By Ryan Prior

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, [including persistent Lyme disease]. 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).

Siloed and underfunded

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.”

Unprecedented opportunity

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.

Eliminating red tape

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.

State-of-the-art research

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 (NASEM) 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.

Republished by permission from FAS.org, the website of the Federation of American Scientists. Journalist Ryan Prior most recently served as a fellow at The Century Foundation, a think tank in Washington, D.C. He is the author of The Long Haul: How Long Covid Survivors Are Revolutionizing Healthcare and writes the Patient Revolution column at Psychology Today.