Research

Several RECOVER studies report on the symptoms of Long COVID. View studies [1], [2], [3], [4], [5], [6]. RECOVER research shows there are symptoms that cluster and present together. View studies [1], [2], [3]. In one study, researchers found six distinct symptom clusters. The clusters involve different body systems at the same time, including: the lung; brain and nervous system; heart and blood vessels. Some clusters include pain, and some are accompanied by abnormal laboratory findings. View the study. Another study found that four Long COVID symptom clusters (heart and lungs, neurological, gastrointestinal, and coexisting medical conditions) differed depending on the age of patients. In the study, children and teens were more likely to have gastrointestinal and upper respiratory problems (such as stomachache and cough); adults aged 21-45 years were more likely to have neurological problems (such as brain fog and fatigue); and adults aged 66 and older were more likely to have coexisting medical conditions (such as heart problems and diabetes). View the study.

RECOVER researchers are also examining how PASC diagnoses, underlying health conditions, and prescription medications might differ geographically. They compared electronic health records from four states (New York City, Florida, Georgia, and Alabama) and found differences in the number of PASC conditions reported across data sites. Researchers found a wide range of diagnosis and medication categories that suggest differences in PASC diagnoses, conditions, and medications among different populations based on neighborhood socioeconomic status, age, gender, race, and outbreak waves. View the study.

Researchers found ethnic and racial differences in PASC symptoms and conditions in a RECOVER study of adults with COVID-19 in New York City between March 2020 and October 2021. In the 30-180 days after infection, compared to White people hospitalized for COVID-19, Black and Hispanic people hospitalized for COVID-19 had higher rates of certain PASC symptoms such as shortness of breath, chest pain, joint pain, and newly diagnosed diabetes. Results also suggest that people from different racial and ethnic groups may experience different symptoms and conditions of PASC. View the study.

RECOVER researchers are interested in understanding the prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in people with Long COVID. They asked 465 people with Long COVID about how often they experience Long COVID symptoms, ME/CFS symptoms, and post-exertional malaise (PEM) (worsening of symptoms after physical or mental activity). They found that over half (58% 272/465) of participants met the definition for ME/CFS. Further, those who met the definition for ME/CFS reported more severe symptoms (e.g. fatigue/extreme tiredness; feeling unrefreshed after waking in the morning; next day soreness or fatigue after nonstrenuous, everyday activities; difficulty paying attention for long periods; and problems remembering things) compared to those who did not meet the ME/CFS definition. Results also show that participants meeting the ME/CFS case definition had a 50% or greater reduction in their self-reported energy level based on a 7-point Likert scale, consistent with case criteria. View the study.

RECOVER researchers are studying large groups of people over a long period of time to gain a deeper understanding of Long COVID, how long its symptoms last, and whether it can have effects later in life. Learn more about RECOVER Longitudinal Observational Cohort Studies.

RECOVER researchers are studying if Long COVID affects other diseases or health problems that people may have. RECOVER researchers compared electronic health records (EHR) to examine the possible link between SARS CoV-2 infection and new diagnoses of type 2 diabetes. Patients who had at least 1 visit 6 months before their SARS CoV-2 infection and 6 months of EHR data post-infection were included in the analysis. Researchers found the number of new diabetes diagnoses to be lower in the months after SARS-CoV-2 infection than in the months before. New diabetes cases in the 6 months after infection were 83% lower than in the 6 months before infection. View the study.

RECOVER researchers are also studying if PASC is associated with worsening type 1 diabetes in youth. Researchers looked at electronic health record (EHR) data of youth under 21 years of age with type 1 diabetes and either a prior COVID-19 diagnosis (SARS-CoV-2 diagnostic test or a diagnosis code for COVID-19), multisystem inflammatory syndrome in children (MIS-C), or a PASC diagnosis. They then compared this data with EHR data of people without a positive test for or diagnosis of COVID-19. Researchers found that some children with both type 1 diabetes and SARS-CoV-2 infection had a temporary increase in HbA1c scores (a marker for diabetes) in the 3-6 months following infection compared to those without infection. While this trend was not statistically significant—meaning it did not meet statistical requirements for the highest confidence in the results—the authors suggest that continued clinical monitoring of children with type 1 diabetes after COVID-19 infection is warranted. View the study.

In another RECOVER study, researchers looked at the relationship between impaired cognition (cognitive concerns or dementia diagnosis) and death after SARS-CoV-2 infection in people with and without HIV. They studied 527 adults with laboratory-confirmed SARS-CoV-2 infection, including 64 people with HIV. People living with HIV had a higher prevalence of dementia (15.6% vs 6.0%) and cognitive concerns (21.9% vs 15.8%). People living with HIV also had a significantly increased risk of death from COVID-19 (17.2% vs. 6.3%). On average, people living with HIV and COVID-19 died at a younger age despite their HIV being under control of medication. View the study.

RECOVER studies are examining risk factors for developing Long COVID.

RECOVER researchers have found that SARS-CoV-2 infection increases the risk of developing PASC and Long COVID. View studies [1], [2], [3]. People who tested positive for SARS-CoV-2 between March and December 2020 and were hospitalized or received mechanical ventilation during their illness had a higher prevalence of multiple symptoms at 1 to 5 months after testing positive compared to those who tested negative. The symptoms included: shortness of breath, heart rate abnormalities, fatigue, brain fog, sleep disorder, type 2 diabetes, and muscle weakness. View the study. In another study, researchers found that 23% of people with SARS-CoV-2 infection developed PASC, while only 3.7% of people without a reported positive test developed symptoms consistent with PASC. View the study.

A large RECOVER study looked at risk factors associated with specific PASC conditions. Researchers found that the risk of PASC increases with hospitalization for acute infection and similarly with reinfections. View the study. Another study found that 39% of people hospitalized with acute COVID-19 developed PASC, compared to 22% of people not hospitalized for acute COVID-19. Among people infected with the Omicron variant, those that had reinfections were more likely to develop PASC (21%) compared to those with one infection (16%). View the study.

RECOVER research using electronic health records (EHR) suggests that obstructive sleep apnea may increase the risk for developing Long COVID after infection. Among people who had COVID-19, adults with obstructive sleep apnea were more likely to experience long-term symptoms suggestive of Long COVID than those without the sleep disorder. The analysis of EHR found that adults with sleep apnea may have up to a 75% higher risk of developing Long COVID after infection. View the study.

RECOVER researchers found that certain environmental factors related to where people live, like air quality, access to food, green spaces, neighborhood characteristics, and social factors, may increase the risk of having Long COVID symptoms. View the study.

In another study, RECOVER researchers examined risk factors for developing PASC. They looked at electronic health record (EHR) data from 31 health systems in the United States, comparing 8,325 individuals with PASC with 41,625 individuals with COVID. They matched data from patients within the same health system whose initial SARS-CoV-2 infections were within 45 days of one another to compare demographics and health conditions between those with and without a PASC diagnosis. Researchers found a higher likelihood of PASC diagnosis among individuals aged 40 to 69 years, female, with acute COVID-19, and living with other health conditions such as depression, chronic lung disease, and obesity. Researchers also found that in counties served by more doctors per capita, residents were more likely to receive a PASC diagnosis or care at a Long COVID clinic. Risk factors associated with a lower likelihood of developing PASC included younger age (18-29 years), male sex, non-Hispanic Black race, and comorbidities including psychosis, dementia, and tobacco smoking. View the study.

RECOVER researchers are exploring whether variants of the SARS-CoV-2 virus and COVID-19 vaccines make a difference for developing Long COVID.

In a study following more than 9,000 people over time, RECOVER researchers found that PASC was more common and associated with more severe manifestations for adults infected before the Omicron variant emerged. View the study. Regardless of the variant, the rates of PASC among those fully vaccinated were lower than those who were unvaccinated. Researchers found the same pattern when they compared vaccinated and unvaccinated adults at three different points in time - in adults with post-acute COVID, pre-Omicron (31% vs. 37%), with acute Omicron infection (9.7 vs. 17%), and post-acute Omicron (16% vs. 22%). Similarly, in a large observational study, RECOVER researchers found that vaccination was consistently associated with lower rates of Long COVID, before and after Omicron emerged. View the study.

RECOVER researchers reviewed the electronic medical records of more than 15 million people (age 5 and older) to compare the risk of rare heart problems in people who had a SARS-CoV-2 infection with people vaccinated for COVID-19. They found that the risk of having a rare heart problem after having COVID is much higher than the risk after vaccination. The risk of rare heart problems after COVID-19 vaccination with an mRNA vaccine (Pfizer or Moderna) were very, very low, supporting the continued use of vaccination to prevent COVID-19. View the study.

In addition to the observational cohort studies that re-examine participants over time, RECOVER researchers are conducting more than 40 different pathobiology studies focusing on COVID-19's effects on different body tissues and organs.

RECOVER researchers are studying Individuals with Long COVID who frequently report constant fatigue, post-exertional malaise (PEM) (symptoms worsening after physical or mental activity), and a variety of cognitive issues, like “brain fog.” RECOVER researchers examined 275 people with and without Long COVID to identify biological features associated with these symptoms. They found people with Long COVID had significant differences in their immune systems compared to those without Long COVID. In participants with Long COVID, researchers saw increases in counts of some immune cell types, while counts of other immune cells decreased. Researchers also saw higher antibody responses to SARS-COV2 and non-COVID viruses, particularly Epstein-Barr virus (a herpesvirus) in participants with Long COVID. Researchers suggest that persistent SARS-CoV-2 antigens, reactivation of herpes viruses, and chronic inflammation may contribute to Long COVID. View the Study.

RECOVER researchers are studying the cells inside the nose that enable smell to understand why some people with COVID-19 experience a loss of their sense of smell, known as hyposmia. They examined 24 biopsies from 9 PASC patients with long-term smell loss after contracting COVID-19. Biopsies from people with their sense of smell intact served as a comparison. In participants with PASC, there was no trace of SARS-CoV-2 virus or its genetic material in olfactory epithelium. However, the cells supporting the protective barrier in the nose, known as sustentacular cells, showed signs of reacting to ongoing inflammation. This reaction was also linked to a decrease in the number of olfactory sensory nerve cells (neurons). These findings suggest that inflammation (mediated by T-cells) continues in the olfactory epithelium even after the virus has been eliminated from the tissue. This is a potential explanation for the persistent loss of smell experienced by some people living with Long COVID. View the study.

Inflammation caused by infections can have a lasting impact on certain types of cells in the human body, including those related to the immune system. In one study, researchers sought to uncover how inflammation could impact a specific cell type—hematopoietic stem and progenitor cells (HSPC)—which are crucial for the formation of blood and immune cells. Researchers found that the cells of individuals who had a serious case of COVID-19 could retain changes for several months to a year after infection. They saw changes in both the physical traits of the cells and their genetic programming. They also linked these changes to proteins that control gene expression, changes in the regulation of inflammatory processes, and a lasting increase in the production of certain immune cells. Importantly, the observed changes in HSPC were passed to their “offspring” as they developed into mature immune cells. Finally, researchers found that a molecule called IL-6 played a role in maintaining these lasting effects in human COVID-19 patients as well as the study model for SARS-CoV-2 infection performed in mice. Overall, researchers suggest changes to HSPC at the genetic level could be responsible for changes in the immune system after infection, especially in people who experienced severe COVID-19. View the study.

At this time, the only known way to prevent Long COVID is to avoid getting COVID-19. The observational cohort studies and the RECOVER Pathobiology Research Program are investigating potential mechanisms for how some people may be protected from Long COVID or some of its symptoms.

RECOVER researchers are making progress toward understanding why some people develop Long COVID and how these long-term symptoms affect one’s health. Based on what the researchers have learned so far, RECOVER has launched clinical trials to test different interventions for Long COVID. Two RECOVER clinical trials have launched, with three more planned: RECOVER NEURO and RECOVER VITAL. RECOVER NEURO focuses on treatments for cognitive symptoms associated with Long COVID. Learn more about RECOVER-NEURO. RECOVER VITAL (viral persistence and reactivation, and immune dysregulation) focuses on treating viral persistence—which is when the SARS-CoV-2 virus stays in the body and damages organs or the immune system. Viral persistence or reactivation are possible explanations for what causes Long COVID symptoms. This trial focuses on treatments to stop the virus from causing continued damage and to resolve symptoms caused by the virus. Learn more about RECOVER-VITAL. RECOVER researchers are also planning to launch three additional clinical trials. Learn more about RECOVER Clinical Trials.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a type of Long COVID that may develop in children and young adults. In a small study with seven outpatient children diagnosed with MIS-C, outpatient treatment alone was sufficient, and they did not need hospitalization. View the study.