Naveed Saleh, MD, MS | March 28, 2022
Physicians are battling COVID-19 on two fronts. The first is waves of emerging variants, which induce acute and deadly infections. The second is cases of post-acute sequelae SARS-CoV-2 infection (PASC), or long-haul COVID, which are still poorly understood, but are debilitating a swath of the infected population.
To understand the symptoms and potential management of long-haul COVID, we reached out to Saurabh Mehandru, MD, for an exclusive interview. He recently co-authored an insightful review on the topic in Nature Immunology.
Dr. Mehandru: It’s a heterogeneous constellation of symptoms. One must separate the wheat from the chaff. The definitions are not very uniform. Those have been the impediments. The scientific community understands that this is a problem and there are real pathophysiological mechanisms behind it. As time goes on, more biological data are emerging.
Dr. Mehandru: Our research, and more recent papers and publications from other groups, suggest common threads. First, people who have long COVID may have autoantibodies that are triggered by the virus. Second, there are sanctuaries within the body where the virus persists beyond the clinical resolution of the disease. Third, there is a dysregulated immune response against the virus that persists beyond the resolution of disease. Fourth, there are clinical associations, such as those with diabetes having a higher incidence of the disease, and CMV-associated bystander activation of immune cells that triggers long COVID early in the gastrointestinal tract.
Dr. Mehandru: Almost every organ system can be involved. Common clinical symptoms are neuropsychiatric, such as difficulty concentrating or “brain fog.” There are also associations with intestinal symptoms and reduced exercise tolerance. Other manifestations include sleep abnormalities, mood impairment, pain syndromes, palpitations, arrhythmias, shortness of breath and cough. It’s quite diverse; the common manifestations would be systemic.
Dr. Mehandru: I don’t have a number. It’s a minority, but the overall numbers of infected patients are substantial.
[Estimates vary widely but one study found that over 1 in 3 patients had one or more features of long-COVID recorded between 3 and 6 months after a diagnosis of COVID-19. This was significantly higher than after influenza.]
Dr. Mehandru: To my knowledge, there isn’t a huge surge of long COVID patients fueled by the recent Omicron spike.
Dr. Mehandru: There are no data that a previous infection protects against long COVID. This will be clarified as we get more data.
Dr. Mehandru: A clinical history of COVID needs to be considered. Some of these symptoms are nonspecific and can be manifestations of other diseases as well.
Dr. Mehandru: There are disease definitions that have been established, which are generally adhered to in the context of research and not practice. It’s universally referred to as post-acute sequelae SARS-CoV-2 infection (PASC), or long COVID/long-haul COVID. There are signs and symptoms present for more than 12 weeks after infection and are not attributable to other diagnoses. This standard disease definition is used by the CDC and European groups. The CDC uses the term post-COVID conditions as an umbrella term for the constellation of symptoms present for more than 4 weeks after an infection. When seeing a patient in the clinic, physicians will not often adhere to these definitions.
Dr. Mehandru: That’s part of the problem. Treatments must be based on the underlying mechanisms, and it appears that in some individuals, such as those with prolonged cough and shortness of breath—with their lungs affected—or other individuals who develop evidence vasculitis or neuropsychiatric problems, the mechanisms could be different. We must understand the underlying pathophysiology.
We were hit so hard and then there were successive waves of infection. Now we need to take stock of things with some semblance of order and structure. Let’s synthesize all of the information and design some studies, and treat patients on what pathways are disordered.
Dr. Mehandru: The biomarkers are immunity-related, including cytokine elevation in the blood. This is an area that is being actively investigated.
Dr. Mehandru: There is a lot of heterogeneity, with lots of rapidly disseminating information. You do hear anecdotes that “I got the vaccine and I developed symptoms of long-term COVID.” [Conversely,] there are anecdotes that people have gotten the vaccine and their long-haul COVID went into remission.
Dr. Mehandru: The best advice is to refer the patient to a specialty center for long-haul COVID until we develop uniform disease definitions and [elucidate] pathways and biomarkers. There are such centers in major US cities, including New York City. They establish cohorts of such patients for research. These centers offer support groups, and the care is better consolidated, with treatment based on existing and emerging data as opposed to anecdotal care, which sometimes is or isn’t data-driven.
Dr. Mehandru: There are lots of viral syndromes present while the body is still recovering. We don’t need to invoke long COVID in these cases where people will recover. There are patients who are debilitated, and those people should be considered as having long COVID. Moreover, some people recover from long COVID.