What We Now Know About Long Covid

Dr. Luis J. Montaner and lab find common, persistent symptoms for long-haulers by reviewing a multitude of research studies.

An international team of researchers led by The Wistar Institute’s lead scientist on HIV-cure research has published a review that codifies some of the key take-aways from a sample size of 2,833 patients with long COVID.

Led by Wistar’s Dr. Luis J. Montaner, director of the HIV-1 Immunopathogenesis Laboratory and leader of the HIV Research Program within the Vaccine & Immunotherapy Center, and published in the Journal of Leukocyte Biology, the review offers supporting evidence that RS-CoV-2 (PASC), or long COVID, reflects tissue injuries to a patient’s system that underscores the vulnerabilities of individuals with the disease or the immunological consequence of their system responding to COVID.

“We conducted a review of all the available literature, summarizing what criteria we could define as long COVID that unifies patients across studies. We then took those unifying themes that identify commonalities in long COVID and identified targets for research we could potentially do something about,” Montaner said. “If you search long COVID, there are multiple different presentations, multiple different organ systems, and it is a challenge to come up with unifying principles of what disease process results in long COVID. We focused on identifying common principles of immunological disturbance and tissue injury mechanisms that could be supported by studies of long COVID to date.”

Many Wistar researchers are using machine learning to crunch complex data. That wasn’t the case here.

“It was more a more manual, elbow grease method,” Montaner said. “Each study used different definitions and data points but with similar populations. We listed all the studies, all the patients, all the definitions used, and the criteria we used to coalesce them. That is something that machines cannot do.”

Montaner was surprised to identify distinct patterns on how long COVID may affect the outcome of either acute injury or the long and projected injury to tissues.

They found mechanisms that contribute to symptoms such as inflammation, antigens that persist even after initial infection and microbial translocation (also known as leaky gut) all contribute to long COVID and can be affected by things like age and gender.

“Long COVID presents itself in many ways so it’s important to understand biologically what causes each type of symptom,” Montaner said. We also hope to address the ongoing debate between treating early against the virus versus treating the immune system against tissue injury caused by our own immune response. Our work will advance efforts to identify therapy strategies to avoid tissue injury leading to long COVID from that initial infection.”

This was not the first time a Wistar-led team has taken this roadmap approach.

“When COVID arrived in 2020, one of the first things we did was conduct a comprehensive review of all the reports that provided insight on the immunological modulation within the disease itself, highlighting what we knew and what was available,” Montaner said.

The objective now is to advance research again but on long COVID, noting that the prior 2020 review has been cited by world researchers more than 500 times since publication.

Wistar received a $4M grant from the State of Pennsylvania in 2021 to advance COVID research on vulnerable populations, in part because the organization has gained access to vulnerable populations through its work with patients living with HIV or people with substance use disorder in Center City Philadelphia, Kensington and other areas associated with drug use.