much we do not know about COVID 19, the infection caused by the novel coronavirus SARS CoV-2. The illness, which was initially characterized as being largely a febrile pulmonary illness similar to influenza, has now been shown to manifest a plethora of more global systemic symptoms that scientists are only now beginning to understand. With nearly 4.7 million cases and 309,000 deaths so far, the disease has emerged as the greatest global public health challenge of this generation. It’s a weird illness with systemic manifestations—and it’s only getting weirder as it evolves.
Dr. Sean Wengerter, chief of vascular surgery at Good Samaritan Hospital in Pomona, New York, described the case of a 38-year-old man with COVID 19 who was self-isolating at home with mild pulmonary symptoms and seemed to be doing well—until he wasn’t.
“He woke up with both his legs numb and cold, and so weak that he couldn’t walk,” says Dr. Wengerter. The diagnosis? Aortic occlusion. The man had developed a blood clot in the main artery that supplies the body with blood, right at the spot where the aorta splits to provide blood into the legs. It’s a condition which is normally fatal in nearly half of all reported cases. Emergency surgery was successfully performed to save the man’s life.
Blood clotting issues are increasingly seen as a manifestation of this unusual disease, which can result in strokes, heart attacks and pulmonary emboli (blood clots going to the lungs) even in young, previously healthy patients. Broadway actor Nick Cordero, 41, had to have his right leg amputated after COVID 19 infection caused blood clots which compromised blood flow to that extremity. It is now recognized that blood clotting issues in the smaller blood vessels in the body may be leading to some of the systemic manifestations that doctors were recognizing earlier in the illness, including kidney and liver failure. Pathologists have found blood clots throughout the body in the blood vessels of COVID 19 patients. Dutch researchers found that 31% of COVID 19 patients in their ICUs has sustained “thrombotic” (clotting) complications.
It is felt that the inflammatory response elicited by the virus causes the body’s intricate blood clotting system to go haywire (https://pubmed.ncbi.nlm.nih.gov/32299776/). For example, physicians often use a test called the D-Dimer titer to assess for clotting events in the bloodstream. A normal D-dimer test is less than 0.5. Drs. Clifford Marks and Trevor Pour of Mt. Sinai Medical Center in New York described a case in which a previously healthy 50-year-old COVID 19 patient had blood clots all throughout his body—and a D-Dimer level of over 10,000 (https://www.newyorker.com/science/medical-dispatch/what-we-dont-know-about-covid-19). Blood clots forming in small blood vessels may be leading to the recently described syndrome known as COVID toes. This condition involves red or purple swelling of the toes, often on the soles of the feet, and often affects younger and otherwise healthy adults and resembles frostbite (https://www.nytimes.com/2020/05/01/health/coronavirus-covid-toe.html?referringSource=articleShare).
One of the more frightening conditions which as emerged recently as a manifestation of COVID 19 is “pediatric multisystem inflammatory syndrome.” It’s shown up in numerous children with COVID 19 and resembles a previously known autoimmune vascular condition called Kawasaki disease, or another condition known as toxic shock syndrome (https://www.cnn.com/2020/05/10/health/coronavirus-mystery-children-symptoms/index.html). Kawasaki disease causes inflammation in the walls of arteries and can limit blood flow to the heart. It produces a high fever lasting over 5 days, a rash, swollen lymph nodes in the neck, cracked lips, swelling of the hands and feet, and redness in the eyes. The COVID 19 patients with this syndrome all presented with some combination of rashes, abdominal pain, vomiting and diarrhea. Children under 5 are most commonly affected. It is felt to be the result of the child’s body overreacting to the virus. There are at least 85 such cases in New York alone, most of whom either tested positive for SARS CoV-2 or had positive antibody tests, and at least three children have died from it. Several cases have also been identified at the Dwaine and Cynthia Willett Children’s Hospital at Memorial Health in Savannah, according to pediatric infectious disease specialist Dr. Stephen Thacker (https://www.newsbreak.com/news/0P26Sgtq/memorial-health-begins-to-see-mysterious-illness-related-to-covid-19-in-children?s=oldSite&ss=i3). Thankfully, Kawasaki disease is treatable with intravenous immunoglobulin and aspirin, and most patients who receive treatment recover. Late complications, which can affect up to 25% of patients who are not treated, can include aneurysms of the coronary arteries (the blood vessels which feed the heart).
One of the more puzzling manifestations of COVID 19 infection has been the description of patients with “happy hypoxia.” These individuals will have blood oxygen levels which are astonishingly low and usually considered incompatible with life—and yet the patients are not short of breath and can carry on normal conversation while blithely swiping away at their phones. A normal blood oxygen level results in greater than 95% oxygen saturation (the “pulse oximetry” values that we are all used to seeing on television or during colonoscopy is an example of this). But some COVID 19 patients are coming in to be seen with oxygen saturation levels of 50-80% and are completely unaware that their oxygen levels are that low. Scientists are uncertain exactly how this is happening—or why. But this observation, and the poor outcomes of many COVID 19 patients who have been placed on ventilators, has led some to suggest that the criteria for intubation and mechanical ventilation may need to be revised in these individuals (https://www.wsj.com/articles/some-doctors-pull-back-on-using-ventilators-to-treat-covid-19-11589103001).
Most people think of COVID 19 as a respiratory illness—and it is, largely. But a recent study of 119 COVID 19 patients published in the journal Gastroenterology found that 32% of COVID 19 patients had gastrointestinal complaints, ranging from loss of appetite and nausea to diarrhea. Some COVID 19 patients may present in this fashion without any pulmonary symptoms. SARS CoV-2 has also been isolated from stool, although it is not clear if it is transmissible in that fashion. A study recently published in the Journal Science Immunology looked at 412 hospitalized COVID 19 patients and found that 134 had abdominal imaging studies performed, including 34 CT scans (https://www.webmd.com/lung/news/20200514/covid-19-can-infect-and-harm-digestive-organs#1). Bowel wall abnormalities were seen in 31% of the CT scans, and often included findings representative of poor blood flow to the intestines, a condition known as mesenteric ischemia. At least to some degree, this set of findings likely reflects the increased propensity COVID 19 patients have demonstrated towards blood clot formation.
Early on in the COVID 19 pandemic, Chinese physicians noted elevated troponin levels in patients with more severe forms of the disease. Those same findings have since been replicated elsewhere. Troponins are proteins in the bloodstream that are normally found only in heart muscle. Very high troponin levels in severely ill COVID 19 patients suggest some sort of heart damage—and, certainly, catastrophic, unexplained heart failure has been seen in many COVID 19 patients who were severely ill. Whether this is due to direct viral damage to heart muscle (a so-called viral cardiomyopathy), as can be seen in other viral illnesses, or due to blood-clotting events in the small vessels of the heart is unclear.
We know that SARS CoV-2 can cause kidney dysfunction. Upwards of 14-30% of ICU patients with COVID 19 have renal failure severe enough to cause them to undergo kidney dialysis, at least temporarily. Again, whether the renal failure is due to direct viral damage, injury mediated by the body’s profound immune response (the so-called “cytokine storm”) or blood clot formation in the small blood vessels of the kidney is at this point unclear, but Chinese researchers using autopsy data have implicated direct virally-mediated damage (https://www.kidney-international.org/article/S0085-2538).
Elderly patients with infectious processes will often present with altered mental status. It’s a phenomenon which has long been described in older patients with urinary tract infections, for example. Mental status changes and delirium are now being seen in elderly patients with COVID 19. Confusion, frequent falls, coma and unexplained fever may all represent atypical COVID 19 presentations in geriatric patients—and some of these patients may have minimal to no pulmonary complaints at all. There are some emerging reports of COVID 19 patients with encephalitis—an inflammation of the brain tissue which can be lethal. This could be a contributing factor in some of these situations. Dr. Sam Torbati, medical director of the ER at Cedars-Sinai Medical Center, has seen older adults who present as trauma patients because of weakness and dehydration. "When they stand to walk, they collapse and injure themselves," Torbati says. He has also seen COVID 19 patients who present with profound disorientation and an inability to speak, like stroke patients. But testing reveals that these symptoms are actually due to central nervous system effects of the coronavirus. Other unusual symptoms of COVID 19 in the elderly may include incontinence, excessive lethargy and repetitive sneezing.
Much has been made of the fact that men seem to have a worse outcome with COVID 19 than women. Chinese research described a case fatality rate of 1.7 % for women and 2.8% for men. The cause for this may lie in the cellular receptors that SARS CoV-2 uses to enter cells. When the virus enters the body, it uses two proteins, ACE2 and TMPRSS2, as portals for entry. These proteins are very common in the respiratory epithelial lining cells and in the GI tract—but they are also found in the heart, brain, urinary bladder, kidney, nose, and in the vascular endothelial cells lining blood vessels. Recently, researchers in the Netherlands found that men have higher levels of ACE2 receptors than women. This may be the explanation for the observed gender-specific differences in mortality (https://www.newsbreak.com/news/0P2XO08D/this-is-the-reason-why-men-get-worse-coronavirus-cases-than-women?s=oldSite&ss=i3).
The heavy expression of ACE2 in the nasal passages may at least partly explain the commonly reported finding of anosmia, or the loss of a sense of smell, which has been seen as many as 30% of cases of COVID 19 (https://www.nytimes.com/2020/03/22/health/coronavirus-symptoms-smell-taste.html?referringSource=articleShare).
We are learning more about the various clinical manifestations of SARS CoV-2 as the pandemic progresses, but a great deal of what the medical community is doing right now is unconventional, seat-of-the-pants stuff, communicated by blogs and anecdotes, and it’s uncomfortable for us. Medical research is typically slow and laborious, fettered by cumbersome peer reviews and research review committees—but it operates in that manner for a reason. We are dealing with peoples’ lives here. As such, we simply cannot afford to be wrong. The lay public, by contrast, thrives on the anecdotal—which is why the mere mention of a possible viable treatment a few weeks ago caused the stock market to spike sharply upward. Research of this sort usually takes years, if not decades.
The COVID 19 pandemic has pulled back the proverbial curtain to allow everyone to see the medical community at its most altruistic—an egalitarian international group sharing the best information it has for the common good of us all. Unfortunately, the patchwork nature of this collaborative research effort has shown the general public things they are not used to seeing (“Don’t wear a mask! No, forget I said that, wear one! And take hydroxychloroquine! No, wait, don’t! Okay, maybe if it’s early!”). We usually come to a consensus before issuing any sort of proclamation. The pandemic has done away with that, constricting the sedate timelines that we normally use. The result is some understandable degree of confusion.
Again, medical research is something that is in a perpetual state of evolution. The pace of research with this virus—an organism no one on earth had even heard of a mere six months ago—has been astonishing. I know that we will not be back to “normal,” whatever that ends up being, for some time now. But as we share information, we will get better at dealing with this thing. And as an inveterate optimist, I believe that each additional day of data collection brings us one step closer to finding the sorts of treatments which will end this pandemic once and for all.
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