UNUSUAL COVID-19 SYMPTOM PRESENTATION

The take-home message from a growing number of recent COVID-19 case reports is that the infection might be far more than a respiratory disease. Although a cause-and-effect relationship is unknown, people with the virus have presented with or developed heart disease, acute liver injury, ongoing GI issues, skin manifestations, neurologic damage, and other problems, especially among sicker people. For example, French physicians described an association with encephalopathy, agitation, confusion, and corticospinal tract signs among 58 people hospitalized with acute respiratory distress (N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597). In particular, Yale New Haven (Conn.) Hospital is dealing with unexpected complications up close. Almost half of the beds there are occupied by COVID-19 patients. Over 100 people are in the ICU, and almost 70 intubated. Of the more than 750 COVID admissions so far, only about 350 have been discharged. "Even in a bad flu season, you never see something like this; it's just unheard of," said Harlan Krumholz, MD, a Yale cardiologist and professor of medicine helping lead the efforts there. Dr Harlan Krumholz Kidney Injuries Prominent "When they get to the ICU, we are seeing lots of people with acute kidney injuries; lots of people developing endocrine problems; people having blood sugar control issues, coagulation issues, blood clots. We are just waking up to the wide range of ways this virus can affect people. Our ignorance is profound," Dr. Krumholz said, but physicians "recognize that this thing has the capability of attacking almost every single organ system, and it may or may not present with respiratory symptoms." It's a similar story at Mt. Sinai South Nassau, a hospital in Oceanside, N.Y. "We've seen a lot of renal injury in people having complications, a lot of acute dialysis," but it's unclear how much is caused by the virus and how much is simply because people are so sick, said Aaron Glatt, MD, infectious disease professor and chair of medicine at the hospital. However, he said things are looking brighter than at Yale. "We are not seeing the same level of increase in cases that we had previously, and we are starting to see extubations and discharges. We've treated a number of patients with plasma therapy, and hopefully that will be of benefit. We've seen some response to" the immunosuppressive "tocilizumab [Actemra], and a lot of response to very good respiratory therapy. I think we are starting to flatten the curve," Dr. Glatt said. Dr Aaron Glatt "Look for Tricky Symptoms" The growing awareness of COVID's protean manifestations is evident in Medscape's Consult forum, an online community where physicians and medical students share information and seek advice; there's been over 200 COVID-19 cases and questions since January.

Σελίδα 2 από 2 Early on, traffic was mostly about typical pulmonary presentations, but lately it's shifted to nonrespiratory involvement. Physicians want to know if what they are seeing is related to the virus, and if other people are seeing the same things. There's a case on Consult of a 37-year-old man with stomach pain, vomiting, and diarrhea, but no respiratory symptoms and a positive COVID test. A chest CT incidental to his abdominal scan revealed significant bilateral lung involvement. A 69-year-old woman with a history of laparotomy and new onset intestinal subocclusion had only adhesions on a subsequent exploratory laparotomy, and was doing okay otherwise. She suddenly went into respiratory failure with progressive bradycardia and died 3 days later. Aspiration pneumonia, pulmonary embolism, and MI had been ruled out. "The pattern of cardiovascular failure was in favor of myocarditis, but we don't have any other clue," the physician said after describing a second similar case. Another doctor on the forum reported elevated cardiac enzymes without coronary artery obstruction in a positive patient who went into shock, with an ejection fraction of 40% and markedly increased heart wall thickness, but no lung involvement. There are also two cases of idiopathic thrombocytopenia without fever of hypoxia. An Italian gastroenterologist said: "Look for tricky symptoms." Expand "patient history, asking about the sudden occurrence of dysgeusia and/or anosmia. These symptoms have become my guiding diagnostic light" in Verona. "Most patients become nauseated, [and] the taste of any food is unbearable. When I find these symptoms by history, the patient is COVID positive 100%." "Make Sure That They Didn't Die in Vain" There was interest in those and other reports on Consult, and comments from physicians who have theories, but no certain answers about what is, and is not, caused by the virus. Direct viral attack is likely a part of it, said Stanley Perlman, MD, PhD, a professor of microbiology and immunology at the University of Iowa, Iowa City. The ACE2 receptor the virus uses to enter cells is common in many organs, plus there were extrapulmonary manifestations with severe acute respiratory syndrome (SARS), another pandemic caused by a zoonotic coronavirus almost 20 years ago. At least with SARS, "many organs were infected when examined at autopsy," he said. The body's inflammatory response is almost certainly also in play. Progressive derangements in inflammatory markers – C-reactive protein, D-dimer, ferritin – correlate with worse prognosis, and "the cytokine storm that occurs in these patients can lead to a degree of encephalopathy, myocarditis, liver impairment, and kidney impairment; multiorgan dysfunction, in other words," said William Shaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center, Nashville, Tenn. Dr William ShaffnerBut in some cases, the virus might simply be a bystander to an unrelated disease process; in others, the experimental treatments being used might cause problems. Indeed, cardiology groups recently warned of torsade de pointes — a dangerously abnormal heart rhythm — with hydroxychloroquine and azithromycin. "We think it's some combination," but don't really know, Dr. Krumholz said. In the meantime, "we are forced to treat patients by instinct and first principles," and long-term sequelae are unknown. "We don't want to be in this position for long."To that end, he said, "this is the time for us all to hold hands and be together because we need to learn rapidly from each other. Our job is both to care for the people in front of us and make sure that they didn't die in vain, that the experience they had is funneled into a larger set of data to make sure the next person is better off."

COVID-19 infection may represent a "hypercoagulable" state, new research suggests.

Researchers from China describe three patients admitted to the intensive care unit (ICU) with confirmed SARS-CoV-2 infection, severe COVID-19, and clinically significant coagulopathy, antiphospholipid antibodies, and multiple cerebral infarcts.

"Antiphospholipid antibodies abnormally target phospholipid proteins, and the presence of these antibodies is central to the diagnosis of the antiphospholipid syndrome," write Yan Zhang, MD, and colleagues from Peking Union Medical College Hospital in Beijing, China.

"However, these antibodies can also arise transiently in patients with critical illness and various infections," they add.

The findings were published online April 8 as a correspondence letter in theNew England Journal of Medicine.

Case Reports

The first patient described in the report was a 69-year-old man with a history of hypertension, diabetes, and stroke who presented with fever, cough, dyspnea, diarrhea, and headache.

Initial treatment for COVID-19 was supportive. However, the patient deteriorated to hypoxemic respiratory failure and he was put on a ventilator. Imaging showed ground-glass opacity and bilateral pulmonary infiltrates.

The patient had evidence of ischemia in both lower limbs and in digits two and three of the left hand. Brain imaging revealed bilateral cerebral infarcts in multiple areas.

Pertinent laboratory results on ICU admission included leukocytosis, thrombocytopenia, an elevated prothrombin time and partial thromboplastin time, and elevated levels of fibrinogen and D-dimer. Serologic tests were positive for anticardiolipin IgA and anti-β₂-glycoprotein I IgA and IgG.

The two other patients were a 65-year-old woman and a 70-year-old man. They had similar findings to the first patient, including positive tests for anticardiolipin IgA and anti-β₂-glycoprotein I IgA and IgG.

Presence of antibodies "may rarely lead to thrombotic events that are difficult to differentiate from other causes of multifocal thrombosis in critically patients, such as disseminated intravascular coagulation, heparin-induced thrombocytopenia, and thrombotic microangiopathy," the researchers write.

Emerging Issue

Carlos del Rio, MD, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, singled out this report during an April 10 media briefing hosted by the Infectious Diseases Society of America to discuss emerging issues with COVID-19.

The issue of hypercoagulability with COVID-19 is "really interesting," del Rio noted. 

"We are seeing a hypercoagulable state in this condition and it's something we don't yet fully understand. We are seeing people present with pulmonary emboli. Also, some of the renal insufficiency that we are seeing...is related to microemboli at the level of the kidneys," he said.

"We know that infections can cause a hypercoagulable state. Understanding the hypercoagulability in this condition is going to be critical," said del Rio.

The research was supported by grants from the National Natural Science Foundation of China and the Chinese Academy of Medical Sciences Initiative for Innovative Medicine. Zhang and del Rio have reported no relevant financial relationships.

N Engl J Med. Published online April 8, 2020. Full text

Gary S. Ferenchick, MD, MS, a professor of medicine at Michigan State University, interviewed his daughter, Hannah R.B. Ferenchick, MD, an emergency and critical care physician working on the frontline in a busy Detroit hospital, about some of the unusual clinical features of patients with suspected or confirmed COVID-19.

Gary S. Ferenchick, MD, MS: I'm Gary Ferenchick with Hannah Ferenchick, who has agreed to join us to talk about what's going on in Detroit, and also about PPE and decontamination processes. Why don't you introduce yourself?

Hannah R.B. Ferenchick, MD: I am Hannah Ferenchick. I'm an ER physician and medical intensivist. I split my time between the medical ICU and the emergency department at Detroit Medical Center.

Dr Gary Ferenchick: We were talking earlier about some of the not-well-described clinical scenarios that patients with definitive COVID might present with. One of these was the idea of "silent hypoxemia." Could you describe that?

Dr Hannah Ferenchick: Silent hypoxemia is being described in many of these COVID patients. That means the patient is very hypoxemic—they may have an oxygen saturation of about 85% on room air, but clinically they look very comfortable—they are not dyspneic or tachypneic and may not even verbalize a significant sense of shortness of breath. It's not every patient, but it has been interesting to see patients sitting there looking fairly normal, with a resting oxygen saturation much lower than you would expect for someone who doesn't have underlying pulmonary disease or other symptoms.

Dr Gary Ferenchick: What abnormalities are you seeing on standard or not-so-standard lab tests?

Dr Hannah Ferenchick: Some of the characteristic lab findings we are seeing are lymphopenia and elevated inflammatory markers (eg, CRP). A couple of other atypical findings seem to be specific for COVID—elevated LDH, ferritin, CPK, and procalcitonin levels. Some of the hematologic markers that we look at—the coagulation profile studies—are also abnormal, showing thrombocytopenia and elevated D-dimer levels.

That constellation of symptoms represents more of a clinical picture. A lot of times we have only a very high clinical suspicion, because in many parts of the country it still takes days to get back a confirmatory PCR test.

Much like we do for the flu, the confirmatory test is a nasopharyngeal swab that is run for COVID/coronavirus PCR. Unfortunately the sensitivity of that test is not great. Some studies have quoted 75%-80%, so even a negative PCR does not necessarily rule out the disease, especially if you have a high clinical suspicion. A clinical suspicion is based on the typical symptoms. Many patients, although not all, will have symptoms of lower respiratory tract infection.

Dr Gary Ferenchick: So the right clinical scenario with the right hematologic/biochemical findings dramatically raises the chance that the patient has COVID?

Dr Hannah Ferenchick: Yes, and one thing that we have all been astonished by is how terrible some of these x-rays can look. There are a lot of typical findings on x-ray. Some describe them as looking like pulmonary edema, but the patient has no history of heart failure. Peripheral consolidation and ground-glass opacities are classically described. If you saw one of these x-rays from a patient with bacterial pneumonia, you would expect that patient to be very ill-appearing. Sometimes we get x-rays on patients who are sitting there, maybe mildly symptomatic on room air, and we are astonished by how terrible their x-rays look.

Unfortunately, imaging studies are something we haven't been able to rely on too much for diagnosis. Part of that is to maintain hospital safety, because to take a patient to CT scan, you have to consider the turnaround time for cleaning the CT scanner and the exposure of additional staff to a possibly infected patient. Some of those logistical considerations have limited the availability of radiography.

Gary S. Ferenchick, MD, MS, is a family physician and professor in the Department of Medicine at Michigan State University in East Lansing, Michigan. His daughter, Hannah R.B. Ferenchick, MD, is an assistant professor in the Department of Emergency Medicine, Division of Pulmonary & Critical Care and Sleep Medicine, at Wayne State University, Detroit, Michigan, and a medical intensivist and emergency medicine physician at Detroit Medical Center.