Complexity of Long COVID
Linda Geng, MD, PhD, co-director of the Stanford Long COVID Collaborative in Palo Alto, Calif., a multidisciplinary clinical and research program, said long COVID is likely underdiagnosed because of its complexity. “It is difficult to diagnose and that’s partially because the definition has evolved.”
More than 200 symptoms fall under the umbrella of long COVID, but research has found 12 that are the most common, including loss of taste and smell; post-exertional malaise, which refers to social and emotional exertion and cognitive exertion, as well as physical; and brain fog, a term that includes cognitive impairment, attention problems and language problems.
Symptoms come in many forms including organ damage, complications from hospitalization and known autoimmune conditions, making long COVID a “syndrome of syndromes,” Dr. Geng said. “That’s what makes it challenging as well, as we think about the pathogenesis,” she said, because it can be difficult to distinguish one category from another.
Viral particle persistence, immune dysregulation, persistent inflammation and imbalance in the microbiome have all been implicated in bringing on long COVID symptoms. “They’re not mutually exclusive,” she said. “Any given patient may have a combination of any of these, and they may be interacting to different degrees.”
The Search for Therapies
Trials studying a 15-day trial of nirmatrelvir-ritonavir, an antiviral used to treat acute COVID, have not found this approach to be effective in long COVID, although a 25-day trial by the long COVID study group RECOVER is underway, with results expected soon, Dr. Geng said.3
Researchers have identified intriguing markers that seem to be involved in long COVID, including translocator protein binding in key brain regions of patients with depressive and cognitive symptoms after COVID, increased levels of interleukin-6 and tumor necrosis factor alpha in long COVID patients, and antineuronal autoantibodies in the cerebrospinal fluid of patients with post-COVID cognitive symptoms.4
The top priority regarding the study of long COVID at this point, Dr. Geng said, are randomized, controlled trials, to more definitely understand the role of these potential markers. “What I think is a confusing aspect of a lot of the emerging biomarkers is, are they pathogenic?” she said. “And if they are, such as viral reservoirs, then if we can target them with the appropriate therapy and show that they actually change clinical outcomes that correlate with these biomarkers, that would be the holy grail.”
In a discussion at the end of the session, Dr. Geng was asked about viral particle persistence with regard to vaccines, particularly in a period of growing vaccine hesitancy.
