A certain percentage of those who have been infected with COVID-19 over the course of the pandemic — including people who have “recovered” — continue to have lingering, persistent COVID symptoms. This has come to be referred to as Long COVID. Extensive investigation into this phenomenon is underway. The University of Colorado Anschutz Medical Campus in Aurora is a recruitment site for one of the more robust investigations, this being the $1.15 billion RECOVER study funded by the National Institutes of Health (NIH).

RECOVER stands for Researching COVID to Enhance Recovery. It’s a four-year Long COVID research study enrolling and following patients from three groups: those who had COVID-19 and experienced Long COVID symptoms, those who recovered without Long COVID symptoms, and healthy controls. Anschutz calls it “a study that aims to probe the mysteries of Long COVID, a condition that plagues millions of people after they recover.”

Monica M. Bertagnolli, M.D., is the Director of the NIH. She said the NIH is making multimillion dollar investments toward the goal of “taking a systematic, comprehensive and rigorous approach to improve our understanding of Long COVID and increase the odds of identifying treatments that work.” The NIH recently announced an infusion of another $515 million for this research.  

Colorado and U.S. Numbers for Long COVID

The Centers for Disease Control and Prevention (CDC) notes that four years after the COVID-19 pandemic began, Long COVID remains an unsolved, complex, and urgent healthcare crisis. The CDC says 1 in 9 adults in the U.S. who have ever had COVID-19 continue to experience Long COVID with a wide range of symptoms. Mirroring that statistic, a 2022 report from Colorado’s Office of Saving People Money on Health Care found that as many as 1 in 10 Coloradans may experience Long COVID. A 2022 report from the state of Colorado, headed by Lt. Governor Dianne Primavera, estimated the “burden” of Long COVID affects hundreds of thousands of people in the state.

Dr. Bertagnolli goes on to observe that infection-associated chronic conditions, such as Long COVID, have been notoriously difficult to solve. Their biological mechanisms have not been identified, and many of their symptoms remain difficult to treat. “However,” she says, “unlike some infection-associated chronic conditions for which the source of infection is unknown, we know that Long COVID is caused by the SARS-CoV-2 virus, which may prove advantageous in research.”

Nationally nearly 90,000 adults and children are participating in RECOVER observational studies through more than 300 clinical research sites across the country. Anschutz is one such site. RECOVER clinical trials use a flexible framework to rapidly identify treatments that work, remove those that don’t, and add new interventions for testing. Study findings, including the identification of major symptom clusters, are helping clinical researchers broaden the identification of Long COVID in their patients and ultimately helping to inform diagnosis, treatment, and care for all those suffering from Long COVID. According to the NIH, these findings inform the design of RECOVER clinical trials and the selection of at least 13 potential interventions and combination of interventions. “NIH expects this investment of time and resources in building a research program of this scale, scope and rigor will increase the odds in finding treatments that work,” Dr. Bertagnolli says.

Learn more about RECOVER at https://recovercovid.org/.

What’s Happening at Colorado’s Anschutz Site with Long Covid

Recruits at Anschutz complete baseline questionnaires and blood draws. Researchers use that information gleaned to search for clues to what drives what it calls the “dizzying array of symptoms that plague Long COVID sufferers.” (See a listing of Long COVID symptoms compiled by the CDC at the end of this article.) Dr. Kristine Erlandson, co-principal site investigator for the RECOVER study at Anschutz, explains that “The bloodwork will hopefully delve into the mechanisms, such as the body’s immune response, inflammation, and changes in the microbiome that might underlie those who go on to develop long-term symptoms.” Dr. Erlandson is also associate professor of Medicine—Infectious Disease at the University of Colorado School of Medicine. She is hopeful the promise of trials for new therapies may encourage more patients to join RECOVER studies as the research moves along.

Specifics Being Looked at in Colorado Trials Re: Long Covid

The Colorado RECOVER site at Anschutz exceeded its enrollment goals for Phase One and was moving into the next phase in late 2023. The clinical trials at Anschutz are focusing on five categories of health issues linked to Long COVID. These include:

  • Viral persistence: damage caused by the SARS-CoV-2 virus staying in the body
  • Cognitive dysfunction: chronic issues that disrupt thinking, such as brain fog
  • Sleep disturbances
  • Autonomic dysfunction: symptoms like dizziness and shortness of breath caused by disruptions to systems that regulate body functions
  • Exercise intolerance and fatigue.

Studies are testing treatments for Long COVID symptoms that have proved particularly troublesome. Dr. Sarah Jolley, assistant professor of Pulmonary Sciences & Critical Care Medicine at the University of Colorado School of Medicine, is the site principal investigator. She is also director of the UCHealth Post-COVID Clinic. The Clinic has treated some 2,000 Long COVID patients since it opened and still averages 20 Long COVID referrals per week. It has at times been a source of enrollees for Long COVID studies.

The study trials are looking into viral persistence, cognitive dysfunction, and sleep disturbances, Dr. Jolley said. The viral persistence trial is dubbed RECOVER-VITAL. It aims to learn if an extended course of Paxlovid, the anti-viral medication used to treat COVID-19, can be safely and effectively used to reduce symptoms in Long COVID patients. Dr. Jolley said the idea is to reduce the “viral reservoir” that appears to remain in some patients after a COVID infection. The study will compare the effects of different Paxlovid regimens and its components.

Another trial is named RECOVER-NEURO. It will test combinations of online brain training programs with different patient groups and something called transcranial direct current stimulation (tDCS), described as “mild impulses of electricity delivered through a headset to specific areas of the brain.” The overall goal is to discover the most effective treatments for dispelling brain fog, concentration issues, memory changes, and other cognitive issues that plague many Long COVID patients. Dr. Erlandson, who was mentioned earlier, noted that tDCS is a safe and effective treatment that has been used for patients with Parkinson’s disease and other neurologic conditions.

Find detailed information here about RECOVER-VITAL (https://trials.recovercovid.org/vital) and RECOVER-NEURO (https://trials.recovercovid.org/neuro).

Additional Efforts by the NIH – Long Covid Effects

At the national level, Dr. Bertagnolli said the $515 million in additional NIH funding will build on and continue the research work by:

  • Testing additional interventions in clinical trials to find effective treatments to reduce the burden of Long COVID.
  • Deepening our understanding of how SARS-CoV-2 affects each part of the body as it triggers Long COVID and identifying potential biological targets for diagnosis and treatment.
  • Investigating longer-term effects of SARS-CoV-2 infection in adults and children to understand who fully recovers over the long term, how the virus affects risk for other diseases such as diabetes, cancer and neurological disorders, and factors and interventions that contribute to recovery.
  • Maintaining support for data management and research infrastructure to continue the collection, integration, analysis, and storage of many diverse types of clinical data and biospecimens necessary to further understand the effects of COVID-19 and inform interventions.

“These studies and others will provide important insights into Long COVID,” she said, “and will improve our understanding of other infection-associated chronic conditions with similar symptoms to inform treatments. NIH will continue to engage with the many communities that make up RECOVER, including patient and community representatives, advocates, researchers, and clinicians, to gather input on potential research and clinical approaches.”

Diverse Coloradans Sought as Study Enrollees in Long Covid Trials

A key factor in these Long COVID studies is the ability to recruit a diverse group of patients for the trials. (Early on, one of the difficulties was finding people in the uninfected population to serve as controls, but that has changed with decreasing infection rates.) Groups that are often under-represented in medical research in general — such as African Americans and Hispanics — are also among those who statistically bear heavier COVID burdens. According to the CDC, the risk of hospitalization from a COVID-19 infection for Black people and Hispanic people was more than double that for white people. The comparative risk was nearly triple for American Indians and Alaska Natives. Reaching Long COVID sufferers in rural areas is another targeting challenge.

A number of recruiting and outreach efforts have been made to address these concerns, including working with community health centers. Dr. Erlandson also pointed to community education and partnerships headed by the Colorado chapter of Community Engagement Alliance (CO-CEAL), which the NIH formed to address the disproportionately heavy burden of COVID-19 on some racial and ethnic groups. Dr. Jolley noted that the UCHealth Post-COVID Clinic is a good source for study participants because more than one-third of the Clinic’s patients are Hispanic, while roughly one-fifth are Black. She says she would like to repay the trust many of these people have in the Clinic with new hope for recovery from the symptoms that have disrupted their lives. “We want to allow patients who have been waiting for treatments to get into these trials,” Dr. Jolley said.

Dr. Jolley additionally observed that attitudes toward Long COVID have also slowly changed. Although not completely gone, there is less need to counter disinformation. Where there was once mistrust between patients frustrated by a lack of help for their symptoms and providers grasping for clues to address them, Long COVID is now well recognized. Now, she says, the task for researchers and clinicians is to learn as much as possible about the condition and use their knowledge to devise evidence-based therapies to help patients. She concluded: “That’s why we need these trials to happen.”

To learn more about enrolling in a RECOVER study, click here and scroll down to “How Can I Participate?” As noted earlier, more information about RECOVER in general is available at https://recovercovid.org/.

Long COVID Symptoms Coloradans May Experience

People who are impacted by Long COVID most commonly report the following symptoms, according to the CDC:

General symptoms (Not a Comprehensive List)

  • Tiredness or fatigue that interferes with daily life
  • Symptoms that get worse after physical or mental effort (also known as “post exertional malaise”)
  • Fever

Respiratory and heart symptoms

  • Difficulty breathing or shortness of breath
  • Cough
  • Chest pain
  • Fast-beating or pounding heart (also known as heart palpitations)

Neurological symptoms

  • Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
  • Headache
  • Sleep problems
  • Dizziness when you stand up (lightheadedness)
  • Pins-and-needles feelings
  • Change in smell or taste
  • Depression or anxiety

Digestive symptoms

  • Diarrhea
  • Stomach pain

Other symptoms

  • Joint or muscle pain
  • Rash
  • Changes in menstrual cycles