The National Institutes of Health should create an Office of Infection-Associated Chronic Illness Research. Reporting directly to the NIH Director, the Office would provide a timely and urgently needed command center for prioritizing innovative research across a group of complex, chronic conditions that are all known to be downstream effects of viral and bacterial infections. These include Long Covid and many others. The Office of IACIR should champion transformative, catalytic research that cuts across multiple institutes and centers.

The Covid-19 pandemic has proven to be a massive disabling event that has shined a bright and historic light on infection-associated illnesses. As many as 1 in 5 adults develops a new health condition in the aftermath of Covid, and for many, the condition could be lifelong. This should not come as a surprise. For decades, millions of sufferers have experienced debilitating illness, gaslighting, misunderstanding, lack of insurance coverage, disability, and no FDA-approved treatment options. In alignment with President Biden’s National Research Action Plan for Long Covid, the Office should pursue a two-pronged approach that includes pioneering next-generation diagnostics while also fast-tracking patient-centered clinical trials for repurposed drugs. The Office would spur creation of a world in which all people with an infection-associated chronic illness have access to a timely diagnosis and effective treatments.

Challenge and Opportunity

The world faces a massive problem with long term disability due to the long-term effects of infections. The cost of Long Covid is estimated at $3.7 trillion over five years, according to Harvard University economist David Cutler. Within the United States, it is estimated that up to 23 million Americans currently have or have had Long Covid or similar complex, chronic conditions.

Long Covid is part of a family of infection-associated chronic illnesses. More than two-thirds of people with Long Covid develop moderate to severe dysautonomia, most commonly presenting as postural orthostatic tachycardia syndrome (POTS), a condition estimated to impact up to 3 million Americans prior to the pandemic. Dysautonomia symptoms, the result of a problem with the autonomic nervous system, include lightheadedness, palpitations, profound fatigue, exercise intolerance, cognitive impairment, gastrointestinal dysmotility and more. Similarly, about half of all Long Covid cases fit the criteria for myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS). With two of the most common symptoms of ME/CFS being unrelenting exhaustion and brain fog. These symptoms are also seen in persistent Lyme disease. Patients with Long COVID, dysautonomia/POTS, ME/CFS or persistent Lyme disease often present with autoimmunity, small fiber neuropathy, gut dysbiosis, migraine, mast-cell activation syndrome (MCAS), Ehlers Danlos syndrome (EDS), and cranio-cervical instability (CCI).

While there appears to be significant shared pathophysiology and symptomatology between these diseases, progress in each of these diseases has been stymied because research has been siloed and underfunded. For instance, one analysis of NIH funding and disease burden showed that ME/CFS received just 7% of research dollars commensurate with disease burden, making it the most underfunded disease at NIH with known disability-adjusted life years data. Reaching parity with diseases of similar severity and prevalence would require a fourteen fold increase in ME/CFS.

Each condition is in its own silo for a different reason, making full coordination impossible until a new NIH office is established. For instance, Gulf War illness doesn’t have an NIH budget line item at all; it is studied through the Department of Defense’s medical research program. And while the NIH studies acute Lyme infections, the agency didn’t formally start studying “post-treatment Lyme disease syndrome” until 2023. For POTS, there is a lack of research showing quality of life disruptions for dysautonomia sufferers. This makes it impossible to quantify the gap in research funding given the disorder’s large economic burden. And for decades, ME/CFS research was hamstrung in part because it was housed in NIH’s poorly funded Office of Research on Women’s Health. In short, to adapt a line from Leo Tolstoy’s Anna Karenina, “Understood diseases are all alike; every misunderstood disease is misunderstood in its own way.”

Therefore, studying infection-related conditions all together, within one multidisciplinary NIH office, provides an unprecedented scientific opportunity to build on existing research and apply a comprehensive molecular biology approach toward unraveling how the body’s systems go awry in complex disorders. Given the urgent need to rapidly scale interventions, these diseases also provide an ideal opportunity to make immediate progress with clinical trials for repurposed drugs.

This synergistic approach is also the most efficient and cost-effective from a financial standpoint, because it creates economies of scale and reduces redundancies that result from researching each disease piecemeal, from their respective silos. Streamlining research under one roof would also eliminate red tape and bureaucratic inefficiencies, thus ensuring the type of low barriers to entry and high return on investment (ROI) that are necessary to attract private sector participation. Moreover, a plan to fast-track FDA approval of promising drug therapies would both incentivize pharmaceutical involvement and guarantee that patients receive life-changing treatments as quickly as possible.

ME/CFS is an often lifelong condition in which about half of all patients are disabled and cannot work full-time. The level of disability for ME/CFS has been compared to that of cancer, heart disease, and last-stage AIDS. POTS is also often a lifelong condition, with a majority of patients reporting symptoms staying the same or worsening over time. Health-related quality-of-life in POTS is worse than what is seen in diabetes, neoplasms, cardiovascular disease, COPD, HIV and chronic kidney disease. Less than half of adult POTS patients are employed, and of those who are able to work, POTS symptoms prevent a majority of them from working as many hours as they would like to work. More than half of college students with POTS drop out of college due to the severity of their POTS symptoms. Given the high rate of POTS and ME/CFS with the Long Covid population, it follows that Long Covid patients can expect a similar prognosis. For all three diagnoses, there are as yet no treatments approved by the Food and Drug Administration. The landscape for drugs to treat these conditions is also undeveloped.

Given the magnitude of the challenge, a realistic budget for a Long Covid “moonshot” should be at least $1 billion per year for 10 years. Therefore, to incorporate all infection-associated chronic illnesses, the budget would need to be a great deal higher. This is an historic opportunity for the U.S. to lead with state-of-the art scientific research. A fully funded and comprehensive research program can tackle these diseases, alleviate suffering, and enable these individuals once again to pursue their dreams as productive members of society.

Several NIH offices created in recent years show us how to seize the current opportunity. In response to the most recent previous global pandemic, HIV/AIDS, the NIH created the Office of AIDS Research in 1988.

Later, the NIH established the Office of Women’s Health Research in 1990, after the Congressional Caucus for Women’s Issues asked the General Accounting Office to conduct an investigation into NIH’s implementation of guidelines for inclusion of women in medical research. The OWHR remedies longstanding inequities in which women were dramatically underrepresented in clinical research.

More recently, in 2023, the NIH launched its Office of Autoimmune Research. The office was originally proposed by then-Senator Joe Biden in 1999. In 2022, the National Academy of Sciences, Engineering, and Medicine held a research symposium, and issued a conclusive report, outlining five options for how to elevate federal research on autoimmune disease. 

One of those called for the establishment of the Office, situated within the Office of the Director. The authors noted the benefits of that high-level placement, including elevated visibility, sustained leadership, and becoming a clear focal point for intramural, extramural, training, and outreach activities. Placing it close to the NIH Director “may provide many of the benefits of a new Institute…with fewer bureaucratic costs or controversies,”they wrote.

On June 29-30, 2023, NASEM held a similar symposium to begin establishing a common research agenda for infection-associated chronic illnesses. The creation of the new Office of IACIR should organically flow out of this past summer’s NASEM meeting, just as the Office of Autoimmune Research did from the 2022 meeting.

Last year’s NASEM symposium was a watershed moment in the history of chronic illness patient advocacy movements, which for decades had effectively been voices in the wilderness. The nation’s most esteemed scientific body had consolidated the foundational literature for each condition, identified the possibilities for common pathophysiology, and illuminated a path forward. This establishes a clear generational opportunity to solve a major set of disabling conditions globally, and positions American institutions to lead in pioneering these breakthroughs.

Plan of Action

Working with champions in Congress, a select group of Administration officials – across Office of Science and Technology Policy, Domestic Policy Council, NIH, and the HHS Assistant Secretary for Health – would serve as executive sponsors and provide oversight.

Each of these primary stakeholders should take responsibility for the following steps in executing this proposal.

Clearly state the goals of the office and its NIH-wide responsibilities.

Since this research must span neurology, immunology, cardiology, pulmonology, virology, and other fields to encompass the multi-system impact of these illnesses, the Office must have a clearly-defined mission and authority to integrate work across multiple NIH institutes.

The key functions of the Office should include:

• Evangelize the concept of infection-associated chronic illnesses to the public, health providers, and researchers and administrators inside NIH
• Ensure that NIH and health systems are responsive to long-term sequelae of current and future pandemics
• Serve as a convener for industry, disease organizations, patient advocates, and patients across IACIs to set research priorities and design studies
• Embrace a spirit of co-producing research with patients, acknowledging the wisdom that those with lived experience bring to the scientific enterprise,
• Advance state-of-the-art IACI research focusing on biomarkers, root causes, and therapeutic targets in collaboration with patient communities
• Hold budgetary authority to fund and coordinate IACI research across all Institutes
• Identify and validate common biomarkers and therapeutic targets across conditions
• Collaborate with other U.S. government agencies (FDA, CDC, SSA, AHRQ, PCORI, etc.), community groups, and global organizations to catalyze rapid diagnosis, effective treatment, and relevant disability services/supports for all IACI patients
• Advise Director of NIH, HHS, and other entities on IACI research. In particular, this Office should directly coordinate with HHS’s Office of Long Covid Research and Practice so that IACI research is synergistic with a cabinet-level champion
  

Identify leadership and staffing.

At minimum, the office would require robust staffing and could be funded through several avenues. 

To begin, the Office of IACIR’s authority could be inaugurated under the auspices of the NIH’s Common Fund. This is a highly attractive option because it wouldn’t require additional Congressional funding allocations. The fund creates a space where investigators across NIH institutes collaborate on innovative research in order to address high-priority challenges and make a broader impact on the scientific community. Among the Common Fund’s most successful initiatives is the Undiagnosed Diseases Network.

To best amplify its mission, the office should be placed within the Office of the Director. Importantly, we stipulate that the NIH Director leads this new Office in consultation with community stakeholders, who have decades of experience managing infection-associated chronic conditions.

Congress could also consider bicameral legislation to create this new NIH office. If passed, policymakers could consider taking approaches similar to those taken for AIDS and Alzheimer’s, which could mandate special oversight of this Office. AIDS legislation, for instance, requires NIH to submit a research plan directly to Congress. Alternatively, Congress should also use the authority of the Congressionally Directed Medical Research Program to support and oversee this Office.

Launch a comprehensive IACI research agenda.

The Office should create a high-level blueprint as well as a more detailed agenda with an implementation plan for carrying it out. Research projects should mirror the most recent findings and avenues for next steps discussed at the NASEM symposium.

Diagnostic research activities should include:

• Advanced central and peripheral nervous system analysis and imaging
• AI-based analysis of immune profiles and comprehensive panels
• Investigation of viral or bacterial persistence, microclotting/coagulation parameters, tissue pathology, and epigenetics

Clinical trial platforms should support state-of-the-art techniques including:

• Decentralized, multi-arm clinical trials with dynamic, adaptable design
• Cross-diagnosis research amongst IACIs with common co-morbidity
• More efficient testing of repurposed medications

Not only would these approaches incorporate best practices scientifically, but by combining multiple diseases into single studies, they would create economic efficiencies that would reduce costs overall and make it easier and more cost-effective to roll out treatments.

Scale it into an Institute.

Once the new Office becomes established in the NIH and has put “points on the board” with early successes in its first five years, leaders at NIH and in the Administration should evaluate how to develop it into a Center or Institute. Alternatively, Congress could pass further legislation to elevate it to the level of an Institute.

An Institute is likely the best vehicle to fully execute a true long-term high investment capable of curing these diseases. Given the economic and social burden of these diseases – and coupled with their historic neglect – an annual research budget measured in the billions of dollars may be required.

Conclusion

Throughout its history, the NIH has continually evolved to meet new and pressing challenges as scientific understanding has progressed. Globalization, microbial resistance, and climate change continue to upset the balance of the natural world, with unpredictable effects on the human population. It’s not a question of if – but rather when – the next global pandemic will occur. Every pandemic causes long-term health consequences. The research advanced by this Office would foster pandemic resilience against the types of global infectious threats that will become increasingly common in the modern world. At the same time, it would help address the large swath of disability from the trickle-down of chronic illnesses triggered by everyday community infections as well.

Just as the NIH Office of AIDS Research has made great strides against AIDS, a new Office of Infection-Associated Chronic Illness Research will turn the tide against Long Covid and its many cousins. By diagnosing, managing, treating and ultimately curing these conditions, this program will help many millions get their lives and careers back. As they rejoin the workforce and contribute to the economy, the returns generated by this Office will exceed its costs by many orders of magnitude.

For over 10 years, physical inactivity has been recognized as a global pandemic with widespread health, economic, and social impacts. Despite the wealth of research support for movement as medicine, financial and environmental barriers limit the implementation of physical activity intervention and prevention efforts. The need to translate research findings into policies that promote physical activity has never been higher, as the aging population in the U.S. and worldwide is expected to increase the prevalence of chronic medical conditions, many of which can be prevented or treated with physical activity. Action at the federal and local level is needed to promote health across the lifespan through movement.

Research Clearly Shows the Benefits of Movement for Health

Movement is one of the most important keys to health. Exercise benefits heart health and physical functioning, such as muscle strength, flexibility, and balance. But many people are unaware that physical activity is closely tied to the health conditions they fear most. Of the top five health conditions that people reported being afraid of in a recent survey conducted by the Centers for Disease Control and Prevention (CDC), the risk for four—cancer, Alzheimer’s disease, heart disease, and stroke—is increased by physical inactivity. It’s not only physical health that is impacted by movement, but also mental health and other aspects of brain health. Research shows exercise is effective in treating and preventing mental health conditions such as depression and anxiety, rates of which have skyrocketed in recent years, now impacting nearly one-third of adults in the U.S. Physical fitness also directly impacts the brain itself, for example, by boosting its ability to regenerate after injury and improving memory and cognitive functioning. The scientific evidence is clear: Movement, whether through structured exercise or general physical activity in everyday life, has a major impact on the health of individuals and as a result, on the health of societies.

Movement Is Not Just about Weight, It’s about Overall Lifelong Health

There is increasing recognition that movement is important for more than weight loss, which was the primary focus in the past. Overall health and stress relief are often cited as motivations for exercise, in addition to weight loss and physical appearance. This shift in perspective reflects the growing scientific evidence that physical activity is essential for overall physical and mental health. Research also shows that physical activity is not only an important component of physical and mental health treatment, but it can also help prevent disease, injury, and disability and lower the risk for premature death. The focus on prevention is particularly important for conditions such as Alzheimer’s disease and other types of dementia that have no known cure. A prevention mindset requires a lifespan perspective, as physical activity and other healthy lifestyle behaviors such as good nutrition earlier in life impact health later in life.

Despite the Research, Americans Are Not Moving Enough

Even with so much data linking movement to better health outcomes, the U.S. is part of what has been described as a global pandemic of physical inactivity. Results of a national survey by the CDC published in 2022 found that 25.3% of Americans reported that outside of their regular job, they had not participated in any physical activity in the previous month, such as walking, golfing, or gardening. Rates of physical inactivity were even higher in Black and Hispanic adults, at 30% and 32%, respectively. Another survey highlighted rural-urban differences in the number of Americans who meet CDC physical activity guidelines that recommend ≥ 150 minutes per week of moderate-intensity aerobic exercise and ≥ 2 days per week of muscle-strengthening exercise. Respondents in large metropolitan areas were most active, yet only 27.8% met both aerobic and muscle strengthening guidelines. Even fewer people (16.1%) in non-metropolitan areas met the guidelines.

Why are so many Americans sedentary? The COVID-19 pandemic certainly exacerbated the problem; however, data from 2010 showed similar rates of physical inactivity, suggesting long-standing patterns of sedentary behavior in the country. Some of the barriers to physical activity are internal to the individual, such as lack of time, motivation, or energy. But other barriers are societal, at both the community and federal level. At the community level, barriers include transportation, affordability, lack of available programs, and limited access to high-quality facilities. Many of these barriers disproportionately impact communities of color and people with low income, who are more likely to live in environments that limit physical activity due to factors such as accessibility of parks, sidewalks, and recreation facilities; traffic; crime; and pollution. Action at the state and federal government level could address many of these environmental barriers, as well as financial barriers that limit access to exercise facilities and programs.

Physical Inactivity Takes a Toll on the Healthcare System and the Economy

Aside from a moral responsibility to promote the health of its citizens, the government has a financial stake in promoting movement in American society. According to recent analyses, inactive lifestyles cost the U.S. economy an estimated $28 billion each year due to medical expenses and lost productivity. Physical inactivity is directly related to the non-communicable diseases that place the highest burden on the economy, such as hypertension, heart disease, and obesity. In 2016, these types of modifiable risk factors comprised 27% of total healthcare spending. These costs are mostly driven by older adults, which highlights the increasing urgency to address physical inactivity as the population ages. Physical activity is also related to healthcare costs at an individual level, with savings ranging from 9-26.6% for physically active people, even after accounting for increased costs due to longevity and injuries related to physical activity. Analysis of 2012 data from the Agency for Healthcare Research and Quality’s Medical Expenditure Panel Survey (MEPS) found that each year, people who met World Health Organization aerobic exercise guidelines, which correspond with CDC guidelines, paid on average $2,500 less in healthcare expenses related to heart disease alone compared to people who did not meet the recommended activity levels. Changes are needed at the federal, state, and local level to promote movement as medicine. If changes are not made in physical activity patterns by 2030, it is estimated that an additional $301.8 billion of direct healthcare costs will be incurred.

Government Agencies Can Play a Role in Better Promoting Physical Activity Programs

Promoting physical activity in the community requires education, resources, and removal of barriers in order for programs to have a broad reach to all citizens, including communities that are disproportionately impacted by the pandemic of physical inactivity. Integrated efforts from multiple agencies within the federal government is essential. 

Past initiatives have met with varying levels of success. For example, Let’s Move!, a campaign initiated by First Lady Michelle Obama in 2010, sought to address the problem of childhood obesity by increasing physical activity and healthy eating, among other strategies. The Food and Drug Administration, Department of Agriculture, Department of Health and Human Services including the Centers for Disease Control and Prevention, and Department of Interior were among the federal agencies that collaborated with state and local government, schools, advocacy groups, community-based organizations, and private sector companies. The program helped improve the healthy food landscape, increased opportunities for children to be more physically active, and supported healthier lifestyles at the community level. However, overall rates of childhood obesity remained constant or even increased in some age brackets since the program started, and there is no evidence of an overall increase in physical activity level in children and adolescents since that time.

More recently, the U.S. Office of Disease Prevention and Health Promotion’s Healthy People 2030 campaign established data-driven national objectives to improve the health and well-being of Americans. The campaign was led by the Federal Interagency Workgroup, which includes representatives across several federal agencies including the U.S. Department of Health and Human Services, the U.S. Department of Agriculture, and the U.S. Department of Education. One of the campaign’s leading health indicators—a small subset of high-priority objectives—is increasing the number of adults who meet current minimum guidelines for aerobic physical activity and muscle-strengthening activity from 25.2% in 2020 to 29.7% by 2030. There are also movement-related objectives focused on children and adolescents as well as older adults, for example:

• Reducing the proportion of proportion of adults who do no physical activity in their free time
• Increasing the proportion of children, adolescents, and adults who do enough aerobic physical activity, muscle-strengthening activity, or both
• Increasing the proportion of child care centers where children aged 3 to 5 years do at least 60 minutes of physical activity a day
• Increasing the proportion of adolescents and adults who walk or bike to get places
• Increasing the proportion of children and adolescents who play sports
• Increasing the proportion of older adults with physical or cognitive health problems who get physical activity
• Increasing the proportion of worksites that offer an employee physical activity program

Unfortunately, there is currently no evidence of improvement in any of these objectives. All of the objectives related to physical activity with available follow-up data either show little or no detectable change, or they are getting worse.

To make progress towards the physical activity goals established by the Healthy People 2030 campaign, it will be important to identify where breakdowns in communication and implementation may have occurred, whether it be between federal agencies, between federal and local organizations, or between local organizations and citizens. Challenges brought on by the COVID-19 pandemic (e.g., less movement outside of the house for people who now work from home) will also need to be addressed, with the recognition that many of these challenges will likely persist for years to come. Critically, financial barriers should be reduced in a variety of ways, including more expansive coverage by the Centers for Medicare & Medicaid Services for exercise interventions as well as exercise for prevention. Policies that reflect a recognition of movement as medicine have the potential to improve the physical and mental health of Americans and address health inequities, all while boosting the health of the economy.

Just over a year ago, I found myself pausing during a research lab meeting. “Why were all the subjects in our studies of wearable devices white? And what were the consequences of exclusion?”

This question stuck with me long after the meeting. Digging into the evidence, I was alarmed to find paper after paper signaling embedded biases in key medical technologies. 

One device stuck out amongst the rest – the pulse oximeter. Because of its crucial role in diagnosing COVID-19, it had caught the attention of a diverse group of stakeholders: clinicians looking to understand the impacts on patient care, engineers working to build more equitable devices, social scientists tracing the history of device and examining colorism in pulse oximetry, policymakers seeking solutions for their constituents, and the FDA, which was examining racial bias in medical technologies for the first time. But what I found as I scoped out this policy area is that these stakeholders weren’t talking to one another, at the expense of coordinated progress towards equity in pulse oximetry. 

With all eyes directed towards the FDA’s Advisory Committee meeting on November 1st, 2022, FAS convened a half-day session of stakeholders on November 2nd to chart a research and policy agenda for near-term mitigation of inequities in pulse oximetry and other medical technologies. Eight experts from medicine, engineering, sociology, and anthropology shared insights with an audience of 60 participants from academia, the private sector, and federal government. Collectively, we developed several key insights for future progress on this issue and outlined a path forward for achieving equity now. You can access the full readout here. We’ll dive into the key highlights below:

Key Insights

Through discussions with experts during the forum, three key themes rose to the surface:

• Racial bias in pulse oximetry cannot be fixed by focusing on “race” alone. Existing evidence suggests reducing bias in pulse oximetry requires replacing devices with less-biased ones. This will take time as new devices are developed and will be a significant cost. 
• Better calibration for skin tone is vital, but measurement is complicated. The crux of the problem is a comprehensive standard for quantifying the full range of skin pigmentation. This is vital to understanding how pulse oximeter accuracy varies by melanin content.
• Proactively identifying and addressing bias in medical devices will require system-wide efforts. Identification of bias in medical devices has been piecemeal rather than the outcome of proactive, deliberative efforts. Further efforts to address bias in medical devices should engage diverse stakeholders to establish best practices for ensuring equity in medical devices.

Resolving the problem of bias in pulse oximeter devices will likely take several years. But in the meantime, this issue will continue negatively impacting patients. Our participants urged that we need to think about actions that can be initiated this next year that will advance more equitable care with existing pulse oximeters. 

In-person stakeholders convening a focused conversation on next steps

Motivating Action for Equity Now

While a daunting problem, a collaborative, multi-stakeholder effort can bring us closer to solutions. We can work together to advance equity in standards of care by:

• Gathering evidence on existing pulse oximeter devices and their use in care [ASAP, start early 2023]. More evidence is required to identify the best approaches to equitable care with existing devices. This evidence gathering process should be initiated over the next year to inform clinicians on 
• Establishing consensus to advance the standard of care [start early 2024]. After growing the body of evidence, there will be a need to convene around key conclusions derived from the evidence. Evidence synthesis will need to be generated and care societies will need to make decisions on how clinicians should use pulse oximeters in their care practice.
• Taking action to ensure equitable care nationwide [2024 onwards]. Once the care standards are changed, there is a need for system-wide efforts to communicate these to clinicians nationwide, inform procurement across federal hospitals, and re-evaluate insurance reimbursement standards.

Mapping out a plan of action towards equity

Looking Ahead

This won’t be easy, but it’s 30 years overdue. We believe correcting the bias will pioneer a model that can be readily applied to combatting biases across the medical device ecosystem, something already underway in the United Kingdom with their Equity in Medical Devices Independent Review. Through a systematic approach, stakeholders can work to close racial disparities in the near-term and advance health equity.