Fear and Understanding in the Time of COVID-19.

Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.

As we write this essay, New York City is ravaged by COVID-19. An anesthesiologist friend tells us that at State University of New York, Stony Brook, they are intubating about 18 patients per day for COVID-19 pulmonary disease. Five friends have died because of COVID-19 complications in the last week, one a pediatric neurosurgeon and the others mostly from the theater world. The fear, uncertainty, and anxiety this pandemic provokes are reminiscent of the AIDS epidemic in the 1980s.

COVID-19 is a coronavirus that may cause mild symptoms. However, some people die, in many cases abruptly. Anecdotally, many of our physicians suggest that critically ill patients are hypercoagulable, with intravenous lines that clot easily and associated kidney and liver disease. Chinese pathologists, anecdotally as well, note that pulmonary arteries and arterioles are involved with clotting. Furthermore, the abruptness of the fatality in some cases is reminiscent of vascular disease. Stroke has been associated with COVID-19 as has heart disease; several adults with a concurrent stroke were treated on our stroke service. To date an increased stroke in either adults or children has not been confirmed, but there are insufficient data to draw definitive conclusions. In a Chinese series comparing patients who died with those who survived, interleukin elevation, reactive protein elevation, and prolonged prothrombin time occurred more often among people who died.

The New York Times reported that some individuals with coronavirus experience brain dysfunction, but this too is largely word-of-mouth. In children little is known about the neurological complications of COVID-19. One patient was reported with acute disseminated encephalomyelitis in 2004 who had a coronavirus (but not COVID-19) in cerebrospinal spinal fluid, suggesting that coronavirus may directly affect the central nervous system in children. Similarly, we recently admitted a child with encephalitis and status epilepticus who was positive for COVID-19, possibly indicating a parainfectious process. Parainfectious here is used to describe a condition that is either infectious or postinfectious (without a direct infectious spread of the pathogen). There have now been over 150 children with a Kawasaki-like syndrome (characterized as pediatric multisystem inflammatory syndrome) associated with COVID-19. This syndrome seems specific to children and is likely postinfectious.

Do children die of this disease? Yes, children may die, although the disease course is generally milder in children than in older patients. The pediatric inflammatory disease appears to have good survival with prompt intensive care. The Centers for Disease Control notes that the risk for severe disease in adults is aggravated by existing cardiovascular disease, diabetes, and pulmonary disease. An artificial intelligence paradigm shows three features that are associated with severe pulmonary disease: high hemoglobin, elevated liver functions, and myalgia. Premorbid pulmonary disease seems a reasonable predictor, high hemoglobin could be associated with chronic hypoxemia, which may be a risk for stroke, and myalgia, which is associated with inflammation.

Early anecdotal data from China and Italy note that patients with COVID-19 have a significant blood-clotting disorder, with the presence of small clots in the lungs and other organs. Megakaryocytes with fibrin deposits are prominent on pathology. Covid-19 infection is caused by binding of the surface spike protein to the human angiotensin-converting enzyme 2 receptor. Angiotensin-converting enzyme 2 is highly expressed in the lung alveolar cells but also in the heart, intestinal epithelium, vascular endothelium, and kidneys, all tissues that have been affected by COVID-19 infection. Many of the same risk factors for vascular disease are associated with poor prognosis in COVID-19, buttressing the concept that vascular disease may play a role for COVID-19–associated critical illness, at least in some patients.

Currently, a study is planned to treat patients with COVID-19 who are deteriorating with tPA by researchers at the University of Colorado. This could lyse clots that may be at play in this infection. The study is in the planning stages and outcome measures are likely to be pulmonary. A small human trial conducted in 2001 noted a reduction in mortality from 100% to 70% in patients with severe respiratory distress who were not expected to survive and were treated with tPA, albeit unrelated to COVID-19.

Potential etiologies of neurological disease could include severe inflammation and upregulation of cytokines, clotting factors, macrophages, and the like (the “cytokine storm”). In addition, there may be direct infection based on the patient reported with coronavirus in the cerebrospinal fluid or possibly postinfectious changes based on our patient with encephalitis and seizures who was sent home. It has been said that coronavirus does not directly infect the brain, but that was also said about HIV-1 before an autopsy study determined that 25% of patients with AIDS had human immunodeficiency virus in brain endothelial cells.

So what should we do? The incidence of COVID-19 in children is unknown because we have been testing too infrequently to know. Similarly, the population incidence of recent and chronic disease is unknown because immunoglobulin G and immunoglobulin M testing has not been completed in either adults or children. These are reasonable goals, but ones beyond the scope of pediatric neurology.

Pediatricians and pediatric neurologists should screen confirmed cases and obtain a good neurological history and examination including cognitive function. We have started this as a quality improvement project. This project is important to do throughout the country and the child neurology associations throughout the world might take a lead on this. Blood tests should include coagulation factors and inflammatory markers to better understand the problem and, ultimately, to facilitate better treatment plans. Dexamethasone has helped some critically ill adults avoid a respirator, but as with everything about this outbreak we are learning and making decisions on a day-by-day time frame. We and our adult colleagues need to obtain autopsy examinations of the brain and endothelial tissues. Stroke investigations in adult patients are planned and pediatric neurology should be investigating stroke associations as well.

Even amid the chaos of a pandemic, research is proceeding rapidly in multiple arenas. We need to know more about the manifestations of the virus, and we desperately need more effective treatment and prevention options. Also as we emerge from the pandemic’s devastation, we must learn the lessons that will help us manage the inevitable next pandemic. We need to turn this chaos around, and neurologists, as always, need to contribute.