Immunology of long COVID

Long COVID refers to the long-term health and cognition effects that some people experience following infection with COVID-19. Patients have reported unrelenting fatigue, brain fog, dysautonomia, shortness of breath, and digestive problems, among over 200 symptoms — in some cases requiring frequent or even long-term hospitalization. The Iwasaki Lab is interested in exploring the biological mechanisms underlying these phenotypes — and how future research can harness this knowledge to engineer more effective and specific biomarkers for long COVID.

As researchers continue to examine how such patterns can provide information indicative of long COVID, Iwasaki proposes four possible hypotheses for the condition’s initiation and progression. They are:

1. Persistent viral loads or remnants hidden away in tissue and causing chronic inflammation. These viruses may not be measurable via nasopharyngeal swabs because they might be “hiding” in other internal organs, such as the gut.
2. Our body’s own disease-fighting B and T cells triggering an immune response — and subsequent inflammation — in a process called autoimmunity. The problem is: the stimulus that triggers autoimmunity in response to an acute infection is oftentimes occurring continuously in the body, making it difficult to pinpoint and shut down.
3. Dormant viruses reactivating, and/or dysbiosis of microbiome disturbing our body’s homeostasis. Humans live with trillions of bacteria and a number of viruses that are latent. When acute infection disturbs the host, these bacteria lose its composition balance and dormant viruses can become reactivated. These viruses and microbes can cause inflammation and throw off body’s homeostasis.
4. Macroscopic and microscopic tissue damage resulting from the initial infection. COVID-19 impacts parts of our body that we don’t commonly think about. Whether it’s our lungs or our brains or the endothelial tissue lining our blood vessels and supporting oxygen change, the virus — and the medication used to treat it — can lead to clotting or scarring in places that are difficult to reach and repair. In addition, inflammation that occurs in one tissue can trigger damage in other tissues.

In reality, long COVID is not a single disease. There are likely multiple endotypes of the disease. We are conducting human studies and developing animal models to understand the underlying pathogenesis of long COVID.

In a cross-sectional study of 215 people — we collaborated with Dr. David Putrino’s group at Mount Sinai School of Medicine and researchers at Yale and other institutions to determine key immunological features that distinguished long COVID from its recovered counterpart. Here are some of the notable immune characteristics that long COVID individuals can have: amped humoral response against the coronavirus; increased antibody response against other non-coronavirus pathogens, such as the Epstein-Barr virus; decreased cortisol levels; and abnormal leukocyte populations. Of these, however, lower cortisol — a hormone that plays a critical role in regulating our body’s stress response — appears to be the most efficient predictor. For more information, see Twitter thread here.

Yale Medicine is home to various other initiatives that are studying long COVID and its opaque dimensions, among which is the LISTEN study. Standing for Listen to Immune, Symptom and Treatment Experiences Now, LISTEN hopes to understand Long Covid, post-vaccine injuries and the corresponding immune responses by collecting information about symptoms and medical history from participants who are members of a patient community, and by collecting blood and saliva samples from some participants.

The study is seeking volunteer adult participants who live in the United States — excluding Alaska and Hawaii — and can speak English or Spanish. If these qualifications apply to you, please sign up through the Hugo Kindred Community here. Our researchers here are all incredibly welcoming, and your responses and contributions will be invaluable to a field of study that remains very opaque but important to our fight against COVID-19. For more information about the logistics of this study, please visit this page or contact the staffers at: listenstudy@yale.edu.

Long COVID adds to a long list of other pathogens that can cause chronic illness in a subset of people, called post-acute infection syndrome (PAIS). The Iwasaki lab wishes to extend the investigation of underlying pathogenesis behind other PAIS, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Plans for future studies include immune phenotyping and biomarker assessment for PAIS including ME/CFS.