Understanding Unusual Presentations of COVID-19

series of brain scans

Despite being highly contagious, a significant portion of people infected with COVID-19 don’t experience any symptoms. Those people who do exhibit symptoms most commonly experience dry cough, fever and difficulty breathing. However, there are also a myriad of atypical symptoms that may be under-reported.

The most commonly documented atypical symptoms include malaise, disorientation or exhaustion. A significant proportion of patients also experience the loss of smell and taste. About 10 percent of COVID-19 patients have gastrointestinal symptoms, such as diarrhea, vomiting and abdominal pain. Cardiovascular complications include dysrhythmias, venous thromboembolic events and myocardial infarction. COVID-19 also may cause clotting in blood vessels in the brain, increasing risk of ischemic stroke.

“We are repeatedly surprised by who turns out to be positive for COVID-19,” says Henrikas Vaitkevicius, MD, a neurologist in the Division of Critical Care Neurology at Brigham and Women’s Hospital. “Patients don’t have to show respiratory symptoms or even be symptomatic to be positive for COVID-19. That’s why there needs to be a very high level of suspicion among a wide range of patients during this pandemic.”

Cytokine Storms May Drive Atypical Symptoms of COVID-19

A number of theories have been put forth to explain the unusual presentations of COVID-19. SARS-CoV-2 has been shown to directly infect many cell types and there’s evidence that SARS-CoV-2 is neuroinvasve. This would account for various neurological manifestations, including the loss of smell during the acute phase of the infection.

An exaggerated immune response also may underlie atypical presentations in COVID-19 patients. Many patients who experience unusual symptoms exhibit a profound activation of their immune system. This response can produce a cytokine storm that can damage many organs, including the lungs, heart and brain.

“It’s now clear that COVID-19 increases the risk of abnormal blood clotting,” says Dr. Vaitkevicius. “When clots form in small blood vessels, like in the extremities, minor skin symptoms can occur. But when clots occur in the lungs, heart or brain, more serious complications can develop, like pulmonary embolism, heart attack or stroke.”

In the Brigham’s Neuro-ICU, Dr. Vaitkevicius has seen a significant increase in strokes among patients who test positive for the virus. Cytokine storms in COVID-positive patients may be responsible for this rise in strokes. They also may cause neurologic features, such as anosmia, encephalopathy and myopathy, according to Dr. Vaitkevicius.

In some cases, an overactive immune system has been shown to trigger autoimmune conditions in COVID-19 patients about two to three weeks after infection. Such neurological autoimmune conditions include: Bickerstaff encephalitis/Guillain-Barré syndrome, acute disseminated encephalomyelitis and rhabdomyolysis.

Treating COVID-19 with Anti-Inflammatory Medications

To quell an overactive immune system in COVID-19, several anti-inflammatory medications are now being investigated in clinical trials. Many of these medications have been approved for other conditions, but none have been approved yet for COVID-19.

The Brigham is a clinical site for a trial evaluating the use of tocilizumab in patients with COVID-19. Tocilizumab is an FDA-approved medication used to treat rheumatoid arthritis by targeting IL-6, the cytokine thought to drive an overactive immune system. The Brigham is also treating COVID-19 patients with several other pharmacological agents, including sarilumab, canakinumab, ibrutinib and zanubrutinib.

“This virus is likely going to stick around for a long time, but the bright side is that we know how to manage COVID-19,” says Dr. Vaitkevicius. “We still need to learn more about how to treat the virus’ effects on clotting cascades, especially as it pertains to strokes.”

To learn more about the possible neurological complications of COVID-19, two Brigham neurologists, Saef Izzy, MD, and Shamik Bhattacharyya, MD, MS, have recently launched separate projects to examine patient data from across the Mass General Brigham system. They aim to build a database of neurological characteristics in COVID-19.

Approaching Patients with a High Index of Suspicion

Increasing the knowledge of the unusual ways COVID-19 presents may help ensure that patients get timely and appropriate treatment. It also may help promote the investigation of screening protocols and biomarkers of disease progression.

“By raising the awareness of atypical symptoms, we may also encourage health care workers to approach patients with a higher index of suspicion for SARS-CoV-2 infection, especially when symptoms are present without explanation,” says Dr. Vaitkevicius.

Dr. Vaitkevicius and Mohammad A. Aziz-Sultan, MD, chief of Vascular/Endovascular Neurosurgery at the Brigham, will soon present insights from their care of acute stroke in COVID-19 patients at grand rounds at other institutions. They also hope to bring awareness to the significant drop-off in presentations of strokes and heart attacks as a result of quarantine measures.

“The Brigham’s management of unusual presentations of COVID-19 wouldn’t be possible without strong collaboration across departments and other hospitals,” says Dr. Vaitkevicius. “We keep clear lines of communication open with everyone and we share clinical protocols to build off of each other’s experiences. It’s impressive to see how so many people are working together during this crisis to make things better.”

For rapidly evolving clinical guidelines and medical recommendations for the treatment of patients with COVID-19, please visit Brigham’s COVID Clinical Guidelines.