Revolutionizing Research and Treatments for Infection-Associated Chronic Diseases

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:

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:

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

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.

Frequently Asked Questions
How does this proposal differ from the NIH’s RECOVER initiative?
In 2021, the NIH received $1.15 billion from Congress for research to understand the long-term effects of SARS-CoV-2 over four years. It created the RECOVER Initiative, which conducts long-term observational studies of individuals experiencing post-acute sequelae of Covid-19, or PASC. RECOVER has also started to organize a few clinical trials. RECOVER’s efforts have laid a foundation. Now the NIH must go further across all fronts, including accelerated clinical trials for repurposed drugs, bolstering patient engagement, and understanding the interconnections between Long Covid and similar infection-associated chronic illnesses. This new NIH office would be a crucial hub for that ongoing research, which should become permanent.
How does this proposal complement or add to existing research at NIH?
The NIH initiated a Trans-NIH Working Group as well as an intramural research program to research ME/CFS at the National Institute of Neurological Diseases and Stroke (NINDS). In 2019, the NIH also convened a stakeholders workshop, Postural Orthostatic Tachycardia Syndrome (POTS): State of the Science, Clinical Care and Research, which led to the publication of two expert consensus papers mapping our high-priority POTS research needs.
How does the office interact with other agencies?

The Office of IACIR should dynamically collaborate with several offices at the cutting edge. First among these is the Office of Long Covid Research and Practice, established in 2023 under the Office of the Assistant Secretary for Health (OASH), includes an advisory committee composed of as many as 20 members.


Next, our future NIH Office should work in partnership with the federal government’s new health moonshot agency – the Advanced Research Projects Agency for Health (ARPA-H) – which is uniquely suited to help lead on building next-generation diagnostics for infection-associated chronic illnesses. Its model calls for rapid high-risk, high-reward science. Launched in 2022, ARPA-H is currently hiring its first slate of program managers, leading innovative projects that are disease-agnostic. Infection-associated chronic illnesses could be a target of a future ARPA-H program manager.


The Office should work closely with the Food and Drug Administration, such that safe and effective repurposed drugs can be approved for this patient population.


And throughout all of this, the Office must collaborate with the Patient Centered Outcomes Research Institute (PCORI), which has funded innovative work by the Patient Led Research Collaborative on Covid-19 to develop patient scorecards to grade the efficacy and quality of research proposals. To improve equity and stakeholder engagement, NIH should consider piggybacking off such efforts.

Which conditions should be included in this Office?
Long Covid, also called post-acute sequelae of Covid-19 (PASC); myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); persistent Lyme disease; Gulf War illness (GWI); Ehlers Danlos syndrome (EDS); Mast cell activation syndrome (MCAS); fibromyalgia, postural orthostatic tachycardia syndrome (POTS) and other infection-triggered dysautonomias, and cranio-cervical instability (CCI).
What types of objectives might the Office tackle in its first five years?

  • Establish a consensus vocabulary; assess which chronic diseases or illnesses are “infection-associated,” and potentially expand into more areas

  • Annually develop and evaluate a strategic plan for all IACI research across NIH Institutes, Centers, and Offices

  • By the end of its first year, hold an international conference to rapidly develop a common research agenda, timeline, and milestones toward key accomplishments by 2030

  • Accelerate development of a common IACI biobank by leveraging existing disease-specific biobanking initiatives

  • Build research infrastructure to seed and sustain diverse and multidisciplinary IACI scientific workforce

  • Establish advisory council for whole-of-government approach to IACI research, care, and services

  • Involve and incentivize the private sector and fast-tracking FDA approval for promising drugs

Under Pressure: Long Duration Undersea Research

“The Office of Naval Research is conducting groundbreaking research into the dangers of working for prolonged periods of time in extreme high and low pressure environments.”

Why? In part, it reflects “the increased operational focus being placed on undersea clandestine operations,” said Rear Adm. Mathias W. Winter in newly published answers to questions for the record from a February 2016 hearing.

“The missions include deep dives to work on the ocean floor, clandestine transits in cold, dark waters, and long durations in the confines of the submarine. The Undersea Medicine Program comprises the science and technology efforts to overcome human shortfalls in operating in this extreme environment,” he told the House Armed Services Committee.

See DoD FY2017 Science and Technology Programs: Defense Innovation to Create the Future Military Force, House Armed Services Committee hearing, February 24, 2016.

“Zika has been sexually transmitted in Texas, CDC confirms” (CNN)

The first identified case of the Zika virus acquired in the continental United States has been confirmed in Texas, contracted via sexual transmission. The CDC is expected to release guidelines on sexual transmission, however relatively little is known. While it has been established that the virus remains in the blood for roughly a week, the viability in semen is yet to be determined. Find out more about the latest research developments of Zika virus at CNN: http://www.cnn.com/2016/02/02/health/zika-virus-sexual-contact-texas/

“Egregious safety failures at Army lab led to anthrax mistakes” (USA Today)

An investigation into the Army labs at Dugway Proving Ground in Utah, responsible for chemical and biological defensive testing, was launched last year after it was discovered to be accidentally shipping live anthrax to laboratories across the country for over a decade. The report reveals gaps that go far beyond that of poor leadership, and include a dozen personnel that are being held accountable and could face disciplinary action as a result. To read more about the findings of the Army investigation report, visit USA Today:  http://www.usatoday.com/story/news/nation/2016/01/15/military-bioterrorism-lab-safety/78752876/

A Social Science Perspective on International Science Engagement

In the previous issue of the Public Interest Report (Spring 2015), Dr. Charles Ferguson’s President’s Message focused on the importance of empathy in science and security engagements. This was a most welcome surprise, as concepts such as empathy do not typically make it to the pages of technical scientific publications. Yet the social and behavioral sciences play an increasingly critical part in issues as far ranging as arms control negotiations, inspection and verification missions, and cooperative security projects.

The Middle East Scientific Institute for Security (MESIS), the organization that I have headed for five years now, has developed a particular niche in looking at the role of culture in these science and security issues. MESIS works to reduce chemical, biological, radiological and nuclear threats across the region by creating partnerships within the region, and between the region and the international community, with culture as a major component of this work.

As with empathy, culture is often a misunderstood and misappropriated concept for most policymakers. Admittedly, it is not something that is easy to capture, describe, or measure, which may explain why it is not a popular topic. Notwithstanding, there is growing evidence that cultural awareness can make a crucial difference to the prospective success of negotiations, inspections, and cooperative endeavors. The Central Intelligence Agency produced a report in 2006 1 that examined how a lack of cultural awareness among those involved in Iraq’s inspection regime in the mid-1990s resulted in misinterpretation of the behavior of Iraqi officials, leading to an assumption that the exhibited behavior was that of denial and deception. The report relayed a wide range of incidents that were misread by those overseeing the inspection regime. These included: 1) Iraqi scientists’ understanding of the limitations of their weapons programs, combined with their fear to report these limitations to senior leaders, created two accounts about how far advanced these programs were; and 2) Iraqi leaders’ intent on maintaining an illusion of WMD possession to deter Iran regardless of the implications this may have on the inspection regime. The report even cites misinterpretations of customary (read: obligatory) tea served to inspectors at sites under investigation as being a delay tactic. These incidents demonstrate that local cultural factors, on both societal and state levels, were major determinants of nonproliferation performance, but were poorly understood by inspection officials who did not have enough cultural awareness.

It has become equally important to consider intercultural awareness when it comes to cooperative endeavors in non-adversarial circumstances. The sustainability of cooperative programmatic efforts, such as capacity building, cannot be achieved without a solid understanding of cultural awareness. Though terms such as “local ownership” and “partnerships” have become commonplace in the world of scientific cooperative engagements, it is rare to see them translated successfully into policy. As a local organization, MESIS cannot compete with any of the large U.S. scientific organizations on a technical level, yet by virtue of its knowledge of the regional context, it has numerous advantages over any other organization from outside the region. Try getting a U.S. expert to discuss the role that cultural fatalism can play in improving chemical safety and security standards among Middle Eastern laboratory personnel and this becomes all the more apparent. For example, a Jordanian expert looking to promote best practices among laboratory personnel once made an excellent argument by referring to a Hadith by the Prophet Mohammad (PBUH) that calls for the need to be safe and reasonable ahead of, and in conjunction with, placing one’s faith in God. There have been several studies about the relationship between the cultural fatalism of Arab and Muslim societies, and their perceptions of safety culture, especially on road safety. Although there is no ethnographic evidence to support the claim that this is applicable to lab safety, an anecdotal assessment would strongly suggest so.

Language is another critical area for cultural awareness, as exemplified by the success of a cooperative endeavor between the Chinese Scientists Group on Arms Control (CSGAC) of the Chinese People’s Association for Peace and Disarmament, and the Committee on International Security and Arms Control (CISAC) of the U.S. National Academy of Sciences. These groups have been meeting for almost 20 years to discuss nuclear arms control, nuclear nonproliferation, nuclear energy, and regional security issues, with the goal of reducing the possibility of nuclear weapons use and reducing nuclear proliferation in the world at large. Throughout the exchanges, it was often evident that beyond the never-simple translation of one language into the other, there was also the difficulty of differing interpretations of terms. Accordingly, a glossary of about 1000 terms was jointly developed by the two sides to ensure that future misunderstandings possibly between new members or non-bilingual speakers could be avoided. 2 In a similar vein, the World Institute for Nuclear Security (WINS) has partnered with MESIS in developing Arabic versions of its Best Practices Guidelines. This is certainly not due to any shortage of Arabic-language translators in Vienna, but rather because they rightly distinguish between translation and indigenization. Typically, a translator with limited understanding of nuclear security is unable to indigenize a text in the way that a local expert can. In the case of the Guidelines, the use of local experts went a long way to ensure that the concepts themselves were understood by Arabic-language speakers (a case not very different from the U.S.-Chinese example).

The sustainability of the international community’s programmatic efforts in the Middle East and elsewhere is strongly tied to this notion of cultural context. MESIS manages the Radiation Cross Calibration Measurement (RMCC) network, which is a project that seeks to raise radiation measurement standards across the Arab world. It has always been a challenge to find funding for this network from funds dedicated to nonproliferation and nuclear security as the project’s relevance or utility is not readily apparent to decision makers. More creative thinking is needed here. A project like RMCC does in fact build the infrastructure and capacity needed for areas such as nuclear forensics and Additional Protocol compliance 3, but it also addresses more local concerns such as environmental monitoring and improved laboratory management. These sorts of win-win endeavors require a strong degree of cultural awareness. If a network of nuclear forensics laboratories had in fact been established, funding would probably be secured with greater ease, while sustainability would certainly be threatened, because ultimately, nuclear forensics is not currently a priority area for the region.

In a period when there is a tremendous amount of skepticism about international science engagement, increased cultural awareness may lead to more meaningful and, in turn, sustainable outcomes. One would expect this to be more readily apparent to members of a scientific community. There may be some merit in taking a page out of the book of another community, the commercial product development one. They are keenly aware of cultural paradigms when developing products for different markets, often leading to better returns.


Nasser Bin Nasser is the Managing Director of the Middle East Scientific Institute for Security (MESIS) based in Amman, Jordan. He is also the Head of the Amman Regional Secretariat under the European Union’s “Centres of Excellence” initiative on CBRN issues.