National Research Action Plan

National Research

Action Plan on Long COVID

August 2022

National Research Action Plan on Long COVID

Preparation Notice

This National Research Action Plan on Long COVID was prepared by the Department of Health

and Human Services.

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Suggested Citation

Department of Health and Human Services, Office of the Assistant Secretary for Health. 2022.

National Research Action Plan on Long COVID, 200 Independence Ave SW, Washington, DC

20201.

National Research Action Plan on Long COVID

Contents

Executive Summary................................................................................................ 5

Letter from the Secretary of Health and Human Services .................................... 10

Chapter 1: Introduction ....................................................................................... 12

Recognizing Long COVID: A Brief Timeline ................................................................................ 12

The Challenges of Long COVID: Public Health, Economic, and Societal Impacts ...................... 12

A Foundational Challenge: Understanding Long COVID and Associated Conditions ............... 14

The Need for a National Research Action Plan on Long COVID ................................................ 15

The Purpose of the National Research Action Plan on Long COVID ......................................... 16

Guiding Principles of the National Research Action Plan on Long COVID ................................ 17

Development of the National Research Action Plan................................................................. 18

References ................................................................................................................................. 19

Chapter 2: Summary of Partner Input .................................................................. 23

Chapter 3: The Current United States Government Long COVID Research Portfolio

............................................................................................................................. 26

1. Characterizing the Full Clinical Spectrum of Long COVID and Diagnostic Strategies ........... 27

2. Pathophysiology .................................................................................................................... 32

3. Surveillance and Epidemiology ............................................................................................. 34

4. Long COVID and Overall Well-Being ...................................................................................... 41

5. Therapeutics and Other Health Interventions ...................................................................... 46

6. Human Services, Supports, and Interventions ...................................................................... 48

7. Health Services and Health Economics Research ................................................................. 50

References ................................................................................................................................. 54

Chapter 4: Accelerating Research and Innovation in Long COVID ........................ 57

Research Priorities for Long COVID ........................................................................................... 57

Strategic U.S. Government Actions for Long COVID Research ................................................. 60

Implementing the National Research Action Plan on Long COVID ........................................... 65

References ................................................................................................................................. 65

National Research Action Plan on Long COVID......................................................... 1

National Research Action Plan on Long COVID

Appendix A: Report Abbreviations ....................................................................... 66

Appendix B: Contributing U.S. Government Departments ................................... 68

Appendix C: Terminology and Definitions ............................................................ 69

Appendix D: Highlights of Current U.S. Government Research Portfolio on Long

COVID

.................................................................................................................. 74

Appendix E: U.S. Government Long COVID Research, Interim Implementation Plan

............................................................................................................................. 83

National Research Action Plan on Long COVID

Executive Summary

On April 5, 2022, President Biden issued the Memorandum on Addressing the Long-Term Effects

of COVID-

⁠

19 outlining actions needed to support the American people in addressing the longer-

term effects of COVID-19. The President charged the Secretary of Health and Human Services

with coordinating a government-wide response to Long COVID. An element of that response

was for the Department of Health and Human Services, in collaboration with federal partners,

to develop two reports

• Services and Supports for Longer-Term Impacts of COVID-19 Report (Services Report)

• National Research Action Plan on Long COVID (the Plan).

The Services Report outlines federal services and mechanisms of support available to the

American public in addressing the longer-term effects of COVID-19. The Plan provides the first

U.S. government-wide national research agenda focused on advancing prevention, diagnosis,

treatment, and provision of services and supports for individuals and families experiencing Long

COVID.

The end of the COVID-19 public health emergency will not signal the end of the effects of the

pandemic. These lingering effects may impact the health of the nation for years to come.

Recovery from infection with SARS-CoV-2, the virus that causes COVID-19, can vary from person

to person. Most individuals seem to recover quickly and completely. However, some report

symptoms that persist or emerge weeks or even months after the initial phase of the infection

has passed, even when the infection was asymptomatic. These sets of conditions are often

referred to as “Long COVID.” This term was created and has been promulgated by patients and

is used in this Plan. The Plan also recognizes the importance of two technical terms, Post-

COVID-19 conditions, or PCC, broadly equivalent to Long COVID, and Post-acute Sequalae of

SARS-CoV-2 infection, focused on the direct effects of the virus.

Research into the causes and consequences of Long COVID and associated conditions, the

underlying biological mechanisms, the therapies that work, and services and supports needed

for persons experiencing Long COVID are necessary to develop strategies to prevent, treat, and

support those with Long COVID. The Plan was developed with four guiding principles: orienting

research towards improving patient care and outcomes, health equity, accelerating and

expanding existing research, and partner engagement. The Plan ensures an effective,

comprehensive, and equitable research strategy to inform the national response to Long

COVID’s impacts on individuals, families, communities, and all of society, inclusive of age,

gender, race, ethnicity, geographic location, socioeconomic status, insurance coverage status,

pregnancy status, and disability status. The actions in the plan will require federal investment.

Action that can be taken with current funding are underway. Additional funding proposed in

the President’s fiscal year 2023 budget and beyond will enable expansion the implementation

of this Plan.

National Research Action Plan on Long COVID

Partner Input

The Plan was developed with engagement from both public and private partners, including

individuals experiencing Long COVID. Meaningful input is critical throughout the research

process, as it can help guide research projects with attention to context and culture, thereby

facilitating translation of research into effective policy and practice. We will continue facilitating

these important conversations with our partners to gain feedback on the Plan, implement the

Plan’s strategies, and iterate the Plan moving forward.

Current U.S. Government Long COVID Research

The Plan builds on ongoing research supported or conducted by the U.S. government and aims

to accelerate and expand it, in addition to calling for enhanced action by the private sector. The

current Long COVID federal research portfolio, ongoing since 2020 and represented in over 100

published articles, demonstrates innovation and early achievements and highlights the

importance of collaboration between the public and private sectors.

The current U.S. government portfolio is described in detail in this report and spans the

following seven areas: characterizing the full clinical spectrum of long COVID and diagnostic

strategies; pathophysiology; surveillance and epidemiology; Long COVID and overall well-

being; therapeutics and other health interventions; human services, supports, and

interventions; and health services and health economics research.

While the U.S. government continues to lead and make advancements in research, much more

must be done to support persons experiencing Long COVID symptoms and to inform care and

support for patients, their families, and caregivers. A national, U.S. government-wide

coordinated, action-oriented approach is urgently needed. By infusing health equity

considerations throughout the Plan, such as having inclusive and diverse participation in

research activities, we are ensuring that our research and resulting policy and programmatic

actions are effective and responsive to the needs of affected populations.

Accelerating Research and Innovation in Long COVID

Fully understanding the implications of Long COVID requires a comprehensive, multi-

disciplinary, effective approach, leveraging the resources of the U.S. research enterprise and

collaborative efforts across the federal government, coupled with strong public and private

partnership. With these core tenets, the Plan includes steps to Accelerate Research and

Innovation in Long COVID.

The Plan provides a detailed call to action across all sectors of research, both public and private,

including academia, to accelerate the delivery of evidence and data. The Plan describes

priorities across the seven research areas, as follows.

1. Characterizing the Full Clinical Spectrum of Long COVID and Diagnostic Strategies.

Build on extensive ongoing research led by National Institutes of Health (NIH), Centers

National Research Action Plan on Long COVID

for Disease Control and Prevention (CDC), the Department of Veterans Affairs (VA), and

other agencies, for example the Researching COVID to Enhance Recovery (RECOVER)

Initiative and Innovative Support for Patients with SARS-CoV-2 Infection (INSPIRE), to

convene public and private partners to better align interim definitions of Long COVID for

clinical care, surveillance, and research; lead further studies of the impact of SARS-CoV-2

infection on development and clinical course of new onset chronic disease states (e.g.

diabetes); initiate research that disentangles the broader longer-term effects of the

pandemic on physical and behavioral health (e.g., mental health and substance use

challenges) from those of SARS-CoV-2 infection and re-infection; and further research to

examine Long COVID and other post-infectious illnesses, including dysautonomia, and

myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS), to identify

commonalities and differences.

2. Pathophysiology. Build on extensive ongoing research, for example the RECOVER

Initiative led by NIH, to achieve a deeper understanding, from the molecular to system

levels, of Long COVID within the broader context of post-infectious chronic conditions

and other diseases that may have infectious origins, including dysautonomia and

ME/CFS.

3. Surveillance and Epidemiology. Build on extensive ongoing research, primarily led by

CDC, such as INSPIRE Study, and the VA, to conduct additional studies of Long COVID

risk factors, health trajectories and outcomes that are inclusive of age, gender, race,

ethnicity, geographic location, socioeconomic status, insurance coverage status,

pregnancy status, and disability status, enabled by new capabilities in data analytics;

and lead studies that can rapidly adapt to examine risk and protective factors as they

emerge (i.e., new variants, vaccinations, repeat infections, and therapies for COVID-19)

on risk of Long COVID.

4. Long COVID and Overall Well-Being. Conduct comprehensive studies of the effects of

Long COVID on educational outcomes in children and youth, with a focus on vulnerable

populations, including racial and ethnic minority groups, those who are economically

disadvantaged, and those in rural communities; and lead research, including qualitative

and mixed methods studies, to understand the impact of Long COVID on health-related

quality of life, behavioral health, employment, disability determinations, education and

development, and the impact on caregivers and family well-being, especially among

disadvantaged groups, expanding upon initial work led by the VA, for example the

COVID-19 Observational Research Collaboratory Long-term Outcomes Study (CORC-

LTO), the Health Resources and Services Administration, for example National Survey of

Children’s Health Longitudinal Cohort Study (NSCH-LC), the Social Security

Administration, and the Department of Labor.

5. Therapeutics and Other Health Interventions. Expand the portfolio of studies, including

the RECOVER Initiative and others, on the effectiveness of therapeutics to prevent and

treat Long COVID to include antivirals, anti-inflammatory, immune modulators, and

National Research Action Plan on Long COVID

other existing or new treatments; further studies to subtype Long COVID including

characterization of distinct sub-entities with distinct set of risk factors and outcomes

and evaluation of treatment strategies for these sub-types; and initiate studies of non-

pharmacologic interventions to prevent and treat Long COVID.

6. Human Services, Supports, and Interventions. Lead new work in identifying and

evaluating optimal person-centered models of care for people with various forms of

Long COVID; and lead comprehensive studies of human services and supports

interventions, including disability services and caregiver supports, to ensure individuals

living with Long COVID can fully participate in their communities, building on work by

the Administration for Community Living ACL), the Department of Defense (DOD), and

the SSA.

7. Health Services and Health Economics Research. Lead new studies, including systems

research, to develop, implement, and evaluate models of care delivery that enable

primary care providers to effectively manage Long COVID and associated conditions;

lead new research to address barriers to effective care in underserved communities and

models of care designed to address and eliminate health inequities; conduct rapid and

ongoing synthesis of new evidence to distill existing research into actionable insights

guiding care of people with Long COVID, including cost-effectiveness modeling of

prevention and treatment strategies; and expand work, for example analyses led by the

Office of the Assistant Secretary for Planning and Analysis, in impact of Long COVID on

and economic costs of Long COVID to the health system, human services and supports

programs, and society.

To lead and coordinate the work on Long COVID and in response to the April 5, 2022,

Presidential Memo, Memorandum on Addressing the Long-Term Effects of COVID-

⁠

19, HHS

established a U.S. government-wide Long COVID Coordination Council (LCCC), chaired by the

HHS Assistant Secretary for Health. HHS will continue the current approach of the Assistant

Secretary of Health serving as the Long COVID coordinator and formalizing the responsibility

through establishment of a new Office of Long COVID Research and Practice. The Assistant

Secretary for Health, in a role as the Long COVID Coordinator, will implement the National

Research Action Plan on Long COVID and coordinate efforts across the federal government

through the Long COVID Coordination Council. The Coordinator will also establish the

Secretary’s Advisory Committee on Long COVID to continually engage non-governmental

partners and develop and implement a strategic communications plan to share findings from

Long COVID research. This new office, which will need resources and staffing, will ensure

standardization and accountability for the Plan through implementation plans and annual

progress reports.

HHS and federal partner agencies will also work with Congress and government leaders through

continued investment in Long COVID coordination and research, to create and establish new

structures to fulfill the calls to action, such as establishing and maintaining a framework for a

multipronged approach to Long COVID surveillance; effective systems and strategies for rapid

National Research Action Plan on Long COVID

implementation of Long COVID clinical trials; considering comprehensive approaches to fund

interdisciplinary research on Long COVID; and engagement of federal agencies to contribute to

a coordinated effort for a national real world evidence approach that would include Long

COVID.

The best prevention of Long COVID and its related impacts remains to avoid infection and re-

infection of SARS-CoV-2 by following basic interventions such as getting vaccinated and

boosted, maintaining social distancing, wearing a mask, and handwashing. At the same time

HHS will work diligently to advance research to prevent, diagnose, treat, and alleviate the

impact of Long COVID for the nation. The Plan affirms the U.S. government’s commitment to

addressing the impacts of Long COVID with federal government resources, in collaboration with

the private sector, and improving our Nation’s health and well-being. The Plan, along with the

accompanying Services Report, represent the federal government’s response to ensure the

acceleration of scientific progress and provide individuals with Long COVID the support and

services they need.

National Research Action Plan on Long COVID

Letter from the Secretary of Health and

Human Services

Thank you, President Biden, for the opportunity to coordinate a U.S. government-wide effort to

develop an interagency national research agenda, the National Research Action Plan on Long

COVID.

The COVID-19 pandemic has been burdensome physically, psychologically, and socially. In May

2022, we marked one million American lives lost to COVID-19. The individuals lost represent

loved ones who were taken from their families, friends, and communities.

The pandemic has disproportionately affected racial and ethnic minorities, with Black, Hispanic,

American Indian, and Alaska Native populations experiencing higher rates of COVID-19 and

death compared to White populations. Individuals with intellectual disabilities were also

disproportionately affected and found to be six times more likely to die from COVID-19 than

other members of the population. The challenges associated with COVID-19 exacerbated the

existing health inequities in our country, highlighting social and racial injustices that impede

equitable health outcomes.

As our nation continues to make advancements in addressing this pandemic through enhanced

vaccine availability, research, testing, and treatment, we are also working to address the impact

of Long COVID and associated conditions. For persons with Long COVID, symptoms like fatigue,

shortness of breath, heart palpitations, and joint pain can persist for months, and new chronic

conditions can prevent them from returning to their baseline state of health.

Conducting research in this area is critical to advancing our understanding of Long COVID and

addressing the associated challenges of the pandemic. The U.S. government has been working

on Long COVID research since 2020, with momentum building through 2021 and 2022. The

Memorandum on Addressing the Long-Term Effects of COVID-

⁠

19 in April of 2022 highlighted the

Administration’s commitment to harness the full potential of the federal government and to

coordinate with public- and private-sector partners to fully and effectively respond to the

longer-term effects of COVID-19 by developing a National Research Action Plan. The Plan builds

on the research already begun across the federal government to improve our understanding of

the underlying biological causes, epidemiology, and impact of Long COVID; help us understand

the burdens of those affected; foster development of new diagnostics and treatments; inform

decisions related to support services and interventions; develop, implement, and scale

innovative models of care delivery; improve data sharing and transparency among researchers;

and explore the impacts of Long COVID on persons who are underserved by the health care

system and public health infrastructure.

National Research Action Plan on Long COVID

Principles guiding the Plan include a commitment to health equity, partner engagement, public-

private collaboration, and prioritization of translational research to inform better health care

delivery and human services.

The challenges posed by Long COVID and associated conditions require that we continue to

work rapidly and share research findings as quickly as possible to drive delivery of effective

health care and supports services. This Plan, along with the companion Services Report,

represent the coordinated, action-oriented, federal government response to ensure the

acceleration of scientific progress and to provide individuals with Long COVID the support and

services they need.

Even as we endeavor to learn more about Long COVID, we already understand that the best

prevention remains to avoid infection and reinfection by following basic prevention

interventions such as getting vaccinated and boosted, maintaining social distancing, wearing a

mask, and handwashing.

I want to thank the staff in the 14 departments and agencies who worked diligently to prepare

this Plan. I also want to thank the Assistant Secretary for Health and the Assistant Secretary for

Planning and Evaluation for their leadership in conceptualizing and driving the production of

this report. Finally, I want to express my sincere gratitude to numerous organizations and

individuals who contributed their time, resources, contacts, and invaluable conversations with

us. This collaboration remains critically important in advancing the science and paving the way

of progress. Those with lived experiences are central to these efforts.

Sincerely,

Xavier Becerra

Secretary of Health and Human Services

National Research Action Plan on Long COVID

Chapter 1: Introduction

Recognizing Long COVID: A Brief Timeline

In April 2020, shortly after the beginning of the pandemic, anecdotal reports from patients

started to emerge that previously healthy individuals were experiencing lingering symptoms

and were not fully recovering from an infection with SARS-CoV-2. These patients coalesced

around each other and formed support groups, started to refer to themselves as “Long

Haulers,” and coined the term “Long Covid.” They surveyed their membership and published

the first landmark survey in May 2020 cataloguing the breadth of symptoms experienced by

people with Long COVID. Controlled large-scale reports soon followed in early 2021 which

provided a detailed systematic characterization of the condition. Studies detailing the breadth

of organ dysfunction in people with Long COVID were published in late 2021 and early 2022.

Overall, the early recognition by the patient community, their effort to organize, colloquially

name the condition, and alert the world to study it, galvanized the research community to

pursue research programs in this area, which in a short period of time resulted in substantial

conceptual advances and significant breakthroughs in understanding the condition. The U.S.

government has been conducting research on Long COVID since 2020 and providing care for

individuals with Long COVID within federally supported healthcare systems such as the

Veterans Health Administration, Federally Qualified Community Health Centers, Certified

Community Behavioral Health Clinics, and the Indian Health Service. Milestones in the U.S.

government response include a call for action on Long COVID in the Presidential Health Equity

Task Force, Final Report and Recommendations, released in October 2021, announcement of

the landmark RECOVER study in February 2021, and inclusion of Long COVID in the National

COVID-19 Preparedness Plan in March 2022.

6,7

2,3

The Challenges of Long COVID: Public Health,

Economic, and Societal Impacts

In August of 2022, it is now well understood that, amidst the many challenges of the pandemic

are the persistent health effects some individuals face well after initial infection. Recovery from

infection with SARS-CoV-2, the virus that causes COVID-19, can vary from person to person.

Most individuals seem to recover quickly and completely. However, some report symptoms

that persist or emerge weeks or even months after the initial phase of SARS-CoV-2 infection has

passed. These sets of conditions are often referred to as “Long COVID.”

Long COVID is a multifaceted disease that can affect nearly every organ system. In total,

about 200 symptoms of Long COVID spanning nearly every organ system have been reported.

Long COVID can manifest as new onset chronic disease, such as heart disease, diabetes, and

1211

5,6,9,10

National Research Action Plan on Long COVID

kidney disease; hematologic (blood)

consequences; as well as mental and neurologic

conditions. While estimates of the general risk

of Long COVID vary between 5 and 30%, a recent

large study by CDC suggested that one in five

adult COVID-19 survivors aged 18 to 65 years

and one in four survivors aged 65 years and over

have a health condition related to their previous

COVID-19 illness. Another recent CDC

mathematical modeling study estimated that

millions of U.S. adults have new long-term

symptoms that limit their daily activities after

infection with the virus that causes COVID-19

and that women may be disproportionally impacted. Finally, based on self-reported data from

adults participating in the Census Bureau’s online Household Pulse Survey, more than a third of

those who report having had COVID-19 reported ever having Long COVID symptoms and nearly

one-fifth of those who have had COVID-19 reported currently having Long COVID symptoms.

While estimates of burden of Long COVID vary across studies and settings, the breadth of

symptoms and conditions that are manifestations of Long COVID and the potential scale are

consistent throughout the scientific literature. It is evident that Long COVID is real, that it

already impacts a substantial number of people, and that this number may continue to grow as

new infections occur.

Reduced health status and complications related to Long COVID are only a small portion of the

consequences of the pandemic. Longer-term disease and disability will have ongoing economic

and societal impacts.

•

For example, in one survey, 44% percent of patients with Long COVID reported not

being able to work at all, compared to their pre-COVID-19 work capacity, and 51% had

reduced their working hours.

•

According to one estimate, roughly one million workers may be out of the workforce at

any given time due to Long COVID. This figure equates to approximately $50 billion

dollars annually in lost salary.

Health care cost burdens are also expected to increase for treatment of Long COVID as well as

new chronic conditions, such as heart disease, diabetes, and kidney disease, that may be

attributable to COVID-19.

As the United States continues to respond to COVID-19, it will be critical to address how Long

COVID is impacting various communities and populations. While racial disparities in Long COVID

are relatively unexplored, it is well understood that some racial and ethnic minority

communities are disproportionately impacted by COVID-19. Of the 61.4 million COVID-19 cases

recorded in the United States through early 2022, race and ethnicity were recorded for 65%.

Among those cases, Hispanic persons had the largest number of cases, and Black persons

“I think it is a mistake to separate Long

COVID and acute COVID. They work

hand in hand. The conversation with

health care providers needs to include

‘If you’ve been diagnosed with COVID-

19, Long COVID symptoms may occur

once you recover.’”

—Representative of a Mental

Health Organization

National Research Action Plan on Long COVID

experienced higher COVID-19-related deaths, relative to their population share. When

adjusted for age, the disparities are even more pronounced, with Hispanic persons being 2.4

times, American Indian or Alaskan Native persons being 3.2 times, and Black persons being 2.5

times more likely to be hospitalized with COVID-19 than their White counterparts. Other

analyses also point to non-Hispanic American Indian or Alaska Native persons being at highest

risk for COVID-19 hospitalization, and death.

In addition to higher rates of COVID-19

in certain racial and ethnic minority

groups, the higher burden of co-morbid

chronic disease conditions seen in these

communities can put people at a higher

risk for severe illness and complications

related to COVID-19, including Long

COVID. Finally, outcomes associated

with Long COVID are likely to be

influenced by social determinants of

health such as housing and income—

likely driving even further an uneven

distribution of the toll of Long COVID.

The health care and services

communities will need to understand

and engage with this new disease

process and learn how to use culturally

and linguistically effective services to

provide the highest quality of care

possible.

The consequences of Long COVID span

individual health and the health care

system, the economy, and society as a

whole. Pandemics such as influenza and

polio resulted in long-term consequences that persisted for decades. If history is any indicator,

COVID-19 will also have long lasting effects that are only starting to be assessed and

understood.

A Foundational Challenge: Understanding Long

COVID and Associated Conditions

The medical, scientific, and public health communities have developed precise terms with

agreed-upon, interim definitions of Long COVID, such as Post-COVID-19 conditions (PCC) and

Post-acute Sequelae of SARS-CoV-2 infection (PASC), to use for communicating about clinical,

research, and public health activities (see text box for an interim public facing definition of Long

Long COVID

Long COVID is broadly defined as signs,

symptoms, and conditions that continue or

develop after initial COVID-19 or SARS-CoV-2

infection. The signs, symptoms, and conditions

• are present four weeks or more after the

initial phase of infection;

• may be multisystemic;

• and may present with a relapsing–remitting

pattern and progression or worsening over

time, with the possibility of severe and life-

threatening events even months or years

after infection.

Long COVID is not one condition. It represents

many potentially overlapping entities, likely with

different biological causes and different sets of

risk factors and outcomes.

National Research Action Plan on Long COVID

COVID; see Appendix C for a detailed list of terms in use).This definition was developed by HHS

in collaboration with other departments including with subject matter experts at HHS Office of

the Secretary, CDC, and NIH. The first, Post-COVID-19 conditions, is equivalent to Long COVID, is

broad to optimize sensitivity, and includes both direct and indirect effects of the virus. It is

useful in various clinical setting, assessing the burden to the health care system, and

surveillance. The second is Post-acute Sequalae of SARS-CoV-2 infection, which includes only

the direct effects of the virus. It is used often in clinical contexts and critical to the medical

research community aiming to understand the root causes of Long COVID. In diagnosing Long

COVID, other illnesses need to be excluded. Additional research is underway to sufficiently

separate the various forms and conditions of Long COVID, including from pre-existing ones. The

differences and nuances among the definitions reflect the central challenge of defining,

studying, and addressing the impact of Long COVID. In addition, some scientists and patient

advocate communities point to the importance of conditions associated with Long COVID,

drawing parallels in symptoms and underlying biology to other diseases, such as post-infectious

conditions. The terminology of Long COVID and associated conditions leverages existing

experience and knowledge to recognize commonalities to better treat and care for the many

affected individuals, including the domains of disability and insurance coverage. Although the

definitions will likely change as we learn more, using terms with commonly understood

definitions helps research and public health communities compare findings across studies and

facilitates turning surveillance and research findings into action to improve patient care.

While the Plan uses the term Long COVID throughout, it will be noted if and where specific

research uses a more specific term (i.e., PCC and PASC). Also, it is emphasized that “Long

COVID” is not just one condition, and the use of the term Long COVID in this report should not

be construed as such.

The Need for a National Research Action Plan on Long

COVID

Research into the causes and consequences of Long COVID and associated conditions, the

underlying biological mechanisms, the therapies that work, and services and supports needed

for persons experiencing Long COVID are necessary to develop strategies to prevent, treat, and

support those with Long COVID. As described in detail in Chapter 3, federal agencies are

currently studying the incidence, mechanism, duration, and severity of symptoms following

SARS-CoV-2 infection, as well as risk factors associated with Long COVID. U.S government has a

leading role in Long COVID research through the work it conducts itself, including research in

government-led health systems such as the VA and Indian Health Service; by funding private

research; and by coordinating efforts across public and private entities. Some of U.S.

government efforts include the Researching COVID to Enhance Recovery (RECOVER) Initiative,

led by the NIH. This research initiative brings together patients, caregivers, clinicians,

community leaders, and scientists from across the nation to understand, prevent and treat

Long COVID. The RECOVER Initiative is focusing on enrolling individuals across all ages, genders,

races, ethnicities, and socioeconomic statuses. Enrollment includes pregnant people,

National Research Action Plan on Long COVID

individuals of reproductive age, individuals with

disabilities, and those from the communities

hardest hit by the pandemic. In addition, CDC is

leading numerous studies, including the

Innovative Support for Patients with SARS-CoV-2

Infections (INSPIRE) Study. It is following nearly

6,000 individuals at select sites across the

country for up to 18 months and conducting

other dedicated research in Tribal and other

hard-hit, high-risk communities. A final

example are studies leveraging the Department

of Veterans Affairs electronic health record data,

which includes over 10 million Veterans, to understand different health impacts of Long COVID

over time as well as evaluating models of care, which has resulted in important early findings

about the clinical manifestations of Long COVID.

While the U.S. government continues to lead and make advancements in research, much more

must be done to support persons experiencing Long COVID symptoms and to inform care and

support for patients, their families, and caregivers. A national, U.S. government-wide

coordinated, action-oriented approach is urgently needed. The National Research Action Plan

on Long COVID ensures an effective, comprehensive, and equitable research strategy to inform

our national response to Long COVID’s impacts on individuals, communities, and our entire

society.

The Purpose of the National Research Action Plan on

Long COVID

The purpose of the Plan is to advance progress in prevention, diagnosis, and treatment of Long

COVID; and provision of services and supports for individuals, families, and communities

experiencing Long COVID. This includes advancing our understanding of the health and

socioeconomic burdens on individuals with Long COVID, including among subcategories of age,

gender, race and ethnicity, rurality, insurance coverage, economic disadvantage, pregnancy

status, and disability status. The research must identify and provide strategies to inform our

national response to address the pandemic’s impact on these communities and populations.

While the Plan describes several U.S. government Long COVID research initiatives, meeting the

challenge of Long COVID will require deep engagement by private partners including academia,

pharmaceutical industry, professional organizations, and private research organizations,

including the role of organizations that provide the patient data without which research cannot

occur. The Plan also recognizes the centrality of persons affected by Long COVID and their role

as active partners at the core of the research enterprise from initial inception until successful

completion. As such, the U.S. government will lead the effort to convene various stakeholders

“I got COVID-19 and I was embarrassed

that I continued to have symptoms

after the 14-day quarantine. I am 70

years old. I doubted my own symptoms

for so long. I was afraid to even go to

my doctor because I thought they

wouldn’t believe me.”

—Person with Long COVID

National Research Action Plan on Long COVID

and partners and facilitate collaborations and partnerships among them to accelerate discovery

and innovation in Long COVID.

Guiding Principles of the National Research Action

Plan on Long COVID

Increasing and enhancing research efforts is imperative to inform and provide equitable

prevention, care, and support to individuals, families, and communities with Long COVID. The

Plan was developed and will be implemented with a coordinated government-wide approach

(see Appendix B for a list of 13 Departments in addition to the Department of Health and

Human Services that participated in the Plan development). The guiding principles of our

coordinated efforts in addressing the impacts of Long COVID are

Orienting the Research Effort to Improve Patient Care and Outcomes. We

will accelerate knowledge synthesis,

dissemination, and implementation of

research findings to promote

coordinated, integrated care models

and expand access to high-quality care

in communities across the country and

drive more effective public health

action.

Health Equity. Issues of access and

utilization of health care are critical

barriers for both COVID-19 and Long

COVID. To achieve our vision, the Plan is guided by health equity principles, building

upon prioritized recommendations made by the Presidential COVID-19 Health Equity

Task Force. These recommendations include, but are not limited to, understanding how

racism, ableism, and discrimination along with provider bias are associated with health

care access, symptom recognition, disease progression, and severity of Long COVID in

communities that are disproportionately disadvantaged and other people who are

underserved, as well as improving data collection, integration, and use so that data can

be disaggregated for these populations who are at higher risk and used to inform

equity-centered response decisions.

25-27

Accelerating and Expanding Current Research. While research on Long COVID is

underway both within and outside of the U.S. government, we must accelerate and

broaden our efforts. The Plan calls for new research partners and data sharing, and new

strategies to extract lessons sooner from existing investments in research. Acceleration

will require rapid short-term trials designed to alleviate the symptoms of those now

living with Long COVID and long-term research on topics such as natural history of

disease and optimal treatments.

“We need to do everything we can now

to learn about Long COVID and how to

help people, because soon we’re going

to have lots of people with this chronic

condition.”

—Person with Chronic

Fatigue Syndrome

National Research Action Plan on Long COVID

Partner Engagement. We will continue to work with people living with Long COVID

and other partners on building relationships with communities that are

disproportionately impacted through transparent and ongoing meaningful engagement

to ensure that these efforts address the highest priority needs of persons experiencing

Long COVID.

This Plan is intended for U.S. government agencies and to inform Congress and researchers

both public and private, including academia. This information is also relevant to other groups

such as state policymakers, foundations and other funders of research, health care and service

personnel, public health partners, Long COVID patients and advocacy groups, pharmaceutical

companies, and the general public.

Development of the National Research Action Plan

Workgroup Formation and Report Development

In response to the April 5, 2022 publication of the Memorandum on Addressing the Long-Term

Effects of COVID-

⁠

19 , a workgroup was created to draft this Plan. Representatives from

agencies across the U.S. government were brought together. As part of the writing process,

each agency’s workgroup members inventoried current and planned Long COVID research,

shared information about published research articles, and coalesced around future research

topics and priorities.

Partner Engagement

An essential part of the Plan, as President Biden highlighted in his Memorandum, is the

engagement of not only U.S. government agencies, but also nongovernmental experts,

organizations, and partners. A coordinated effort within and outside of the U.S. government is

required to adequately address the research challenges we face with Long COVID.

The Plan workgroup gathered relevant information and individual input from a variety of

partners, including persons with Long COVID, through a series of listening sessions. Over a

dozen sessions were held during the drafting on this Plan and the Services Report. Sessions will

continue after publication of the reports.

Participants in these listening sessions included

• Long COVID patients and caregivers, as well as Long COVID advocacy groups

• Patients with disabilities and chronic illness and their caregivers, as well as disability and

chronic illness advocacy groups

• Provider groups and organizations (health care organizations and systems, community

health centers, behavioral health providers, and hospitals)

National Research Action Plan on Long COVID

• Researchers, including patient researchers

• Public health partners

• Professional medical organizations and societies

• Mental health advocates

• Children’s advocates

• Organizations representing health and health care for people who are underserved,

such as African Americans or Black persons, Latino persons, Asian and Pacific Islander

persons, American Indian and Alaskan Native persons, and LGBTQIA+ persons.

We also invited participants to share resources and reviewed relevant plans, reports, and

guidelines. These resources highlight the burden of Long COVID and of other post-infectious

conditions, set out strategic goals and research priorities to address these conditions, and

demonstrate skillful approaches to partner engagement.

29-32

Concurrently, we sponsored non-governmental partners to conduct a human-centered research

project, termed Health+, to better understand Long COVIDThis approach works to co-create

solutions with—not for—people impacted by Long COVID. By listening and learning from

patients experiencing Long COVID and associated conditions, caregivers, frontline workers, and

those with lived experience, we will accelerate understanding and breakthroughs together.

Most importantly, the Health+ Long COVID cycle will generate insights with actionable

opportunity areas to improve the quality of care and life.

References

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York Times. Published April 13, 2020. Accessed June 26, 2022.

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Patient-Made Term 'Long Covid' is needed. Wellcome Open Research. Published

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4. Patient Led Research Collaborative. Report: What Does COVID-19 Recovery Actually

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5. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of

COVID-19. Nature. 2021;594(7862):259-264. doi: 10.1038/s41586-021-03553-9

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8. Alwan NA. The road to addressing Long COVID: Reporting, recognizing, and researching

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10. Bull-Otterson L, Baca S, Saydah S, et al. Post–COVID conditions among adult COVID-19

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11. Xie Y, Xu E, Bowe B, et al. Long-term cardiovascular outcomes of COVID-19. Nat

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12. Xie Y, Al-Aly Z. Risks and burdens of incident diabetes in long COVID: A cohort study. The

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8587(22)00044-4

13. Bowe B, Xie Y, Xu E, Al-Aly Z. Kidney outcomes in Long COVID. Journal of the American

Society of Nephrology. 2021;32(11):2851-2862.

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14. Xie Y, Xu E, Al-Aly Z. Risks of mental health outcomes in people with COVID-19: Cohort

study. BMJ. 2022;376:e068993. https://doi.org/10.1136/bmj-2021-068993

15. Tenforde MW, Devine OJ, Reese HE, Silk BJ, Iuliano AD, Threlkel RT, Vu QM, Plumb ID,

Cadwell BL, Rose C, Steele MK, Briggs-Hagen M, Ayoubkhani D, Pawelek P, Nafilyan V,

Saydah SH, Bertolli J. Point Prevalence Estimates of Activity-Limiting Long-Term

Symptoms among U.S. Adults ≥1 Month After Reported SARS-CoV-2 Infection,

November 1, 2021. The Journal of Infectious Diseases. 2022; jiac281.

https://doi.org/10.1093/infdis/jiac281

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16. Centers for Disease Control and Prevention. (2022). Long COVID: Household Pulse

Survey. Published June 22, 2022. Accessed June 22, 2022.

https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm

17. Cutler DM. The costs of Long COVID. JAMA Health Forum. 2022;3(5):e221809.

doi:10.1001/jamahealthforum.2022.1809

18. Hill L, Artiga S. COVID-19 cases and deaths by race/ethnicity: Current data and changes

over time. kff.org. Published February 22, 2022. Accessed March 15, 2022.

https://www.kff.org/coronavirus-covid-19/issue-brief/covid-19-cases-and-deaths-by-

race-ethnicity-current-data-and-changes-over-time

19. Centers for Disease Control and Prevention. Risk for COVID-19 infection, hospitalization,

and death by race/ethnicity. cdc.gov. Updated June 2, 2022. Accessed June 15, 2022.

https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-

discovery/hospitalization-death-by-race-ethnicity.html

20. Berger Z, Altiery De Jesus V, Assoumou SA, Greenhalgh T. Long COVID and health

inequities: The role of primary care. The Milbank Quarterly. 2021;99(2):519–541.

https://doi.org/10.1111/1468-0009.12505

21. Spinney L. Pandemics disable people—the history lesson that policymakers ignore.

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24. Department of Veterans Affairs, Office of Research and Development. VA research

during the COVID-19 pandemic. research.va.gov. Updated January 27, 2022. Accessed

June 15, 2022. https://www.research.va.gov/covid-19.cfm

25. Centers for Medicare & Medicaid Services. CMS Strategic Plan Pillar: Health Equity.

cms.gov. Accessed June 15, 2022. https://www.cms.gov/sites/default/files/2022-

04/Health%20Equity%20Pillar%20Fact%20Sheet_1.pdf

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2032. cms.gov. Published April, 2022. Accessed June 15, 2022.

https://www.cms.gov/files/document/cms-framework-health-equity.pdf

27. Presidential COVID-19 Health Equity Task Force. Final report and recommendations.

minorityhealth.hhs.gov. Published October, 2021. Accessed June 15, 2022.

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eam%20WIP11-compressed.pdf

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28. The White House. Memorandum on addressing the long-term effects of COVID-19.

whitehouse.gov. Published April 5, 2022. Accessed June 15, 2022.

https://www.whitehouse.gov/briefing-room/presidential-

actions/2022/04/05/memorandum-on-addressing-the-long-term-effects-of-covid-19

29. Albarracin D, Bedford T, Bollyky T, et al. Getting to and sustaining the next normal: A

roadmap for living with COVID. covidroadmap.org. Published March, 2022. Accessed

June 15, 2022.

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08195cbfb6/1647287147076/Next+Normal+Roadmap+2022.pdf

30. Dimmock M, Joslyn R, Poirier S, Seltzer J, Kanas A. ME/CFS research priorities. NIH

ME/CFS Collaborative Research Centers. Published May 3, 2022. Accessed June 15,

2022. https://cfsformecfs.files.wordpress.com/2022/05/final-public-cac-me_cfs-

research-priorities.pdf

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32. Raj SR, Bourne KM, Stiles LE, et al. Postural orthostatic tachycardia syndrome (POTS):

Priorities for POTS care and research from a 2019 National Institutes of Health Expert

Consensus Meeting - Part 2. Auton Neurosci. 2021;235:102836.

doi:10.1016/j.autneu.2021.102836

National Research Action Plan on Long COVID

Chapter 2: Summary of Partner Input

The Long COVID National Research Action

Plan was developed with engagement of

individual public and private interested

persons. The Department of Health and

Human Services’ Office of Intergovernmental

and External Affairs hosted a series of

interactive listening sessions to inform the

development of the Plan. The sessions

included a broad range of participants

including persons with Long COVID,

researchers, health care personnel,

organizations representing health

professionals, public health partners, and

advocacy organizations.

Across listening sessions, some messages

were consistently voiced. These messages

influenced the development of the report

and are reflected in the Plan.

Urgency

An overarching concern among Long COVID

patients, health care personnel, researchers,

and public health partners is the urgent need

for information that can guide health care,

programs, and services. Since the start of the

pandemic, people with Long COVID and

associated conditions have been in need of

symptom relief, health care services, and

financial assistance. Research represents

hope for persons with Long COVID and those

who care for them. To provide relief to those

with Long COVID, legislatures and

governmental and nongovernmental partners must recognize the urgency of this work and act

accordingly.

Partner Engagement throughout the Research Enterprise

An integral way to address research gaps and provide the most insightful and effective results is

to ensure that partners, particularly Long COVID patients are integrated into every stage of the

Summary of Recommendations as

Reflected in the Plan

The Long COVID National Research Action

Plan workgroup considered and

incorporated many individual concerns and

recommendations. The highest priority

recommendations were

• Assuring patient engagement in all

government-sponsored research

throughout the research enterprise

• Inaugurating a central coordinating

office for Long COVID research

• Accelerating therapeutic research

• Engaging researchers and harnessing

prior research on other post-infectious

conditions

• Ensuring transparency in

communications about the research and

findings.

Conversations will continue with a broad

set of partners to gain individual feedback

on the Plan, work to implement the Plan’s

strategies, and iterate the Plan moving

forward.

National Research Action Plan on Long COVID

research process. Existing studies and initiatives have engaged patients, but advocacy

organizations indicated that these efforts need to be more robust and occur earlier in the

planning process when research questions and study designs are planned. Long COVID patients’

perspectives are critical to effective, meaningful research.

Research Coordination

Participants in the listening sessions called for cross-governmental coordination to maximize

current and future federal research efforts. The government and private researchers, including

those in academia are conducting a great deal of COVID-19 research. Coordination is required

to ensure that the nation’s research agenda is comprehensive, transparent, and effective.

Standard Definitions

Many inside and outside of government have highlighted an important, yet basic, action of

moving towards a set of standard research, clinical, and surveillance definitions of Long COVID.

Partners indicated a concern over insufficient clarity and consistency in the emerging terms and

definitions, as they might affect the diagnosis of the condition. Others point to the critical

importance of inclusion and the risks with moving too quickly to narrowly define a set of

conditions as yet not sufficiently understood.

Research Gaps and Funding

Participants identified a number of knowledge gaps that should be addressed by research.

Some topics recommended for future research include identification of innovative therapies,

Long COVID in pediatric populations, the impact of reinfection on Long COVID, and the impact

of medical bias on patients with Long COVID. It is particularly important to develop a portfolio

of clinical trials to test as many therapeutics and models of care delivery as possible to enhance

understanding of what works for Long COVID patients. All areas require further research and

funding.

To expedite this research, academic researchers and patient-led research groups requested

faster research funding mechanisms. Due to the highly dynamic nature of Long COVID,

conventional funding mechanisms have limitations to addressing the urgent questions related

to the condition. There was a call for the U.S. government to establish new funding mechanisms

that can help dynamically resource researchers who are working on Long COVID.

Some partners expressed concerns about

current governmental research projects, based

on their personal participation in, or

engagement with them. For example, patient

advocates highlighted the need to integrate

evidence and learnings from prior and current

research on post-infectious conditions, including

dysautonomia and myalgic encephalomyelitis

“A National Research Action Plan must

be explicit and intentional about

including, recruiting, and engaging a

diverse research cohort.”

—Long COVID Researcher

National Research Action Plan on Long COVID

and chronic fatigue syndrome (ME/CFS), into ongoing Long COVID research. Some also

expressed concerns with studies that require a positive SARS-CoV-2 test result to be eligible for

enrollment, which excludes persons who were not tested, had false negative results, or those

who were asymptomatic during the initial infection. The importance of relevant control groups

in studies of Long COVID was emphasized. One of the lessons learned from the Centers for

Disease Control and Prevention’s (CDC) longstanding ME/CFS program, echoed by some

individual partners, is that ME/CFS-like illnesses are often unrecognized or overlooked. There is

a need to distinguish the ME/CFS-like (medically unexplained) subgroup of Long COVID from

subgroups with COVID-19-related well-established chronic conditions (such as heart disease,

diabetes, and renal disease) and prioritize research on Long COVID ME/CFS-like illnesses. There

are parallel observations for dysautonomia.

National Research Action Plan on Long COVID

Chapter 3: The Current United States

Government Long COVID Research

Portfolio

The National Research Action Plan on Long COVID will build on ongoing efforts across the

federal government. The current federal Long COVID research portfolio demonstrates

innovation and early achievements, as evidenced by a growing body of published studies

funded or conducted by the U.S. government. The portfolio highlights the importance of a

collaboration between the public and private sectors in advancing progress in prevention,

diagnosis, treatment and provision of health care, public health, and human services for

individuals experiencing Long COVID. Ensuring broad representation in research activities of

underrepresented groups remains a challenge, and attention and innovation are required to

specifically address these challenges. The description of the federal research portfolio in this

chapter is intended to be a summary with highlights, and it is not an exhaustive inventory of all

U.S. government supported Long COVID research.

Organization of the Research Portfolio

The federal Long COVID research portfolio described in this chapter is organized into the

following topic areas with subtopics:

1. Characterizing the Full Clinical Spectrum of Long COVID and Diagnostic Strategies

2. Pathophysiology

3. Surveillance and Epidemiology

4. Long COVID and Overall Well-Being

5. Therapeutics and Other Health Interventions

6. Human Services, Supports, and Interventions

7. Health Services and Health Economics Research.

Within each topic area there is a brief synopsis of research, with descriptions of a small

number of the principal research initiatives. Studies may appear in more than one topic

area; for example, a survey of patients with Long COVID can provide information about

impacts of illness as well as access to health care.

Text boxes in each area highlight the core research questions, health equity considerations,

and anticipated impacts of research. Appendix D, the U.S. government Long COVID

Research Portfolio, complements this Chapter by providing an alphabetical list of studies

with basic information and includes more studies than those mentioned here.

National Research Action Plan on Long COVID

1. Characterizing the

Full Clinical Spectrum

of Long COVID and

Diagnostic Strategies

It is a public health priority to identify,

understand, and effectively diagnose

conditions across the full clinical spectrum

of Long COVID.

∗

These are necessary first

steps toward the development of optimal

prevention and treatment strategies.

Important research topics include clinical

manifestations of Long COVID and

associated conditions, how these may vary

across the lifespan and across different

demographic groups, how they may

change over time, and how they may be

affected by viral variants, reinfections, and

various interventions such as vaccines.

The observed heterogeneity of Long

COVID thus far strongly suggests that,

rather than being a singular condition,

Long COVID is likely multiple clinical

conditions. Data being collected from

longitudinal studies on Long COVID

include a wide range of data from

laboratory testing, imaging, functional

studies, genomics, mobile health-

wearable devices, participant surveys,

electronic health records, demographic

data, information on social determinants

of health, and other data sources. In

addition, the breadth and complexity of

data being collected in current studies will

necessitate advanced analytics, such as

machine learning, artificial intelligence,

∗

Much of the research described in this section is specific to Post-Acute Sequelae of SARS-CoV-2 Infection (PASC),

but the term “Long COVID” used throughout the report includes PASC.

Core Research Questions

• What is the clinical spectrum of recovery from

acute SARS-CoV-2 infection and how does it

change over time?

• What are the clinical manifestations of Long

COVID? Are there distinct subtypes

(phenotypes) of Long COVID?

• What is the natural history of Long COVID?

How do the clinical manifestations of Long

COVID vary across the lifespan and different

demographic groups? How do they change

over time? How are they affected by various

interventions, such as vaccines?

• Are there distinct phenotypes among those

patients who do not fully recover or who

develop new onset symptoms?

• What are the biologic causes of Long COVID

and how can they be reversed?

• How does SARS-CoV-2 infection initiate or

promote the pathogenesis of conditions or

findings that evolve over time to cause organ

dysfunction or increase the risk of developing

other disorders?

• What are the clinical criteria for diagnosing

Long COVID?

• What diagnostic tests and assays can be used

to accurately and reliably diagnose Long

COVID?

National Research Action Plan on Long COVID

natural language processing, or deep learning to extract

meaning and create the needed specialized tools for

prediction, detection, prognosis, diagnosis, and

monitoring treatment response for Long COVID.

Clinical Spectrum of Long COVID

Multiple U.S. government studies are currently

underway investigating important factors of the clinical

spectrum of Long COVID including understanding

different presentations and symptom clusters;

identifying factors that may modify Long COVID such as

the impact of variants and severity of acute illness;

determining the risks for development of other medical

conditions (such as diabetes or cognitive impairment)

after a SARS-CoV-2 infection; and understanding how

Long COVID may impact pre-existing health conditions.

Many of these U.S. government studies are recruiting

diverse adult and pediatric populations and focusing on

specific populations, including Veterans, pregnant

people and their infants, those with pre-existing health

conditions, and persons from medically underserved

populations.

Federal agencies and departments have formed

strategic partnerships that leverage individual missions,

resources, and capabilities to launch collaborative

research efforts and strengthen areas of synergy. For

example, Centers for Disease Control and Prevention

(CDC) and the National Institutes of Health (NIH) are

working together on refining definitions; NIH and the

Patient-Centered Outcomes Research Institute (PCORI)

have worked together on patient-reported outcome

measures; and CDC, the Centers for Medicare &

Medicaid Services (CMS), the Food and Drug

Administration (FDA), and the Department of Health

and Human Services (HHS) are engaged in governance

of the Researching COVID to Enhance Recovery

(RECOVER) Initiative.

Federal departments and agencies recognize that as the

science of Long COVID evolves, discoveries will emerge

and yield new avenues for pursuing research. Many of

NIH RECOVER Initiative:

Principal Features

RECOVER is a multi-pronged,

multi-disciplinary research effort

of national scale to improve

understanding of Post-Acute

sequelae of SARS CoV-2 infection

(PASC) and to inform the

development of safe and

effective diagnostic, treatment,

and preventive strategies.

Features include

• Clinical cohorts with

thousands of diverse

participants across the

lifespan

• Patient involvement in all

levels of the initiative

• Inclusive, diverse

participation

• Community engagement

• Studies with access to tens of

millions of de-identified

electronic health records and

mechanistic studies of

pathogenesis

• Tissue pathology and autopsy

studies of more than 50 tissue

types

• Clinical trials of promising

treatments

National Research Action Plan on Long COVID

the large, U.S. government research initiatives are gathering comprehensive data and

biospecimens with the intent to leverage these in the short and long term.

Principal Research Initiatives

A critical component of the U.S. government

approach to researching the clinical spectrum of

Long COVID is the RECOVER Initiative. NIH

launched RECOVER to improve understanding of

and ability to predict, treat, and prevent PASC.

RECOVER is a multi-study, patient-centered

initiative of national scale with diverse

participation and community engagement.

RECOVER has multiple scientific aims and seeks to

understand the clinical spectrum and the biology

underlying recovery over time, as well as define

distinct subtypes of Long COVID. It includes

multiple sub-studies, such as longitudinal

observational clinical cohort studies with

thousands of diverse participants across the

lifespan; ancillary clinical studies leveraging cohort

data and specimens; pathobiology studies;

analyses of electronic health records; and clinical

trials. RECOVER will also conduct clinical trials to

test promising treatments in subsets of persons

with Long COVID for their ability to reduce

symptom burden and correct or prevent the

abnormal biologic factors that give rise to the

conditions.

Given the variety of organs in the body affected by

Long COVID and the multitude of symptoms

observed, RECOVER will examine a wide array of

body systems. Assessments are tailored to

different populations including adults, children

and their caregivers, pregnant participants and

their newborn infants, and people of reproductive

age. The methodology helps capture different

types of data including radiology, laboratory tests, surveys, immune assays, and genome

analyses. These analyses will be complemented by electronic health record-based studies that

collectively access de-identified health records of tens of millions of adult and pediatric patients

accessible through the National COVID Cohort Collaborative (N3C), the National Pediatric-

Centered Clinical Research Network (PCORnet) and PEDSnet (the Pediatric Learning Health

System consortium of PCORnet). Attention is given to include participants who live in rural

NIH RECOVER Initiative:

Research Questions

Goal: To understand, diagnose, treat,

and prevent post-acute sequelae of

SARS-CoV-2 infection (PASC)

• What are the various forms of

PASC? Characterization of full

clinical spectrum and phenotypes

• How long does PASC last? Can it

have effects later in life? Does it

alter the course of or risk for other

diseases and conditions?

• What are the risk factors for

developing PASC?

• What are the impacts of different

variants and vaccination?

• What are the underlying biologic

mechanisms responsible for PASC?

• What are the underlying

mechanisms responsible for

resilience and resistance to PASC?

• What are specific therapeutic

targets for clinical interventions

(treatment and prevention)?

National Research Action Plan on Long COVID

areas, those who are medically underserved, and those who are non-English speaking. The

surveys and research protocols for adults and children are available in multiple languages.

In addition to the RECOVER Initiative, NIH leads or funds additional prospective observational

cohort studies that include adults and children with varying severities of underlying disease,

which will help characterize the clinical sequelae of SARS-CoV-2 over time. Some studies are

characterizing immune responses, while others are focused on specific populations, such as

children and adults who developed diabetes mellitus after SARS-CoV-2 infection, individuals

with dysautonomia, myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS), and

children with multisystem inflammatory syndrome (MIS-C).

Additional NIH-supported studies are investigating

the persistent neurological and cognitive

symptoms experienced by many patients who

have recovered from SARS-CoV-2 infection. These

studies are recruiting across adult and pediatric

populations and enrolling pregnant people and

their infants, patients with other neurological

diagnoses, and those from historically

underserved backgrounds. The studies are

gathering different types of information and

biospecimens, such as performance on cognitive

measures, Magnetic Resonance Imaging (MRI),

cerebrospinal fluid (CSF), blood specimens, and

autopsy tissue to better understand the

neurological sequelae associated with Long

COVID.

NIH-supported researchers have also been

studying the mental health impacts of Long

COVID. Researchers have developed a publicly

available dataset of COVID-19 patients’ firsthand

accounts of their illness and recovery, including

their anxiety about illness and its lasting effects on

their mental and behavioral health. In addition, researchers supported by RECOVER developed

a machine learning model that uses electronic health record data to identify COVID-19 patients

who experienced Long COVID. Thus far, this research has revealed that diagnosis features such

as dyspnea, dyssomnia and other sleep disorders, and malaise are informative for recognizing

potential Long COVID. These conditions and other features of Long COVID can interact to

exacerbate patients’ experiences with new or pre-existing mental health conditions.

The Department of Veterans Affairs (VA) is conducting several collaborative studies as part of

the Post COVID Collaborative Merit Program that focus on the clinical spectrum of Long COVID,

Anticipated Impacts of Research

• Evidence generated by research

will inform researchers, guidelines

developers, health care personnel,

payers, patients, caregivers, and

policy makers. Information will be

disseminated through publications,

professional scientific and medical

society meetings, federal

webpages, and webinars.

• Practitioners will be better able to

diagnose, manage, and monitor

Long COVID.

• The research will inform the

development of new treatment and

prevention strategies.

National Research Action Plan on Long COVID

including cognitive impairment, mental health effects, persistent fatigue (as seen in ME/CFS),

functional impairment, sleep disturbances, and recurrent pain symptoms.

CDC has completed and published several studies that have assessed clinical presentation of

Long COVID through both survey and analyses of electronic health record data. Also, CDC’s

National Health Interview Survey (NHIS) contains questions in 2022 and will again in 2023 on

ME/CFS and will provide data to examine the connections between ME/CFS, Long COVID, and

other chronic conditions.

3-5

The Department of Defense (DOD) is conducting the

Epidemiology, Immunology, and Clinical

Characteristics of Emerging Infectious Diseases with

Pandemic Potential (EPICC) study, a prospective

observational cohort study evaluating Long COVID

chronic symptoms and health care encounters after

SARS-CoV-2 infection. EPICC also includes machine

learning approaches to identify Long COVID early

symptom clusters, predict return to pre-illness

health, and identify subtypes of Long COVID.

In conjunction with EPICC, the VA launched the

Epidemiology, Immunology, and Clinical

Characteristics of COVID-19 (EPIC ), which is

following a cohort of Veterans after a positive or

negative test result for the presence of SARS-CoV-2.

The study will describe the clinical trajectory from

acute to Long COVID over time, as well as examine

the role of biomarkers influencing the risk for Long

COVID. At completion of the respective studies

(EPICC and EPIC ), researchers plan to compare

findings from the two participant groups.

Futhermore, the NIH and the VA are partnering on a

cohort study that aims to define risk factors for

severe COVID-19, with a focus on the role of the

immune system, inflammation, and tissue damage.

This research will aid in our understanding of how

the immune system affects whether an individual

develops severe COVID-19. Results from these

studies will complement evidence generated from

other studies to build a more complete and

comprehensive understanding of Long COVID.

Health Equity Considerations

• Inclusive and diverse

participation in Long COVID

research helps ensure that the

results of the research are

applicable to the wide range of

populations affected

• Meaningful patient and

community engagement is a

guiding principle of RECOVER,

which has intentionally

engaged patients, caregivers,

and individuals from

communities most affected by

SARS-CoV-2 at nearly all levels

of the Initiative. RECOVER

includes a National Community

Engagement Group and, at the

level of enrolling sites,

collaborates with the NIH

Community Engagement

Alliance Against COVID-19

Disparities program

• Research methods must

establish the validity of

instruments in diverse

populations that are the focus

of the studies

National Research Action Plan on Long COVID

Diagnosis of Long COVID

The heterogeneity of Long COVID, likely representing multiple clinical conditions, poses

enormous challenges to development of diagnostic strategies for Long COVID. Different

diagnostic tests may be required for different types of Long COVID. Research is just beginning

to establish clinical criteria for diagnoses and to inform laboratory and other test development

and other diagnostic strategies.

Principal Research Initiatives

The NIH RECOVER Initiative is collaborating with the NIH Rapid Acceleration of Diagnostics

(RADx®) Radical (RADx-rad) program, which focuses on rapid detection devices and home-

based testing technologies to address COVID-19 testing needs. The RADx-rad-RECOVER

collaboration is leveraging the National COVID Cohort Collaborative (N3C) to support the

development and validation of data-driven artificial intelligence, including machine learning and

natural language processing (using deep learning software tools) to better understand the

clinical, environmental, social, and behavioral risk factors for developing Long COVID and for

Long COVID prognosis. In addition, a request for information on technologies and approaches

that can identify individuals susceptible to PASC was published in 2021.

Several NIH-supported studies are also investigating specific symptoms. For example, the loss of

smell (anosmia or hyposmia) and its occurrence in Long COVID is one such focus. These projects

aim to develop a quick, inexpensive, self-administered smell tests to screen for COVID-19 at the

individual level and assess prevalence in communities, especially those that have been

traditionally underserved by the health care system and public health infrastructure. For those

with Long COVID, the developed smell tests will facilitate recovery monitoring.

2. Pathophysiology

There is an urgent need to identify the

pathological processes that underpin Long

COVID. It is important to rapidly advance

understanding at the molecular level of the

mechanisms at the root of the clinical

phenotypes and symptoms and other

observed health effects and identify targets

for preventive and therapeutic interventions.

Multiple hypotheses currently exist regarding

underlying biological processes, including

persistence of SARS-CoV-2 or viral antigens,

reactivation of other latent viruses (such as

Epstein-Barr virus), dysregulated

immunological or inflammatory responses,

and central or peripheral neurological

Core Research Questions

• What are the pathophysiologic

mechanisms of Long COVID?

• What potential role do the following

play in the development of Long COVID:

immune dysregulation (including

autoimmunity), persistent SARS-CoV-2

virus, reactivation of endogenous

viruses, and organ injury during acute

infection?

National Research Action Plan on Long COVID

damage (including autonomic dysfunction,

and inflammation of blood vessels). As Long

COVID is likely not one singular condition,

there will likely be multiple underlying

pathophysiologic mechanisms at play.

Principal Research Initiatives

Multiple studies across the U.S. government

are examining a broad range of potential

pathophysiological mechanisms of Long

COVID in both adult and pediatric

populations. The DOD’s EPICC study and the

parallel VA EPIC study are focused on

examining the pathophysiology of Long

COVID, including the role of viral and inflammatory markers to inform the Military Health

System clinical care and practice guidelines that aim to improve clinical care and management

of those with COVID-19, as well as inform future disease prevention strategies. These studies

are capturing clinical and laboratory data from patients with SARS-CoV-2 infection to better

understand the disease’s natural history, including

the clinical, virologic, and immunologic

determinants of severe disease. NIH’s RECOVER

Initiative includes a broad suite of pathobiology

studies to identify mechanisms underpinning clinical

phenotypes and symptomatic manifestations,

pathology in multiple organ systems that has led or

will lead to clinically significant health problems,

and potential therapeutic targets. RECOVER also

includes tissue pathology studies conducted at five

centers across the country that utilize a common

protocol with standardized methodologies to

analyze organs and tissue obtained at autopsy,

including the brain. These studies will enable

detailed identification of tissue injury in critical

organs and systems due to SARS-CoV-2 infection, its

sequelae, or both that lead or contribute to Long

COVID.

Additional NIH studies seek to understand the

underlying pathobiology of Long COVID. This

includes studies of immunology of both severe and

mild to moderate COVID-19, including longitudinal

in-depth immunophenotyping. Longitudinal cohorts

of both adult and pediatric populations with prior

Health Equity Considerations

Inclusive, representative, and diverse

participation in pathophysiology research

helps ensure that the results of the

research are applicable to the wide range of

populations affected. Ensuring that

interventions for Long COVID are effective,

acceptable, and accessible for diverse

populations contributes to future uptake

and effectiveness.

Anticipated Impacts of

Research

The most important target audience

for this information is other

researchers.

Information will be shared primarily

through publications and

professional meetings.

These studies will contribute to our

understanding of the causes of Long

COVID, help identify biomarkers and

enable risk stratification, contribute

to the development of new

therapeutic targets, and help inform

Long COVID clinical trials.

Understanding Long COVID at the

molecular level is critical to inform

better diagnostics and targeted

interventions for prevention and

treatment.

National Research Action Plan on Long COVID

SARS-CoV-2 infection include the assessments of immune responses and other investigations

neurological symptoms following a mild to moderate SARS-CoV-2 infection.

NIH’s RECOVER Initiative is also collaborating with the NIH All of Us research program, which is

enabling precision medicine research using five major data types (biometrics, genomics,

electronic health records, surveys, wearable devices) and biospecimens longitudinally obtained

from participants across the United States, with a goal to enroll one million diverse participants.

The collaboration will evaluate the use of biospecimens in potential ancillary studies to analyze

features of the immune system and genomes to further our understanding of the biology that

underpins Long COVID. The VA’s Million Veterans Program genomic program includes over

40,000 patients with documented SARS-CoV-2 infection among 800,000 subjects with genomic

and survey data; surveys are planned to examine the role of genomic markers in the

development of Long COVID symptoms. A principal audience for this information is the broad

community engaged in empirical research to improve the lives of persons living with Long

COVID.

3. Surveillance and Epidemiology

Public health surveillance is the systematic and ongoing collection, analysis, interpretation, and

dissemination of data linked to public health action. Surveillance tracks the occurrence and

burden of Long COVID in the population and can provide insights into groups affected. The

ultimate objectives of surveillance for Long COVID are to inform and guide the planning and

implementation of private and public programs

designed to reduce Long COVID and its

complications, and to evaluate the effectiveness of

public health interventions and policies.

7,8

Epidemiologic studies investigate the causes and

risks of health-related events in populations and the

application of new insights to control or mitigate

health problems. The aims of epidemiologic studies

are to provide estimates of the risk of Long COVID by

demographic groups and identify potential risk or

protective factors compared with groups without

history of COVID-19. While surveillance of Long

COVID tracks the burden in the population and can

provide insights into groups impacted, epidemiologic

studies provide estimates of the occurrence of Long

COVID by demographic groups and potential risk or

protective factors.

Core Research Questions

•

What are the population-level

incidence and prevalence of

Long COVID and associated

conditions?

• What are the population-level

incidence and prevalence of

activity limitation and disabilities

associated with Long COVID and

associated conditions?

• What are the factors associated

with incidence and prevalence of

Long COVID?

aims to evaluate the effects of immunotherapies on patients experiencing persistent

aimed at understanding the underlying biology of Long COVID. Further, an NIH-supported study

National Research Action Plan on Long COVID

Characterizing the numbers of people living with Long COVID, tracking these numbers over

time, and identifying protective and risk factors will require the use of multiple epidemiologic

studies and surveillance approaches leveraging different sources of information. Federal

agencies have implemented a diverse, layered, research and surveillance portfolio to answer

questions.

There are several challenges in surveillance and epidemiologic research for Long COVID given

the wide range of symptoms, effects, and spectrum of severity. These challenges lead to

differing characterizations of Long COVID across studies. Studies vary greatly in how assessment

and measurement are conducted. Studies to date have included patient-reported outcomes,

clinical assessments, laboratory measures, and diagnoses of new conditions and symptoms.

Some studies, but not all, have included measures of Long COVID severity, disability, and

disruption in activities of daily living. Some have focused on hospitalized patients, others only

on ambulatory patients, and others on persons with initial infections that were asymptomatic.

Few studies have included children.

Because many of the individual symptoms and conditions that comprise Long COVID are

common, the inclusion of a comparison group is vital to understand the excess burden of these

symptoms and conditions among persons infected with SARS-CoV-2. Studies currently

underway have approached this in multiple ways, some using participants who test negative

but have COVID-like symptoms, others using historical (pre-pandemic) participants, and others

using participants with no evidence of SARS-CoV-2 infection or COVID-like symptoms.

Diverse Research Portfolio Needed for Long-COVID Surveillance and

Epidemiology

Prospective Cohort Studies: Assess how Long COVID progresses and measure short-term

and longer-term impacts.

Cross Sectional Surveys: Provide point-in-time view of Long COVID in the population by

demographic factors, underlying medical conditions, and other risk factors.

Medical Record Review: Provide insights into common conditions, symptoms, care, and

treatment that patients are receiving in the medical setting.

Modeling studies: Provide population-level estimates of numbers of people affected by

Long COVID when it is not feasible or practical to count all cases.

Electronic Health Care Data: Leverage large numbers of patients to provide estimates of

the incidence of new conditions, symptoms, and health care utilization among persons who

had COVID-19 compared with persons who did not.

National Research Action Plan on Long COVID

Several federal interview surveys harmonize the

Long COVID data collection, including the National

Health Interview Survey, the Household Pulse

Survey, and the Behavioral Risk Factor Surveillance

System. Along with these self-reported interview

data, data from complementary methods such as

cross-sectional health surveys, cohort studies,

analyses of electronic health record data, and

sentinel surveillance are needed to fully characterize

the natural history of post-COVID-19 conditions.

More work needs to be done to align these efforts

across the U.S. government. For all areas, published

studies provide new and important findings that

contribute to the evidence-base for Long COVID

surveillance and epidemiology.

Population-Level Incidence and

Prevalence

There is a growing body of research to provide

measures of population-level incidence (the

proportion of people with new occurrence of Long

COVID among those at risk during a specific period

of time) and prevalence (the proportion of persons

with Long COVID at a specific point in time).

Prospective observational cohort studies, electronic

health care data analysis, and health surveys

currently underway will provide estimates of the incidence and prevalence of Long COVID in the

general population and in specific subpopulations. Building on the existing evidence-base, we

will continue to learn more about estimates of population-level incidence and prevalence, for

specific populations and by subpopulation. Studies from CDC, FDA, HRSA, NIH, VA, and their

partners will help us fill in the gaps in our understanding of incidence and prevalence of Long

COVID.

Principal Research Initiatives

CDC, the Department of Commerce (the Census), FDA, HRSA, NIH, and VA are leading several

studies that will provide estimates of incidence and prevalence (see Appendix D). Select

examples include CDC’s National Health Interview Survey and Behavioral Risk Factor

Surveillance System. Starting in January 2022, CDC’s National Health Interview Survey (NHIS)

added questions to identify the prevalence of Long COVID based on self-report (for adults) and

parent-report (for children). Also, in 2022, CDC’s Behavioral Risk Factor Surveillance System

(BRFSS) added a question to collect information about symptoms of post-COVID-19 conditions

to produce state and territorial-level estimates of burden among adults based on self-report.

Health Equity Considerations

The COVID-19 pandemic has had a

disproportionate impact on some

racial and ethnic communities,

people with lower socio-economic

status, and some people with

disabilities. Understanding risks for

Long COVID and the impact of the

inequities that led to the

disproportionate outcome in

infection, hospitalization, and death

are critical. Groups may be more at

risk for Long COVID due to the

inequities that put them at risk for

COVID-19 or there may be other

factors. Studies of Long COVID must

examine race and ethnicity, socio-

economic status, disability status and

other factors impacted by health

inequities and assess associations

within groups, not just across groups.

National Research Action Plan on Long COVID

Other examples include CDC’s multi-state

Long COVID survey that surveyed adults who

had a positive test result for SARS-CoV-2 for

self-reported acute and post-COVID-19

symptoms lasting four weeks or more to

estimate burden of post-COVID-19 conditions

and identify demographic and disease-

specific risk factors for developing post-

COVID-19 conditions.

Starting in June 2022, questions were added

to the Household Pulse to identify Long

COVID in adults through self-report. Early

results indicate a high level of respondents

stating that they have symptoms of Long

COVID. The Household Pulse Survey, led out

of the Census Bureau, in partnership with

CDC, is one of the first federal data systems

to collect information on Long COVID and will

be a valuable resource to understand

disparities within the U.S. population.

The Health Resources and Services

Administration (HRSA) is administering the

National Survey of Children’s Health

Longitudinal Cohort Study (NSCH-LC). By

leveraging the large nationally- and state-

representative sample of the NSCH, the NSCH-LC will be among the only national studies with

pre- and post-pandemic information on children and youth, including racial and ethnic minority

groups and children with special health care needs.

Individual-Level Incidence and Prevalence

Many of these same studies detailed above and in Appendix D also provide estimates of the

individual-level risk of developing Long COVID. Many of these studies include persons without

evidence of SARS-CoV-2 infection as a comparison group. Comparison of the incidence of Long

COVID-19 conditions and symptoms between persons with and without COVID-19 provides an

estimate of both relative and absolute risk. Although each research platform can provide

estimates by subpopulations, the subpopulations included in each varies. The multiple studies

across CDC, CMS, NIH and the VA capture a wide group of populations and subpopulations,

while the longitudinal study at HRSA is focused on children and is expected to provide multiple

independent estimates of the risk of Long COVID as well as risk disaggregated across multiple

factors.

Anticipated Impacts of Research

Evidence generated by surveillance and

epidemiology is useful for the public,

patient groups, health care personnel,

health care systems, patient groups, and

policy makers.

Synthesized information on Long COVID is

being analyzed and shared through peer-

reviewed publications, news media, social

media, webinars, professional associations,

and websites aimed at professional and

general audiences.

Evidence from surveillance and

epidemiology studies is used by the public

to understand individual risk and make

informed decisions, by health care systems

and service providers to project and plan

for human, financial and infrastructure

resources, and by policy makers to similarly

plan for resources and to develop and

promote effective programs and services.

National Research Action Plan on Long COVID

Many of these studies will also measure whether COVID-19 can result in new disease states or

exacerbate pre-existing disease. Studies from both the VA and CDC have already documented

increased occurrence of many chronic diseases, such as heart disease, diabetes, and kidney

disease.

Understanding the impact of Long COVID on behavioral health (mental health and

substance use), quality of life, activities of daily living and any resulting disability is vital to

understanding the overall impact on society, health care systems, and persons with Long

COVID. Some studies are directly assessing the impact of Long COVID resulting in disabilities

either through detailed abstraction of medical records, or through direct patient reported

outcomes.

Principal Research Initiatives

The VA initiated the COVID-19 Observational Research Collaboratory Long-term Outcomes

Study (CORC-LTO) to investigate outcomes up to 36 months after SARS-CoV-2 infection using a

national cohort of over 200,000 COVID-infected Veterans along with matched controls to

estimate the incidence of and risk factors for Long COVID and the impacts on specific health

outcomes, including functional status and quality of life. The study used a combination of

electronic health record (EHR) data and structured telephone surveys of subsamples from

different time periods to document new diagnoses, symptoms, health-care related quality of

life and health care utilization up to 36 months after infection.

The VA’s Epidemiology, Immunology and Clinical Characteristics of COVID-19 [EPIC ]) is a

prospective controlled cohort study of SARS-CoV-2 infection among Veterans recruited from 16

VA medical centers, conducted in partnership with DOD. EPIC will describe the clinical

trajectory from acute to Long COVID and examine clinical risk factors (including prior infection

or vaccination) in influencing the risk for Long COVID.

Several of CDC’s studies using electronic health care data and patient databases have and will

continue to provide estimates of incidence. For example, CDC is partnering with the American

Board of Family Medicine to analyze electronic health record data from COVID-19 patients seen

at approximately 700 primary care and family medicine practices to assess frequency of new

symptoms and conditions among patients with COVID-19 diagnosis compared with patients

with other respiratory diagnoses. CDC is also conducting analyses of several large health care

data sources to provide estimates of new symptoms and conditions following COVID-19

diagnosis in outpatient and inpatient settings by patient demographic and clinical

characteristics.

Another CDC study focusing on the Navajo and White Mountain Apache communities, COVID-

19 within American Indian Communities at High Risk in the Southwest United States, follows

people who are infected with SARS-CoV-2 for up to 12 months to assess the development and

duration of symptoms, complications from infection, and the immune response to infection.

The DOD established a COVID-19 patient registry in 2020, as a pandemic response capability for

clinical performance improvement in the DOD. Currently, the COVID Registry is capturing and

analyzing data and information on Long COVID, conditions occurring after COVID-19 disease

National Research Action Plan on Long COVID

and after vaccination. Current analyses will examine Long COVID diagnosis requiring a health

care visit 30-180 days after COVID-19 or vaccination; number of individuals with a diagnosis

associated with Long COVID; and number of individuals with each combination of Long COVID

associated diagnosis (such as fatigue plus headache, plus loss of taste).

Risk Factors

Understanding what risk factors may be associated with occurrence of Long COVID is a critical

research question. Both prospective cohort studies and those using electronic health care data

include data on potential risk factors associated with Long COVID such as age, genders, race,

ethnicity, and underlying medical conditions, including multiple co-morbidities. Those with

more severe illness requiring hospitalization are at highest risk of developing Long COVID.

Most people experiencing Long COVID were never hospitalized and so additional information

on premorbid characteristics, genetics, education level, employment, and social determinants

of health is necessary and is more likely to be captured in prospective cohort studies. A few

electronic health care data sources can also provide residential and facility geographic

information linked to measures of social deprivation or vulnerability or other measures of social

determinants of health.

13,14

Important risk factors for the occurrence of Long

COVID are the SARS-CoV-2 variant associated

with the infection and the vaccination status of

the individual. Studying how different SARS-CoV-

2 variants may be related to Long COVID

symptoms and conditions is important to our

understanding of protective and risk factors.

Because many of these studies are ongoing, they

will include persons infected with SARS-CoV-2 at

different waves of the COVID-19 pandemic and

will capture infections with different variants.

Vaccination has also been observed to decrease the risk of an individual developing Long

COVID.

Principal Research Initiatives

CDC’s Immune Response to SARS-CoV-2 among patients in Louisiana follows patients recovering

from COVID-19 to assess longer term clinical and immunity related outcomes up to one year

after the beginning of the illness. The study includes a subgroup of COVID-19 patients

hospitalized for severe COVID-19 illness. Multiple virologic and immunologic specimens are

collected during acute illness, and then patients are followed for one year to determine what

acute factors are correlated with adverse longer-term outcomes.

The longitudinal observational studies of the NIH RECOVER Initiative provide a robust scientific

platform and infrastructure for systematic and ongoing long-term assessments of Long COVID

in highly diverse populations. With its national scale, standardized methodologies, biospecimen

“Like so many other health-related

struggles in the pandemic, Long COVID

illustrates the underlying, fundamental

challenges with our health care

system. More urgent attention and

action to its reform is a priority for

pandemic preparedness."

—State Epidemiologist

National Research Action Plan on Long COVID

Vaccination is perhaps the most prominent of protective factors currently under investigation.

Evidence is emerging that vaccinated people who are subsequently infected with SARS-CoV-2

are about less likely to report symptoms of Long COVID than people who received one dose of

COVID-19 vaccine or were unvaccinated in the short-term (four weeks after infection), medium-

term (12 to 20 weeks after infection) and long-term (6 to 12 months after infection).

11,15-18

Vaccine effectiveness studies measure the effectiveness of the COVID-19 vaccine in preventing

infectious, symptomatic illness, hospitalization and death, and the acute outcomes of SARS-

CoV-2 infection. With the recognition of Long COVID as an outcome from SARS-CoV-2

infection, many of these studies are including longer follow-up of participants to estimate the

effectiveness of prior COVID-19 vaccination in reducing Long COVID among persons infected

with SARS-CoV-2. Most studies to date have focused on adults, with only a few including the

adolescent population. In addition, studies have not reported results by subpopulations or

underlying medical conditions or risk factors. In addition to vaccine effectiveness studies, many

of the studies in Appendix D include collection of information on COVID-19 vaccinations and

boosters. Some of this is through available electronic health data, other directly reported by the

patient, and other with linkage to state vaccine information. Some studies will be able to

examine if COVID vaccination prior to SARS-CoV-2 infection reduces the occurrence of Long

COVID, and others if COVID-19 vaccination after SARS-CoV-2 infection reduces on-going Long

COVID symptoms. Importantly, studies will also consider the impact of COVID-19 vaccine dose

and boosters on Long COVID.

Principal Research Initiatives

The FDA is collaborating with the VA and CMS to study the safety and effectiveness of vaccines

and Long COVID. The FDA and the VA are describing the main medical outcomes associated

with Long COVID and their severity, estimating the incidence of Long COVID among U.S.

Veterans, selecting among all potential Long COVID outcomes, those more likely to be

collection, comprehensive data, and studies of molecular pathogenesis, RECOVER will be critical

for understanding the risk factors for developing Long COVID and informing development of

diagnostic, treatment, and preventative strategies. RECOVER’s EHR-based studies, which

leverage health records from tens of millions of diverse patients across the lifespan, including

pre-exposure health records, are also ideally suited for identifying risk factors for Long COVID.

In association with CMS, the FDA is using Medicare claims data to study the frequency of

possible Long COVID health outcomes and the risk factors associated with the occurrence of

these outcomes among Medicare Beneficiaries who were discharged from a hospital with a

COVID-19 diagnosis.

Protective Factors, Including Vaccination

Protective factors can help guide public health messaging and efforts to prevent Long COVID.

Potential protective factors under investigation include pre-existing health status, COVID-19

treatments such as Paxlovid

(nirmatrelvir 150 mg and ritonavir 100 mg), and vaccination.

National Research Action Plan on Long COVID

associated with prior COVID-19 than with other respiratory infection, and lastly, evaluating

potential risk factors for Long COVID. CDC has developed multiple longitudinal cohort studies

that will assess vaccine effectiveness in adults and children and has worked to incorporate

specific objectives that will assess Long COVID outcomes (including ongoing symptoms, health

status, disability, missed work, and missed school) in similar ways across these studies.

Validation of Operational Definitions of Long COVID in Real-World

Data Sources

The validation of operational definitions of Long COVID, for different purposes, in real-world

data sources considers that there are a wide range of physical and behavioral health

consequences that can follow SARS-CoV-2 infection. To operationalize the definitions, many

studies look for evidence of COVID-19 and SARS-CoV-2 infection determined through either

medical record review or abstractions, confirmation of SARS-CoV-2 test results, or identification

of cases in other electronic health care data, and then look for new or persistent symptoms or

conditions to identify cases of Long COVID. One recent approach to operationalize a definition

has included the use of machine learning using large electronic health care data to identify Long

COVID clinic patients. Since October 2021, there is an ICD-10 code (code U09.9, Post COVID-19

condition, unspecified) for classifying diagnoses and reason for visits in all health care settings.

The ICD-10-CM code for Long COVID is gaining acceptance and also provides a method to assess

and possibly validate Long COVID definitions. Further validation of operational definitions in

real-world data sources will include linkage of patient reported outcomes with electronic health

care data in prospective cohort studies.

4. Long COVID and Overall Well-Being

The persistent health effects of COVID-19

have broad ramifications. In addition to the

discrete physiologic effects of Long COVID

outlined previously, longer-term symptoms

can have serious impacts on important

aspects of life that are not captured in clinical

diagnoses or self-report of individual

symptoms. These include impacts on quality

of life, education, employment, disability,

mental health and substance use challenges,

and caregiving. Persistent symptoms may

affect quality of life, and patients

experiencing severe fatigue or cognitive

symptoms and impairment (also known as

“brain fog”) may have trouble with schooling or employment and may require caregiving from a

family member or professional. These effects in turn can have severe economic impacts on

individuals with Long COVID and their families. Although outcomes of COVID-19 have been

found to be less severe in young people and current data show that the prevalence of Long

Core Research Questions

What are the impacts of Long COVID on

• Health related quality of life

• Employment, insurance, disability, and

socioeconomic status

• Educational and developmental

outcomes

• Caregivers and families?

National Research Action Plan on Long COVID

COVID is low , Long COVID can occur in

children and may impact normal development;

if not mitigated or otherwise addressed, these

effects may have a long-lasting impact. The

RECOVER Initiative is developing a cohort of

children to study such issues. Family caregivers

of people with Long COVID may be at risk for

secondary effects, including psychological

stress and economic impacts if they must

reduce their paid work. From a societal level, it

is important to capture the magnitude of these

impacts, which may be as important as the

direct health impacts for many individuals and

their families. The COVID-19 pandemic and its

burden of infection has already had detrimental

effects on the physical and behavioral health

and financial well-being of the population.

Overall, the impact of Long COVID will likely

compound these existing repercussions,

reverberating in every dimension of our lives,

as Long COVID does not only impact the health

and well-being of those directly affected with

this disease, but may have consequential

ramifications on labor force participation,

economic productivity, and societal well-being.

Efforts to address these questions take a

variety of approaches. Some cohort studies of

affected patients are adding questions related

to employment, schooling, and income. Many

federally sponsored national health surveys are

beginning to include questions on past SARS-

CoV-2 infection. Relevant federal agencies are tracking change in outcomes, such as education

and employment over the pandemic period. There are a few national databases for tracking

child development, education, or employment. Some researchers are attempting to link these

databases to clinical databases to learn more about these factors. Furthermore, policy research

is important to enable and ensure alleviation of impacts based on traditional knowledge gained.

Thus, while pandemic impacts on many of these outcomes have been reported, it can be

difficult to separate out the direct effects of Long COVID from the disruption caused by COVID-

19 or the indirect effects of pandemic disruption to child development, schooling, families, and

employment. Detailed work in survey research is therefore critical.

Why Is This Important?

The wider impacts of Long COVID are

important to patients and families and to

the local, state, and federal organizations

responsible for supporting children’s

health and education, persons with

disabilities, families and caregivers, and

unemployed persons. Such information

will be critical for developing policies

regarding support for patients, students,

and families with Long COVID and for

planning programs to help patients

recover and regain productive schooling

or employment.

Information is developing rapidly on the

medical effects of Long COVID, and large

representative studies from the United

States and other countries are beginning

to allow for population-based estimates.

With respect to effects on development,

educational outcomes, employment and

long-term disability, data from individual

patients has documented the profound

and prolonged effects for some children

and adults, but at this time we lack

representative data to inform guidelines

or policies at this time.

National Research Action Plan on Long COVID

Health-Related Quality of Life

Individual symptoms may not adequately capture the

overall impact on patients of an illness like Long

COVID, which may be accompanied by multiple

symptoms affecting many activities. Several federal

research agencies are funding large, longitudinal

cohorts involving either patients with new COVID-19 or

patients meeting some diagnostic criteria for Long

COVID. These include the RECOVER cohorts funded by

NIH, the EPIC cohort of Veterans funded by the VA,

the parallel DOD study of active-duty military, and

multiple studies from CDC that use standardized

instruments for collecting patient-reported outcomes.

All three of these efforts are including validated self-

reported quality of life outcomes in addition to other

more specific outcome measures. Populations included

in these studies include a broad range of geographic

locations, racial and ethnic, and sociodemographic

groups and settings.

Principal Research Initiatives

The VA has also launched the COVID-19 Observational Research Collaboratory Long-term

Outcomes Study (CORC-LTO) to investigate the longer-term effects of SARS-CoV-2 infection in a

nationally representative sample of SARS-CoV-2 infected Veterans and controls. Patient surveys

will include quality of life measures along with more specific symptom scales. The methods for

identifying the cohorts of persons with Long COVID vary somewhat by study, as does the

presence and nature of any control population. Nonetheless, this portfolio of projects will

provide estimates of health-related quality of life (HRQOL) in Long COVID for a proportion of

the U.S. population in the near term.

Data are much more limited for children. The RECOVER Initiative has as its goal to enroll a

pediatric cohort of approximately 19,000 children. The Pediatric COVID Outcomes Study

(PECOS) led by the Children’s National Hospital in collaboration with NIH’s National Institute of

Allergy and Infectious Diseases (NIAID) will examine the longer-term effects of COVID-19 and

multisystem inflammatory syndrome in children (MIS-C), including health-related quality of life

and social impacts for participants and families and caregivers. Finally, the Maternal and Child

Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA) is

supporting the National Survey of Children’s Health Longitudinal Cohort Study (NSCH-LC), which

aims to produce publicly available data on the longer-term effects of the COVID-19 pandemic

on children and families in the United States, including their quality of life. In 2023, MCHB will

follow up with the parents and caregivers of approximately 60,000 children from birth through

age 17 years, who were originally interviewed right before the pandemic in 2018 to 2019 for

Health Equity Considerations

Factors such as health care access

and use, occupation, and gaps

related to education, income, and

wealth are associated with higher

rates of COVID-19 infection,

hospitalization, and death among

racial and ethnic minority groups.

Implications of Long COVID on

such factors affecting health

equity could further exacerbate

disparities, particularly among

racial and ethnic minority and

socioeconomically disadvantaged

communities who have been

historically underserved.

National Research Action Plan on Long COVID

the NSCH. As part of the 2023 data collection, the NSCH-LC will collect data on children’s

mental health diagnoses and behavioral problems, impact of children’s health on their quality

of life, children’s education and young adults’ employment outcomes, as well as family-level

employment impacts. The NSCH-LC will also have information on children’s chronic conditions

to assess the impact of Long COVID on children with prior chronic conditions.

Employment, Health Insurance, and Other Economic Impacts

Data on the effects of Long COVID on employment, health care coverage, medical costs, and

loss of personal income are far more limited than data regarding the effects on health

outcomes. Current efforts to assess these impacts include some population-based surveys of

Veterans; a variety of study cohorts of individuals with Long COVID that include questions on

one or more of these outcomes; and some employment datasets that are being augmented or

linked to try to identify patients with Long COVID. Three Department of Labor (DOL) programs

are trying to fill in gaps. Retaining Employment and Talent After Illness/Injury Network (RETAIN)

anticipates enrolling 15,900 working age participants from health care settings with a work

limiting illness or injury including Long COVID with an emphasis on individuals who are

medically underserved. These data may help determine whether early coordinated services will

improve employment outcomes for people experiencing work disabilities from Long COVID. The

DOL Office of Workers Compensation Programs collects information on workers compensation

claims, including for federal employees who contract COVID-19 as part of their duties. Another

DOL Survey of Occupational Injuries and Illnesses

(SOII) estimates nonfatal occupational injuries

and illnesses across 200,000 employers in the

private and public sectors (state and local

government). Although data to date do not

include a specific mention of Long COVID, trends

may be inferred from COVID-related cases that

require days away from work. Also, the NSCH-LC

(previously mentioned) will collect data on the

impact of children’s health on young adults’

employment outcomes, as well as family-level

employment impacts. CDC is funding a study to

evaluate Long COVID in U.S. state workers'

compensation systems. The study is focused on

essential and public-facing workers (such as

health care, public safety, retail industries) in a

detailed population of workers for six states (California, Illinois, Michigan, Ohio, Washington,

Wisconsin) and a broader sample of 27 states through the Workers Compensation Research

Institute (WCRI) for up to a two-year period (January 2020 to 2022).

“People with Long COVID are

experiencing mental health harm as the

world returns to normalcy. It is difficult

for children with Long COVID to return

to schools that no longer have mask

mandates. It is difficult for someone

with Long COVID to return to a

workplace that has removed

accommodations like remote work or

masking.”

—Public Health Administrator

National Research Action Plan on Long COVID

Education and Development

The COVID-19 pandemic had profound impacts on education from pre-school through post-

graduate education, due to suspension of in-person classes at the height of the pandemic,

prolonged remote learning, disruptions among families with COVID-19, and illnesses among

teachers and staff. Most of these effects are due to policies imposed because of the pandemic

or to direct effects of illnesses. Little data currently exist on the specific effects of Long COVID

on educational outcomes, with most coming from anecdotal reports from patients. Because the

prevalence of Long COVID in school-age children and adolescents appears low, national

surveys may have a hard time capturing this effect and distinguishing it from other pandemic-

related disruptions.

22,24

Although Long COVID was first recognized in adults, cohort data and national survey data

confirm that children and young people do experience post-COVID-19 conditions. Initial data

indicate children may be less affected than adults, but data are limited. Attributing

symptoms to Long COVID is complicated by the fact that COVID-19 in children may be missed

due to milder or more general symptoms that could be overlooked. Studies have shown that

Long COVID can have a negative effect on quality of life for children and adolescents by limiting

physical activity and creating feelings of distress about symptoms, behavioral health challenges,

and decreased school attendance and participation. Improved study design and methods are

needed to better address these challenges.

25-28

Principal Research Initiatives

Two studies are expected to provide some data on developmental outcomes and impact on

education. The National Survey of Children’s Health Longitudinal Cohort Study (NSCH-LC)

collects a wide range of outcomes from parents and caregivers of children who were ages 0 to

17 years from 2018 to 2019, including development, education, and behavioral concerns. The

Pediatric COVID Outcomes Study (PECOS) will enroll up to 1,000 children and young adults in a

study from Children’s National Hospital in collaboration with the National Institute of Allergy

and Infectious Diseases (NIAID) to examine the longer-term effects of COVID-19 and MIS-C after

these patients have recovered from a COVID-19 infection. Outcomes assessed include social

impacts for participants, families, and caregivers.

Disability

The Social Security Administration (SSA) Office of Disability Policy is collecting information on

the effects of COVID-19 and resulting Long COVID through review of disability claims with

reports of COVID-19 and Long COVID, and research on the effects of Long COVID, primarily

through a contract with the National Academies of Science, Engineering, and Medicine

(NASEM), Health and Medicine Division (HMD) to support a Consensus Committee on the Long-

Term Functional Effects of COVID-19. This effort will examine the relationship between Long

COVID and Social Security’s definition of disability, convening a consensus committee to study

Long COVID following an HMD workshop in March 2022. This workshop discussed disparate

National Research Action Plan on Long COVID

impacts of the virus experienced by people

facing barriers and the effects on work-related

functioning due to Long COVID. The Consensus

Committee will study and provide information

about similar topics.

The National Institute on Disability, Independent

Living, and Rehabilitation Research (NIDILRR)

within the Administration for Community Living

is supporting a five-year research grant

examining employment among people with

physical disabilities, including a small qualitative

study of how Long COVID has affected return-to-

work (RTW) efforts for people with disabilities.

NIDLRR also supports a three-year project on

COVID-19 pandemic-related experiences of working-age adults with disabilities. Data collection

launched May, 2022 and includes a newly developed supplement on Long-COVID.

Impact on Caregivers and Family Well-Being

Data are similarly limited on impacts of Long COVID on caregivers and family well-being. The

two studies of children noted earlier, The National Survey of Children’s Health Longitudinal

Cohort Study (NSCH-LC) and the Pediatric COVID Outcomes Study (PECOS), are collecting

information on families and caregivers. The NSCH-LC will also collect family outcomes for

parents of children with Long COVID, including food security, housing, employment, and mental

health of caregivers, but at this time there are no other U.S. government studies focused on

family and caregivers for affected adults.

The companion report to this Plan, the Services and Supports for Longer-Term Impacts of

COVID-19, provides links to U.S. government programs currently available to support those

impacted by Long COVID.

5. Therapeutics and Other

Health Interventions

With potentially millions of Americans

experiencing Long COVID, the development

and testing of strategies to prevent and treat

Long COVID are public health priorities. A

challenge of Long COVID is that it is likely

multiple conditions with a wide range of

symptoms and health effects. Therefore, it is

necessary to test and develop a range of

intervention and prevention strategies to

"Although the pandemic has

highlighted the importance of data,

this is not a new issue. The solutions

are not technically hard, but the

administrative and political complexity

and its resource intensive nature are

formidable. Continued support for

comprehensive, national, public

health-driven data modernization

efforts are needed."

—Hospital Chief Informatics Officer

Core Research Questions

• What treatments are safe and effective

for persons diagnosed with Long

COVID? For which persons are they

effective?

• Which treatments are ineffective or

unsafe?

• What strategies will effectively prevent

Long COVID?

National Research Action Plan on Long COVID

address the various symptom clusters and

underlying mechanisms of pathobiology and

improve functioning and quality of life for persons

with Long COVID.

It is critically important that

clinical trials are well-designed and have the scale

and power necessary to generate clear evidence

regarding the safety and effectiveness of strategies

for treating or preventing Long COVID. This will be

especially challenging due to the various

definitions of Long COVID in use and lack of

agreed-upon outcome measures for assessing

meaningful improvements.

Principal Research Initiatives

A major component of the U.S. government efforts

in therapeutics research is the RECOVER Initiative.

In April 2022, NIH issued two research opportunity

announcements: one for a clinical trials data

coordinating center to provide overall project

coordination and support and comprehensive data

management; and the other to solicit trial proposals to identify safe and effective treatments

and preventive strategies for Long COVID in

those ages 18 years and over. The research is

anticipated to begin by the end of 2022. The

focus and design of RECOVER clinical trials

are being informed through a consultative

process that engages patients, clinical

practitioners, and experts from academia

and industry regarding symptom clusters,

outcome measures, and interventions. As is

the case with RECOVER longitudinal

observation studies, RECOVER clinical trials

will include diverse communities and

populations. As our understanding of the

underlying mechanisms of Long COVID

improves through basic and pre-clinical

research, additional candidate interventions

will be evaluated and prioritized for testing.

Two federal initiatives will provide

opportunities to study interventions for Long

COVID in real-world settings. The VA is in the

process of establishing a Long COVID Practice

Health Equity Considerations

Inclusive and diverse participation in

clinical trials, including those typically

underrepresented in biomedical

research and those disproportionately

affected by SARS-CoV-2 infection,

helps ensure that the results of the

research are applicable to the wide

range of populations affected.

Ensuring that interventions for Long

COVID are effective and accessible for

diverse populations enhances future

uptake and effectiveness. This

includes language access and

culturally competent care.

Anticipated Impacts of Research

Information from Long COVID clinical trials

will be important for patients, caregivers,

practitioners, third party insurers, clinical

care guideline developers, and policy

makers.

Information will be shared through

publications and professional meetings,

webinars, and government websites.

Interventions are needed to improve

functioning and quality of life for persons

experiencing Long COVID.

Evidence regarding effective therapies is

needed to inform guidelines for health care

and payers.

National Research Action Plan on Long COVID

Based Research Network to coordinate research in the growing number of VA Long COVID

clinics (currently 22 and growing). This will allow real-world examination of what interventions

patients are undergoing (including self-administered treatments such as supplements) and

whether there are any early signals of effectiveness on safety. In addition, DOD’s EPICC

observational study aims to address numerous gaps in the current understanding of COVID-19

and support the development of treatment and prevention strategies that will benefit

uniformed service personnel and civilian populations.

6. Human Services, Supports, and Interventions

Long COVID impacts a person's ability to

participate fully in society and introduces

complex needs and challenges beyond

individual or community health. The

accompanying Services Report outlines the

services and supports available to individuals

experiencing Long COVID, health care

personnel who work with and treat

individuals experiencing Long COVID,

individuals experiencing longer-term impacts

of COVID-19, including mental health

conditions and substance use challenges, and

individuals dealing with losing a family

member or loved one to COVID-19. In

addition to understanding the landscape of

federally supported services and

mechanisms, researchers must also lay the

groundwork to systematically collect data on the human services, supports, and interventions

to address the unmet needs of individuals with Long COVID. Conceptualizing disability in Long

COVID is essential for this research agenda.

Disability and rehabilitation researchers and

practitioners and individuals with lived

experience are positioned to inform a research

agenda and lead future research on the human

services, supports, and interventions for Long

COVID.

Principal Research Initiatives

Federal agencies have initiated data collection

that may address some domains of the human

services, supports, and interventions for Long

COVID. The only published work thus far has

been related to return to work needs for

Core Research Questions

• What are the human services and

supports needs of individuals with Long

COVID?

• What are the service delivery gaps or

barriers for individuals with Long COVID

in existing human services?

• What interventions can be adapted or

created to meet the needs of individuals

with Long COVID to promote their full

participation in society?

Health Equity Considerations

Individuals may have a disability due to

Long COVID or have a pre-existing

disability in addition to Long COVID.

Individuals from underserved

populations may experience

multifaceted systemic barriers to

accessing human services, supports and

interventions for Long COVID.

National Research Action Plan on Long COVID

individuals with Long COVID in a single small qualitative study of rehabilitation professionals on

how Long COVID has affected return-to-work efforts for people with a disability, funded by the

NIDILRR in the Administration for Community Living (ACL). In the area of understanding the

human services and supports need, several efforts are underway by ACL, DOL, and SSA. These

will provide information from national survey data on the experiences of working-age adults

with disabilities and Long COVID as well as information on participants in the RETAIN initiative.

The DOL is also conducting internal synthesized literature reviews of existing research on

COVID-19 and Long COVID and developing resources for employers on interventions to meet

the needs of persons with Long COVID including a forthcoming guide for employers to support

individuals with Long COVID. Together this body of work will drive the emerging evidence-base

on the impacts of Long COVID on an individual’s ability to work, the needs and challenges

relating to employment services and supports including disability benefits, and information on

potential interventions to maintain employment. Multiple years are likely needed to produce

and disseminate high-quality, rigorous research.

NIDILRR is funding two grantees collecting data

on Long COVID as part of their larger data

collection efforts. The Rehabilitation Research

and Training Center (RRTC) on Employment for

People with Physical Disabilities completed a

small qualitative study with rehabilitation

professionals on how Long COVID has affected

return-to-work efforts for people with

disabilities. Research participants discussed

challenges in working with “long-haulers” and

recommendations included modifying workplace

policies and providing individualized workplace accommodations. The University of Kansas

Center for Research is administering another iteration of the National Survey on Health and

Disability to document the COVID-19 pandemic-related experiences of working-age adults with

disabilities. This survey includes a Long COVID supplement. Data are being collected from May

to September 2022.

Several agencies and programs within the DOL are collecting data on Long COVID through

discretionary grants and other existing data collection mechanisms. The Office of Disability

Employment Policy (ODEP) and the Employment and Training Administration in DOL and

the SSA jointly administer the Retaining Employment and Talent after Injury/Illness Network

(RETAIN) initiative. RETAIN programs in five states (Kansas, Kentucky, Minnesota, Ohio,

Vermont) target individuals with work-related or non-work-related injuries and illnesses,

including Long COVID, who are employed or, at a minimum, in the labor force when the injury

or illness occurs. ODEP collects a comprehensive set of administrative data from each of the

RETAIN states that includes information on individuals’ primary and secondary injury/illness

ICD-10-CM codes (including the ICD-10-CM code for post-COVID-19 conditions), demographics,

socioeconomic indicators, program characteristics and employment outcomes. This data

“Enrollment in Long COVID studies are

often limited to English and Spanish

speakers. Asian American, Native

Hawaiian, and Pacific Islander

communities speak over 100 different

languages. We want to be involved

too.”

—Person with Long COVID

National Research Action Plan on Long COVID

collection is underway. Also, ODEP’s Employer Assistance and Resource Network on Disability

Inclusion is conducting meta-analyses of existing research on COVID-19 and Long COVID and

developing resources for employers on how to support individuals with these conditions.

As noted previously, the SSA sponsored the Health and Medicine Division of the National

Academies of Sciences, Medicine, and Engineering (HMD/NASEM) to conduct a public

workshop on the Long-Term Health Effects from COVID-19 and Implications for the SSA in

March 2022. A proceeding of the

presentations and discussions at the

workshop will be prepared.

HHS’s Office of the Assistant Secretary for

Health is sponsoring a human-centered

research project to better understand Long

COVID, termed Health+. The approach works

directly with patients experiencing Long

COVID and associated conditions, caregivers,

frontline workers, and those with lived

experience. The goal of Health+ Long COVID

is to generate insights with actionable

opportunity areas to improve the quality of

care and life.

7. Health Services and

Health Economics

Research

As the world learns more about Long COVID

and discovers ways to diagnose, treat, and

manage its effects, it is also important to

learn how best to provide person-centered

health care for people living with Long COVID

in the context of co-existing illness and risk

factors including social risks. The science of

how care is delivered and how care delivery

can be improved is called health services

research, including mathematical modeling.

Health services research will help the nation

improve the quality, safety, patient-

centeredness, and value of Long COVID care.

It will also allow us to understand if that care

is accessible to all who need it and if not how

to expand access and ensure equity.

Core Research Questions

• What is the current level of access to

care for persons with Long COVID?

• What are the barriers to care for

persons with Long COVID?

• How can the quality of care for persons

with Long COVID be improved?

• What are the best models of care for

Long COVID, and how can those models

be more widely adopted?

• How do we leverage primary care to

diagnose and manage the care of

people with Long COVID in collaborative

care models that provide effective

access to needed specialty services?

• What are the impacts of Long COVID on

health care utilization?

• What are the medical costs of Long

COVID for individuals, families,

communities, the health care system,

states, and the nation?

• How can we improve the financing of

Long COVID care in the United States.?

• What are the broader economic impacts

of Long COVID?

National Research Action Plan on Long COVID

For evidence-based health policy, decision

makers must resolve outstanding questions

including: which health services are needed, who

receives Long COVID health care services, how

the services will be financed, and the total cost of

the care? Health economics research can help

address these questions.

Access to Care, Models of Care,

Quality of Care

The U.S. government will do more to examine

access and barriers to care, models of care, and

quality of care for persons with Long COVID.

Health care services include access to acute care,

outpatient services, behavioral health, and

supportive services.

Principal Research Initiatives

The VA has led the nation in thinking

systematically about how best to provide

coordinated care for Veterans living with Long

COVID, which is helping to inform how to treat

the general public. The VA has conducted a

baseline assessment of the Long COVID-19 care

delivery models currently used in different

regions and facilities across the country. Their

initial and on-going evaluations of Long COVID

care delivery models, including the use of Long

COVID multispecialty clinics, may provide valuable lessons for the rest of the nation. With the

establishment of a Long COVID Practice Based Research Network, the Veterans Health

Administration (VHA) will begin to compare the outcomes of different care models within and

between clinics.

CDC is funding the Long COVID and Fatiguing Illness Recovery Program, which aims to improve

the health of patients in underserved communities who have Long COVID and other complex

chronic conditions with similar symptoms, such as myalgic encephalomyelitis and chronic

fatigue syndrome (ME/CFS) and other post-infectious fatiguing illnesses. Embedded in the

program is a randomized trial of online educational interventions for primary care providers in a

Federally Qualified Health Center, to support their management of long COVID and associated

conditions. The Long COVID and Fatiguing Illness Recovery Program will provide guidance on

how online participatory learning and mentoring can make primary care more effective in

treating Long COVID and accelerate the delivery of evidence-based care

Health Equity Considerations

As in all forms of health research, it is

critical to consider equity when working

to understand health care access,

barriers to care, effective models of

care delivery, and the quality and safety

of care. Analysis of health care use,

medical costs, and broader economic

costs must also consider domains of

equity.

Individuals who are medically

underserved and historically

marginalized communities whose

perspectives and needs must be

included in health services and

economics research include but are not

limited to racial and ethnic minority

groups, people living in rural areas,

people with disabilities, people with

limited English proficiency and LGBTQ+

people. In addition, research must

consider Long COVID care for people of

all age groups, people who are or who

want to become pregnant, and all

genders.

National Research Action Plan on Long COVID

CDC is conducting an on-line needs assessment of health care professionals to identify

information gaps around Long COVID. This information will be used to inform educational and

outreach materials for health care professionals.

AHRQ, along with other HHS and other

government agencies, is leveraging

health information technology to collect

real-world data to better understand

the impact of Long COVID on health

outcomes in diverse populations. AHRQ

in partnership with NIDDK is developing

and testing three open-source,

Substitutable Medical Applications,

Reusable Technologies (SMART®) on

Fast Health care Interoperability

Resources (FHIR®) electronic care (e-

care) plan applications for clinicians,

patients, and caregivers that include

standardized data elements to study

and manage Long COVID. AHRQ is also

developing living clinical decision

support to build the capacity to readily

bring evolving evidence on Long COVID

to the point of care. This living CDS will

be freely available on AHRQ’s CDS

Connect web-based platform.

Testing and Laboratory

Capability

Laboratory testing in clinical medicine

(for diagnostic purposes) and public

health (for example, needed for

screening and surveillance) is critically

important to render care to patients

and to guide interventions to

communities. As highlighted by the

pandemic, testing outside of the

laboratory in other clinical venues,

pharmacies, and in homes

complements laboratory-based testing

by enhancing access, efficiency, and

speed. Systems and operational

Anticipated Impacts of Research

•

The results of health services research are

relevant to health care professionals, public

and private health care delivery

organizations, payers, public health, and

health services researchers

• Information from this research will be

important for the growing number of

individuals and caregivers seeking to make

informed decisions about services

• Information will be shared through

publications, professional meetings,

professional associations, webinars, and

government websites

• When implemented, the findings from health

services research will guide the expansion of

equitable access to effective, safe, high-

quality, high-value, and patient- and family-

centered Long COVID care

• Care will be inclusive of rehabilitation and

therapies to ensure full participation in

society. Tremendous potential exists for this

research to prevent further marginalization

and lead to more equitable outcomes and

societal participation by individuals who

experience Long COVID

• The findings from health economics research

will allow local, state, and federal policy

makers to make informed decisions about

financing Long COVID care and ensuring

effective support for individuals, families, and

communities with Long COVID

National Research Action Plan on Long COVID

research are needed to ensure testing is

available in a timely fashion, that it generates

accurate results based on sufficient and

optimized test performance, and that it delivers

those results primed to aid decision making for

the patient and public health purposes. The

pandemic highlighted some previously

unanticipated systems research questions in

manufacturing, supply chain, test performance

(e.g., balancing test accuracy to diagnosis

infection vs. the need to determine

contagiousness), results reporting, and

integration of data across systems.

Health Care Utilization, Medical Costs, Financing Models, and Broader

Economic Impacts

Although there is ongoing research on the economic impacts of COVID-19, much work remains

to examine health care use, medical costs, options for financing Long COVID care, and the

broader economic impacts of Long COVID. As data and coding systems advance, many types of

health economics research will become easier and more accurate.

Principal Research Initiatives

CMS, in partnership with the HHS Office of the Assistant Secretary for Planning and Evaluation

are conducting analyses to document health services use by Medicare beneficiaries who have

been diagnosed with COVID-19.

Prior to the pandemic, the Health Resources and Services Administration (HRSA) began a

longitudinal, observational cohort study that enrolled approximately 60,000 children and their

families. By collecting information on COVID-19 infections and the emergence of Long COVID in

these families, along with information about health care use, health care expenses, and

experience of care, this study may provide some important information on pediatric health care

utilization for Long COVID, costs to families, and the accessibility and experience of Long COVID

care for families.

The VA is conducting a large, population-based study of the longer-term impacts of COVID-19

using a group of matched cases and controls to examine a range of clinical outcomes, health

care utilization, and health care costs. Although not focused on Long COVID, the study will

permit comparison of a subset with longer-term symptoms to patients with resolved symptoms

and controls who were never infected. VHA is also establishing a practice-based research

network involving Long COVID clinics (currently 22 in the VA) that will collect data on the care

received and costs of patients presenting with Long COVID symptoms.

“Where should you tell someone with

Long COVID to go? What if they don’t

have a doctor that they regularly see?

What if they don’t have health

insurance? Even when there is a Long

COVID expert in the area, there is a

wait time of at least four months to be

seen.”

—Community Health Care Worker

National Research Action Plan on Long COVID

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https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5013a1.htm

7. Centers for Disease Control and Prevention. Updated Guidelines for Evaluating Public

Health Surveillance Systems: Recommendations from Guidelines Working Group.

MMWR. 2001;50(RR 13):1-35. https://www.cdc.gov/mmwr/pdf/rr/rr5013.pdf

8. Centers for Disease Control and Prevention. CDCs vision for public health surveillance in

the 21st Century. MMWR. 2012;61(Suppl):1-44.

https://www.cdc.gov/mmwr/pdf/other/su6103.pdf

9. Saydah S, Brooks J, Jackson B. Surveillance for post-COVID conditions is necessary:

Addressing the challenges with multiple approaches. J Gen Intern Med. 2022;37:1786-

1788. https://doi.org/10.1007/s11606-022-07446-z

10. Centers for Disease Control and Prevention. Long COVID: Household pulse survey.

Published June 22, 2022. Accessed July 22, 2022.

https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm.

National Research Action Plan on Long COVID

11. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of

COVID-19. Nature. 2021;594:259-264.

12. U.S. Department of Veterans Affairs. VA.gov | Veterans Affairs. Seattle Epidemiologic

Research and Information Center (ERIC). Accessed July 22, 2022.

https://www.seattle.eric.research.va.gov/research/CSP-2028-EPIC3/home.asp

13. Zhang X, Wang F, Shen Y, et al. Symptoms and health outcomes among survivors of

COVID-19 infection 1 year after discharge from hospitals in Wuhan, China. JAMA Netw

Open. 2021;4(9):e2127403. doi:10.1001/jamanetworkopen.2021.27403

14. Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. Incidence, co-

occurrence, and evolution of long-COVID features: A 6-month retrospective cohort

study of 273,618 survivors of COVID-19. PLoS Med. 2021;18(9):e1003773.

https://doi.org/10.1371/journal.pmed.1003773

15. Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med.

2022. https://doi.org/10.1038/s41591-022-01840-0

16. Mohr NM, Plumb ID, Harland KK, et al. Presence of symptoms 6 weeks after COVID-19

among vaccinated and unvaccinated U.S. health care personnel. medRxiv: Pre-Print.

2022. https://doi.org/10.1101/2022.02.16.22271092

17. UK Health Security Agency. The effectiveness of vaccination against long COVID: A rapid

evidence briefing. Published February, 2022. Accessed June 21, 2022.

https://ukhsa.koha-ptfs.co.uk/cgi-bin/koha/opac-retrieve-

file.pl?id=fe4f10cd3cd509fe045ad4f72ae0dfff

18. Zisis S, Durieux J, Mouchati C, Perez J, McComsey G. The protective effect of COVID-19

vaccination on post-acute sequelae of COVID-19 (PASC): A multicenter study from a

large national health research network. Open Forum Infect Dis.

2022;fac228. https://doi.org/10.1093/ofid/ofac228

19. Centers for Disease Control and Prevention (CDC). COVID-19 Vaccine Effectiveness. CDC

Website. Updated December 23, 2021. Accessed July 20, 2022.

https://www.cdc.gov/coronavirus/2019-

ncov/vaccines/effectiveness/index.html?msclkid=8c0ea00cd10d11ecadbf4a719825d1a0

20. Pfaff ER, Girvin AT, Bennett TD, et al. Who has long-COVID? A big data approach.

MedRxiv. 2021;10.18.21265168. DOI: https://doi.org/10.1101/2021.10.18.21265168

21. Pfaff ER, Madlock-Brown C, Baratta JM, et al. Coding Long COVID: Characterizing a new

disease through an ICD-10 lens. MedRxiv. 2022.04.18.22273968. DOI:

https://doi.org/10.1101/2022.04.18.22273968

National Research Action Plan on Long COVID

22. Radtke T, Ulyte A, Puhan MA, Kriemler S. Long-term symptoms after SARS-CoV-2

infection in children and adolescents [published online ahead of print, 2021 Jul

15]. JAMA. 2021; 326(9):869-871. doi:10.1001/jama.2021.11880

23. Malik P, Patel K, Pinto C, et al. Post-acute COVID-19 syndrome (PCS) and health-related

quality of life (HRQoL)—A systematic review and meta-analysis. J Med Virol. 2022;

Jan;94(1):253-262. DOI: 10.1002/jmv.27309

24. Osmanov IM, Spiridonova E, Bobkova P, et al. Risk factors for post-COVID-19 condition

in previously hospitalised children using the ISARIC Global follow-up protocol: a

prospective cohort study. Eur Respir J. 2022 Feb 3;59(2):2101341. DOI:

10.1183/13993003.01341-2021

25. Borch L, Holm M, Knudsen M et al. Long COVID symptoms and duration in SARS-CoV-2

positive children—a nationwide cohort study. Eur J Pediatr. 2022;181:1597–1607.

https://doi.org/10.1007/s00431-021-04345-z.

26. Berg SK, Palm P, Nygaard U, et al. Long COVID symptoms in SARS-CoV-2-positive

children aged 0–14 years and matched controls in Denmark (LongCOVIDKidsDK): A

national, cross-sectional study. The Lancet. 2022. https://doi.org/10.1016/ S2352-

4642(22)00154-7.

27. Office for National Statistics. COVID-19 Schools Infection Survey, England: mental health

and long COVID, November to December 2021. Updated February 28, 2022. Accessed

June 15, 2022.

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditio

nsanddiseases/bulletins/covid19schoolsinfectionsurveyengland/mentalhealthandlongco

vidnovembertodecember2021#toc.

28. Hernandez-Romieu AC, Carton TW, Saydah S, et al. Prevalence of select new symptoms

and conditions among persons aged younger than 20 years and 20 years or older at 31

to 150 days after testing positive or negative for SARS-CoV-2. JAMA Netw Open.

2022;5(2):e2147053. Published 2022 Feb 1. doi:10.1001/jamanetworkopen.2021.47053.

29. National Institute of Health. Pediatric COVID Outcomes Study. Updated January 14,

2022. Accessed June 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04830852

30. Wong J, Ezeife N, Kudla A et al. Employment consequences of COVID-19 for people with

disabilities and employers. J Occup Rehabil. 2022. https://doi.org/10.1007/s10926-021-

10012-9

National Research Action Plan on Long COVID

Chapter 4: Accelerating Research and

Innovation in Long COVID

The end of the declared Public Health Emergency will not signal the end of the COVID-19

pandemic. Long after the more immediate effects of the pandemic, the long-term impacts on

the health of the nation will continue for years to come. The scale of Long COVID morbidity and

the breadth of its clinical manifestations represent an unprecedented, but not insurmountable,

challenge.

Federal agencies have already launched ambitious and significant research efforts to

understand Long COVID and ameliorate its devastating impacts, as demonstrated in Chapter 3

and Appendix D. The current Long COVID research enterprise demonstrates solid scientific

foundations, dedicated researchers, and sound partnerships. However, we acknowledge that

conventional research endeavors are not sufficient to address the serious and urgent

challenges posed by post-infectious illnesses of pandemic proportion. The current lag in

research being translated into practice is simply not acceptable in the current environment. We

must aggressively innovate how we do research and accelerate the pace of research to meet

the challenge of the moment. We must collaborate with private research entities and the

pharmaceutical industry to focus our efforts on the highest priority research questions. We

need to rethink how we disseminate research and translate findings into practical solutions

more quickly.

Long COVID demands a comprehensive, multi-disciplinary, effective approach, leveraging the

resources of the U.S. research enterprise and collaborative efforts across the U.S. government

coupled with strong public and private partnership. Beyond the U.S. research enterprise, the

global health research community and international health organizations play an important

role. This chapter is outlined in three sections. The first section, Research Priorities, describes

priority research areas for both public and private research, including academia. The second

section, Strategic Actions, describes actions that the U.S. government will take to not only drive

public-sector research but also accelerate private-sector research, through funding,

collaboration, and data sharing; disseminate research; and translate research into policy and

program. The final section describes Implementation.

Research Priorities for Long COVID

The following are the research questions and topics that we deemed to be of highest

importance and with the greatest potential to yield early, safe, and effective benefit for persons

with Long COVID. This Plan is a call to action to enhance research efforts as well as to rapidly

deliver evidence and data in these areas. Addressing the challenge of Long COVID and the most

pressing research priorities will require an urgent and coordinated all-hands-on-deck whole-of-

government approach, including robust public-private partnership. Research questions that can

National Research Action Plan on Long COVID

be investigated with current funding are underway. Additional federal investment will be

necessary in fiscal year 2023 and beyond as well as commitment from partners in the private

sphere include academia, the pharmaceutical industry, private research organizations, public

health entities, and medical professional organizations. To most efficiently and effectively

accelerate research on Long COVID, it is particularly important to leverage knowledge and

expertise (of affected individuals and researchers) gained from research of conditions with

similarities to Long COVID including dysautonomia, myalgic encephalomyelitis and chronic

fatigue syndrome (ME/CFS), and other post-infectious illnesses.

While this is a call to action to the U.S. research enterprise, this Plan also lays out the U.S.

government commitment in these areas. Appendix E describes new and enhanced activities

that the U.S. government intends to take within the areas, which will build on the portfolio of

ongoing research described in Chapter 3 and Appendix D, and documented in over 100

published U.S. government Long COVID research articles.

1. Characterizing the Full Clinical Spectrum of Long COVID and

Diagnostic Strategies

a. Convening public and private partners to better align interim definitions of Long

COVID for clinical, surveillance, and research

b. Further study of the impact of SARS-CoV-2 infection on development and clinical

course of new onset chronic disease states including diabetes mellitus, kidney

disease, heart disease, gastrointestinal disease, neurologic disease, hematological

(blood) illnesses, and other potential long-term consequences

c. New research that disentangles the broader longer-term effects of the pandemic on

physical and behavioral health (i.e., mental health and substance use challenges)

from those of SARS-CoV-2 infection, for example, distinguishing the neurocognitive

and behavioral effects on children and adolescents of infection with SARS-CoV-2

from the cumulative effects of loss of access to in-person early childhood education

and learning environments

d. Leveraging of existing research on post-infectious chronic illness to support

identification of commonalities and differences with Long COVID, accelerate

research and innovation, as well as prepare for the long-term consequences of

future pandemics

e. Further research to identify clinical screening tools and diagnostic tests and assays

National Research Action Plan on Long COVID

2. Pathophysiology

a. Deeper understanding, from the molecular to system levels, of Long COVID within

the broader context of post-infectious chronic conditions and other diseases that

may have infectious origins, including dysautonomia and ME/CFS

3. Surveillance and Epidemiology

a. Coordinated and enhanced surveillance to characterize and understand Long COVID,

the potential health impacts, and provide information for public health and health

care planning

b. Additional studies of Long COVID risk factors, health trajectories and outcomes that

are inclusive of age, gender, race, ethnicity, geographic location, socioeconomic

status, insurance coverage status, pregnancy status, and disability status, enabled by

new capabilities in data analytics

c. Studies that can rapidly adapt to examine risk and protective factors as they emerge,

including new variants, vaccinations, repeat infections, and therapies for COVID-19

on risk of Long COVID

4. Long COVID and Overall Well-Being

a. Comprehensive studies of the effects of Long COVID on educational outcomes in

children and youth, with a focus on vulnerable populations, including racial and

ethnic minority groups, those who are economically disadvantaged, and those in

rural communities

b. Research, including qualitative and mixed methods studies, to understand the

impact of Long COVID on health-related quality of life, behavioral health,

employment, disability determinations, education and development, and the impact

on caregivers and family well-being, especially among disadvantaged groups

5. Therapeutics and Other Health Interventions

a. Expanded and expansive portfolio of studies on the effectiveness of therapeutics to

prevent and treat Long COVID to include antivirals, anti-inflammatory, immune

modulators, and other existing or new treatments, based on molecular level

understanding and disaggregated by age, gender, race, ethnicity, and pregnancy

status

b. Further studies to subtype Long COVID including characterization of distinct sub-

entities with distinct set of risk factors and outcomes and evaluation of treatment

strategies for these sub-types

National Research Action Plan on Long COVID

c. New studies of non-pharmacologic interventions to prevent and treat Long COVID

6. Human Services, Supports, and Interventions

a. New work in identifying and evaluating optimal person-centered models of care for

people with various forms of Long COVID in the context of co-existing illness, risk

factors, and social and community circumstances

b. Comprehensive studies of human services and supports interventions, including

disability services and caregiver supports, to ensure individuals living with Long

COVID can fully participate in their communities

7. Health Services and Health Economics Research

a. New studies, including systems research, to develop, implement, and evaluate

models of care delivery to enable primary care providers to effectively manage Long

COVID and associated conditions in partnership with specialty care when needed

and community service organizations

b. Research to address barriers to effective care in underserved communities and

models of care designed to address and eliminate health inequities

c. New work in identifying and evaluating optimal models of care for people with

various forms of Long COVID and associated conditions

d. Rapid and ongoing synthesis of new evidence to distill existing research into

actionable insights guiding care of people with Long COVID, including cost-

effectiveness modeling of prevention and treatment strategies

e. Expanded work in impact of Long COVID on and economic costs of Long COVID to

the health system, human services and supports programs, and society

Strategic U.S. Government Actions for Long COVID

Research

The following are the structures and processes to be created within the U.S. government

specifically to drive the research described above. Innovation and comprehensive approaches

will drive an accelerated and enhanced research portfolio. To address the urgency of this

moment and the monumental challenges of Long COVID, HHS will need to work with private

partners and with Congress to fund and support action on these items.

Establish the HHS Office of Long COVID Research and Practice to lead efforts across the U.S.

government and with private partners. On the basis of the April 5, 2022 Memorandum, the

HHS Secretary directed the Assistant Secretary for Health to lead a U.S. government response,

who, in turn, formed a Long COVID Coordination Council with two workgroups. To formalize

National Research Action Plan on Long COVID

and further the work, HHS will transition to

more permanent high-level leadership by

designating the Assistant Secretary as the

Long COVID Coordinator to oversee the

newly created HHS Office of Long COVID

Research and Practice. The Office will be

charged with the implementation of the

National Research Action Plan on Long COVID

and the Services and Supports for Longer-

Term Impacts of COVID-19 Report. The Office

will be responsible to update the Plan on a

regular basis. To stand up and maintain the

Office and ensure the needed long-term

focus on Long COVID dedicated funding for

permanent staff and operations will be

necessary.

The Coordinator will maintain the Long

COVID Coordination Council (established in

May 2022 in response to the Presidential

Memorandum on Addressing the Long-Term

Effects of COVID-19) as a mechanism for

coordination and communication across the

government. The Coordinator will also

establish the Secretary’s Advisory Committee

on Long COVID. The Coordinator and the

Office will establish methods to ensure

standardization and accountability across all

U.S. government conducted or sponsored

research, including the following

 Harmonize an approach in U.S.

government-sponsored Long COVID cohort research to include measurement of the

broader impacts of the disease (such as development, education, employment,

disability, and health-related quality of life)

 Incorporate the voices of patients and others with lived experience into research from

inception to completion and including dissemination. The Coordinator will

comprehensively place the lived experiences of patients at the core of the research

enterprise to inform development of research priorities, research design, execution,

interpretation, and dissemination. Building on existing model patient engagement

strategies, the Secretary’s Advisory Committee on Long COVID will establish principles

for patient and stakeholder inclusion in research and identify and implement strategies

to address barriers to engagement of underrepresented groups and to prioritize the

Federal Government Efforts That

Will Improve Identification of Long

COVID and Connect Patients to Care

• Convene public and private partners to

better align the definitions of Long

COVID and develop agreed upon

terminology for clinical care,

surveillance, and research

• Develop comprehensive and equitable

Long COVID diagnosis, care, and

treatment guidance

• Make available tools to help individuals

recognize symptoms of Long COVID and

to discuss their symptoms with their

health care providers

• Advance research that helps separate

the broader effects of the pandemic on

an individual’s physical and mental

health from those of the initial SARS-

CoV-2 infection and re-infections

• Use findings from Health+ Long COVID

patient-centered research to improve

the way individuals access and receive

health care and services.

National Research Action Plan on Long COVID

voices of patients disproportionately affected by COVID-19 and Long COVID. The

Coordinator will be responsible for implementation and monitoring of these strategies.

 Implement strategies to measure and mitigate inequities in Long COVID. This includes

continuing efforts to collect detailed information on age, gender, race, ethnicity,

rurality, economic disadvantage, insurance coverage, pregnancy status, and disability

status in all U.S. government-conducted and sponsored research in Long COVID, in line

with Office of Management and Budget (OMB) and other U.S. government policies, and

ensuring diverse representation in all research activities including clinical trials, with

focused efforts to identify and address barriers to participation. This also includes

ensuring access to U.S. government-funded clinical trials and proposed Centers of

Excellence.

 Identify strategic collaborations between public and private entities needed to

accelerate Long COVID diagnostic and therapeutic research and identify and address

barriers to collaborations. Host convenings of research partners, including government,

public health, academia, pharmaceutical industry, national pharmacy chains, and health

systems to initiate collaborations.

 Further harmonization of and consensus on clinical care, surveillance, and research

definitions of Long COVID, described above. The definitions will evolve as our

understanding of Long COVID progresses, and while multiple definitions for different

purposes will be needed, developing consensus on evidence-based definitions will

facilitate clinical care, surveillance, and research, including clinical trials, epidemiology,

and health services research.

 Translate research into evidence and guidance. Work with partners to rapidly develop

comprehensive and equitable Long COVID diagnosis, care, and treatment guidance, and

compile existing guidance. Develop mechanisms to synthesize new data about therapies

(such as innovative drugs, rehabilitation), models of care, and services and supports so

that national guidelines can be developed and updated quickly.

 Develop and implement a strategic communications plan to share findings from Long

COVID research, including evidence-based guidelines, with the broader research

community, including public and private research institutions, federal and state policy

makers, health care, rehabilitation, payers, industry, patients, care givers, and

advocates. An accelerated phase of generating knowledge must be accompanied by an

intentional strategy to share information in rapid fashion, combat misinformation,

generate and maintain momentum in implementing a shared research agenda, promote

stakeholder engagement, and facilitate translation of evidence into practice. The

communications plan will include strategies to ensure materials are culturally and

linguistically effective and include digital resources, such as a public reporting portal and

website. Simultaneously, develop and implement a plan specifically for health care

personnel, services and supports providers, and policy makers to drive adoption of

National Research Action Plan on Long COVID

effective interventions. Implementation strategies may include expanding and tailoring

existing state-of-the-art tele-mentoring and practice facilitation.

 Broadly share U.S. government research on Long COVID. Leverage existing platforms

and resources for clinical trial, genetic data, and literature (e.g., ClinicalTrials.gov,

GenBank, Sequence Read Archive, and PubMed Central) to provide broad access to

information about U.S. Long COVID research and the results as a foundational

component of the communications plan.

Establish a framework for a multipronged approach to Long COVID surveillance. Given the

medical and public health complexity of Long COVID, surveillance is best achieved through

integrated approaches leveraging other data modernization initiatives, which requires

collaboration with public health, health care, and developers of data collection systems. The

approach needs to build on established methods and approaches to implement sustainable

surveillance to monitor incidence and prevalence. Progress will be parallel to other approaches

depending on innovation in electronic health record surveillance and serve as a model for

surveillance of post-infectious sequelae in future pandemics. In the interim, prompt analyses of

varied estimates of incidence, prevalence, and risk factors (including vaccination status) in the

overall U.S. population and in various demographic groups will provide up-to-date estimates of

the burden of Long COVID that can be shared publicly to guide policy-making and resource

allocation Additional funding is being requested in FY23 to support these efforts.

Build on existing programs and infrastructure to improve systems and strategies for rapid

implementation of clinical trials to test existing and new diagnostic tests and therapies for

Long COVID. The U.S. government, in partnership with academia, patients, health care systems,

and pharmaceutical companies, developed tests, vaccines, and therapeutics for COVID-19 in

record time. Continue this level of urgency, ingenuity, and flexibility in developing therapies for

Long COVID; testing whether existing therapeutic interventions (both pharmacologic and non-

pharmacologic) can be repurposed; and developing new therapies. Long COVID may also be

considered as an area of focus for the newly formed Advanced Research Projects Agency for

Health (ARPA-H). Additional funding has been requested in FY23 to support these efforts.

Engage U.S. government agencies to contribute

to a coordinated effort for a national real world

evidence approach, which would include Long

COVID. Engage private partners (such as

industry, health care systems, payers, state

governmental public health and other

stakeholders) to develop a prompt data sharing

and harmonization approaches to address urgent

knowledge gaps in Long COVID. The COVID-19

pandemic demonstrated well that coordinated, real-time, real-world evidence collection

“Once there is agreement on evaluation

tools and outcome measures, we need

to create a model for linkages to care.

This is a critical component of anything

we do and the data we are collecting.”

—Long COVID Researcher

National Research Action Plan on Long COVID

systems need to be in place and ready for major emerging issues. The standing up of a true

real-world evidence center will require coordination of EHR Vendors and large health care

systems, resources, and time. Long COVID should be part of broader efforts supported by the

U.S. government. For example, this effort shall leverage the computing prowess and new

computational mechanisms of the Department of Energy, CDC’s Data Modernization Initiative,

and engagement of biomedical, clinical, and social science researchers to analyze data and

generate evidence. The strategic priorities will be to understand the longer-term health

consequences of SARS-CoV-2 infection and accelerate the discovery of therapeutics of Long

COVID.

Develop a network of Long COVID Centers of Excellence to integrate gold-standard patient-

engaged care delivery and research. Establish and engage a network of Long COVID Centers of

Excellence that will advance implementation research in care delivery models that include

state-of the-art and evidence-based rehabilitation services, behavioral health, and linkages to

human services and supports programs and to primary care. Funding has been requested in

FY23 to grow this network.

Establish primary care networks to develop, implement, evaluate, and scale person-centered

models of care to enable primary care to prevent, diagnose, and manage Long COVID. These

primary care networks will work in partnership with diverse communities to determine the

most effective strategies for improving access, quality, equity, and outcomes of care for Long

COVID, integrating behavioral health and primary care, implementing stepped care and

collaborative models with specialty care and Long COVID clinics, and building linkages to public

health. The Long COVID Centers of Excellence and primary care networks will collaborate to

help assure that all persons with Long COVID receive the level of care they need in a timely

fashion and make it easier to navigate the health system. Funding has been requested in FY23

to grow this network.

Continue to prioritize the recruitment and retention of investigators tackling interdisciplinary

Long COVID research. Support a diverse body of researchers and research portfolios to solve

the interdisciplinary challenges facing people with Long COVID.

Overall, we must build upon lessons learned in addressing other public health crises, such as

HIV, to drive innovation in terms of how research is conceived, funded, conducted, and

disseminated. Research should facilitate data integration, harmonization, and novel approaches

of developing synthesized and linked data that safeguard privacy and facilitates rapid research.

Improved methods to synthesize findings will assist in the rapid dissemination and

implementation of important research.

National Research Action Plan on Long COVID

Implementing the National Research Action Plan on

Long COVID

The National Long COVID Coordinator, supported by the Long COVID Coordination Council and

in consultation with the Secretary’s Advisory Committee on Long COVID, will be responsible for

coordinating the implementation of this Plan. HHS will develop regular implementation plans,

including performance and progress metrics, to execute the strategic priorities and coordinate

the activities of federal agencies and private partners to expedite research on Long COVID (see

Appendix E for an Interim Implementation Plan). Regular reports shall be produced

documenting progress made and outlining any new strategic directions and priorities that

should be incorporated into the strategic plan.

Implementation of this Plan will maintain focus on the principles set forth in this report,

including a commitment to health equity, partner engagement, and orientation of the research

effort to improve patient care and outcomes. Strategic plans and implementation plans must

reflect the recommendations of, and contribute to, the overall U.S. government’s

implementation of the Presidential COVID-19 Health Equity Task Force. These plans must push

the needle in measuring and responding to health inequities in Long COVID.

While there is reason to be optimistic and an opportunity to seize the incredible momentum of

the moment, there are important challenges to acknowledge and address. The COVID-19

pandemic is not over, and other threats to our nation’s health unrelated to SARS-CoV-2

continue to demand our attention. Challenges specific to Long COVID include various research

approaches, complicated by distinct agency missions; the need to elevate the patient voice

across the research portfolio; persistent challenges in engaging underrepresented groups into

clinical research; and, most importantly, the challenge of implementing a comprehensive and

coordinated research portfolio, from basic science all the way to services delivery, for a set of

symptoms and conditions with emerging understanding. Nevertheless, with this Plan, the U.S.

government affirms its commitment to leverage existing and future resources to implement the

necessary steps to address the still-unfolding pandemic sequelae of SARS-CoV-2 infection.

References

1. Office of the Assistant Secretary for Preparedness & Response. Renewal of Determination

that a Public Health Emergency Exists. Published April 12, 2022. Accessed June 28, 2022.

https://aspr.hhs.gov/legal/PHE/Pages/COVID19-12Apr2022.aspx

National Research Action Plan on Long COVID

Appendix A: Report Abbreviations

ACL

Administration for Community Living, HHS

CDC Centers for Disease Control and Prevention, HHS

CMS

Centers for Medicare & Medicaid Services, HHS

COCA

Clinician Outreach and Community Activity

CORC-LTO

COVID-19 Observational Research Collaboratory Long-term

Outcomes

COVID-19

Coronavirus disease of 2019

CSF

Cerebrospinal fluid

DOD

Department of Defense

DOL

Department of Labor

EPIC

Epidemiology, Immunology, and Clinical Characteristics of

COVID-19

EPICC

Epidemiology, Immunology, and Clinical Characteristics of

Emerging Infectious Diseases with Pandemic Potential

FDA

Food and Drug Administration, HHS

HHS

Department of Health and Human Services

HMD

Health and Medicine Division

HRQOL

Health-related quality of life

HRSA

Health Resources and Services Administration, HHS

ICD-10-CM

10th revision of the International Statistical Classification of

Diseases and Related Health Problems

INSPIRE

Innovated Support for Patients with SARS-CoV-2 Infections

LGBTQI+

Lesbian, gay, bisexual, transgender, queer, intersex

MCHB

Maternal and Child Health Bureau, HRSA, HHS

ME/CFS

Myalgic encephalomyelitis and chronic fatigue syndrome

MIS-C

Multisystem Inflammatory Syndrome—Children

National Research Action Plan on Long COVID

MMWR

Morbidity and Mortality Weekly Report

MRI

Magnetic resonance imaging

N3C

National COVID Cohort Collaborative

NASEM

National Academies of Science, Engineering, and Medicine

NHIS

National Health Interview Survey

NIAID

National Institute of Allergy and Infectious Diseases, NIH, HHS

NIDILRR

National Institute on Disability, Independent Living, and

Rehabilitation Research, NIH, HHS

NIH

National Institutes of Health, HHS

NSCH-LC

National Survey of Children’s Health Longitudinal Cohort

ODEP

Office of Disability Employment Policy, DOL

PASC

Post-acute sequelae of SARS-CoV-2 infection

PCC

Post-COVID-19 Conditions

PCORnet

National Patient-Centered Clinical Research Network

PECOS

Pediatric COVID Outcomes Study

RECOVER

Researching COVID to Enhance Recovery (NIH Initiative)

RETAIN

Retaining Employment and Talent After Illness Injury Network

RRTC

Rehabilitation Research and Training

RTW

Return-to-work

SARS-COV-2

Severe acute respiratory syndrome coronavirus 2

SOII

Survey of Occupational Injuries and Illnesses

SSA

Social Security Administration

Department of Veterans Affairs

VHA

Veterans Health Administration, VA

National Research Action Plan on Long COVID

Appendix B: Contributing U.S.

Government Departments

Departments

Department of Defense (DOD)

Department of Labor (DOL)

Department of Education (ED)

Department of the Treasury

(DOT)

Department of Energy (DOE)

Department of Veterans Affairs

(VA)

Department of Health and

Human Services (HHS)*

Equal Employment Opportunity

Commission (EEOC)

Department of Homeland

Security (DHS)

Federal Emergency

anagement Agency (FEMA)

National Council on Disability

(NCD)

Department of Housing and

Urban Development (HUD)

Office of Personnel

Management (OPM)

Department of Justice (DOJ)

Social Security Administration

(SSA)

HHS Divisions*

Administration for Children and Families (ACF)

Administration for Community Living (ACL)

Agency for Healthcare Research and Quality (AHRQ)

Centers for Disease Control and Prevention (CDC)

Centers for Medicare & Medicaid Services (CMS)

Food and Drug Administration (FDA)

Health Resources and Services Administration (HRSA)

Indian Health Service (IHS)

National Institutes of Health (NIH)

Office for Civil Rights (OCR)

Office of Global Affairs (OGA)

Office of Intergovernmental and External Affairs (IEA)

Office of the Assistant Secretary for Administration (ASA)

Office of the Assistant Secretary for Health (OASH)

Office of the Assistant Secretary for Planning and

Evaluation (ASPE)

Office of the Assistant Secretary for Preparedness and

esponse (ASPR)

Office of the Secretary (IOS)

Office of the Surgeon General (OSG)

Substance Abuse and Mental Health Services

dministration (SAMHSA)

National Research Action Plan on Long COVID

Appendix C: Terminology and

Definitions

“Long COVID” is the term used in the National Research Action Plan and reflects the voice of

patients. Several terms for Long COVID exist, such as Post-COVID-19 Conditions (PCC), Post-

Acute Sequelae of SARS-CoV-2 (PASC) infection, and persistent symptoms, or COVID-19

consequences. While there has been progress towards a common understanding of the two

technical terms (i.e., PCC and PASC) differences in understanding and usage remain. The table

below provides historic information regarding some terms used, the primary source for the

term along with an online reference and definition. The list is not exhaustive but demonstrates

the challenges with terminology for a new, emerging set of complex, inter-related conditions

and the need to promote consensus for research, clinical care, and surveillance.

Source Term Definition Reference

Patients and

people with lived

experience;

patient-

researchers

Long COVID

Can be broadly defined as signs, symptoms, and

sequelae that continue or develop after acute

COVID-19 or SARS-CoV-2 infection for any period

of time; are generally multisystemic; might

present with a relapsing–remitting pattern and a

progression or worsening over time, with the

possibility of severe and life-threatening events

even months or years after infection

How and why patients

made Long Covid,

ScienceDirect

Centers for

Disease Control

and Prevention

(CDC)

Post-COVID-

conditions

(plural)

Umbrella term for the wide range of physical and

mental health consequences experienced by

some patients that are present four or more

weeks after SARS-CoV-2 infection, including by

patients who had initial mild or asymptomatic

acute infection; equivalent to the lay term, “Long

COVID”

Long COVID or Post-

COVID Conditions |

CDCl

Department of

Veterans Affairs

(VA)

Post-COVID

Conditions

Post-COVID conditions are symptoms that last or

start weeks or months after a person was infected

with the SARS-CoV-2 virus. This is the virus that

causes COVID-19. This can happen even if you

didn’t know you had the virus. You may hear

these conditions called long COVID, post-acute

COVID, chronic COVID, or other terms. The

symptoms can include tiredness, headaches, loss

of taste and smell, trouble breathing, and

dizziness

About Post-COVID

Conditions (Long

COVID, Chronic COVID)

| Veterans Affairs

(va.gov)

National Research Action Plan on Long COVID

National Institutes

of Health (NIH)

Post-acute

Sequelae of

SARS CoV-2

infection

Ongoing, relapsing, or new symptoms, or other

health effects occurring after the acute phase of

SARS-CoV-2 infection (i.e., present four or more

weeks after the acute infection). The definition

will be revised in an iterative manner based on

existing and new data, medical literature, and

feedback from the scientific community

Understanding the

Long-term Impact of

COVID-19 in Adults

(recovercovid.org)

Food and Drug

Administration

(FDA)

Post-COVID

conditions

(plural)

While most people with COVID-19 have resolution

of their symptoms within weeks of their illness,

some people experience post-COVID conditions.

Post-COVID conditions are new, returning, or

ongoing health problems people can experience

four or more weeks after initial infection with the

SARS-CoV-2 virus. These conditions have also

been termed long COVID, long-haul COVID, post-

acute sequelae of COVID-19, long-term effects of

COVID, or chronic COVID. Post-COVID conditions

have been observed in people with mild to severe

COVID-19 infection, and can present with

localized and systemic symptoms impacting

nearly all organ systems.

FDA CERSI Lecture on

Long COVID: Risk

factors, Symptomology

and Patient Reported

Outcomes Captured

Through a Novel Digital

Platform by Dr. Erica

Spatz & Dr. Kelli

O’Laughlin -

11/09/2021 -

11/09/2021 | FDA

World Health

Organization

(WHO)

Post-COVID-19

Condition

(singular)

Post-COVID-19 condition occurs in individuals

with a history of probable or confirmed SARS-

CoV-2 infection, usually 3 months from the onset

of COVID-19 with symptoms that last for at least 2

months and cannot be explained by an alternative

diagnosis; common symptoms include fatigue,

shortness of breath, and cognitive dysfunction,

and generally have an impact on everyday

functioning; symptoms might be new onset after

initial recovery from an acute COVID-19 episode

or persist from the initial illness; symptoms might

also fluctuate or relapse over time; a separate

definition might be applicable for children;

recognize “Long COVID”

A clinical case

definition of post-

COVID-19 condition by

a Delphi consensus -

The Lancet Infectious

Diseases

Broader

Research

Community

Persistent

symptoms or

COVID-19

consequences

Persistent signs and symptoms that continue or

develop after acute COVID-19 for any period of

time

Persistent symptoms

following SARS-CoV-2

infection amongst

children and young

people: A meta-

analysis of controlled

and uncontrolled

studies - ScienceDirect

National Research Action Plan on Long COVID

American

Academy of

Physical Medicine

and

Rehabilitation

Post-acute

sequelae of

SARS CoV-2

infection

(equates it

with Long

COVID)

Post-Acute Sequelae of SARS-CoV-2 infection

(PASC) or Long COVID is a condition that occurs

in individuals who have had COVID-19 and report

at least one persistent symptom after acute

illness. Long COVID encompasses a constellation

of varied and ongoing symptoms – even in the

same patient across time – and may include

neurological challenges, cognitive symptoms

such as brain fog, cardiovascular and respiratory

issues, fatigue, pain and mobility issues, among

others.

PASC Guidance

(aapmr.org)

American College

of Cardiology

Post-acute

sequelae of

SARS-CoV-2

Infection

PASC encompasses a constellation of symptoms

that emerge or persist weeks to months after

recovery from COVID-19 [referencing CDC,

WHO]. Although evidence guiding the care of

these patients continues to evolve, there is a

need to develop common taxonomies and

approaches to care that can be updated

iteratively as new data become available.

2022 ACC Expert

Consensus Decision

Pathway on

Cardiovascular

Sequelae of COVID-19

in Adults: Myocarditis

and Other Myocardial

Involvement, Post-

Acute Sequelae of

SARS-CoV-2 Infection,

and Return to Play: A

Report of the American

College of Cardiology

Solution Set Oversight

Committee | Journal of

the American College of

Cardiology (jacc.org)

American

Thoracic Society

Long COVID

The term that is often used to describe these

persistent symptoms. You are considered to

have ‘Long COVID’ when you are still having

symptoms at least 4 weeks after the initial

infection. Long COVID may also be referred to by

other names such as post-COVID conditions,

PASC (post-acute sequelae of SARS-CoV-2

infection) or long-haul COVID.

Long COVID Patient

Fact Sheet

(thoracic.org)

Humana Military Long COVID

While most people with COVID-19 get better

within weeks, some continue to have

symptoms—or develop new ones—after their

initial recovery. The technical term for this is

post-acute sequelae of SARS-CoV-2 infection

(PASC), or simply “long COVID.” People with long

COVID are often called “longhaulers.” A person

of any age who has had COVID-19 can later

develop a post-virus condition.

Long COVID resource

guide (humana.com)

Infectious Disease

Society of

America

Post-COVID-

19 Conditions

(plural)

References other definitions, Long COVID, CDC,

and WHO

Post COVID Conditions

(e.g., Long COVID)

(idsociety.org)

National Research Action Plan on Long COVID

Wikipedia Long COVID

Long COVID is a condition characterized by long-

term consequences persisting or appearing after

the typical convalescence period of COVID-19. It

is also known as post-COVID-19 syndrome, post-

COVID-19 condition, post-acute sequelae of

SARS-CoV-2 infection (PASC), or chronic COVID

syndrome (CCS). Long COVID can affect nearly

every organ system, with sequelae including

respiratory system disorders, nervous system

and neurocognitive disorders, mental health

disorders, metabolic disorders, cardiovascular

disorders, gastrointestinal disorders,

musculoskeletal pain, and anemia. A wide range

of symptoms are commonly reported, including

fatigue, malaise, headaches, shortness of breath,

anosmia (loss of smell), parosmia (distorted

smell), muscle weakness, low fever and cognitive

dysfunction.

Long COVID - Wikipedia

International

Classification of

Diseases (ICD)-10-

CM code

U09.9 Post-

COVID

condition,

unspecified

No definition is given, but the following are

noted:

• This code enables establishment of a link

with COVID-19.

• This code is not to be used in cases that are

still presenting with active COVID-19.

However, an exception is made in cases of

reinfection with COVID-19, occurring with a

condition related to prior COVID-19.

•

Post-acute sequelae of COVID-19

2022 ICD-10-CM

Diagnosis Code U09.9:

Post COVID-19

condition, unspecified

(icd10data.com)

National Institute

for Health and

Care Excellence

(NICE)

Ongoing

symptomatic

COVID-19

Signs and symptoms of COVID-19 from 4 weeks

up to 12 weeks

Guideline COVID-19

rapid guideline:

managing the long-

term effects of COVID-

19 (nice.org.uk)

National Institute

for Health and

Care Excellence

(NICE)

st-COVID-

19 syndrome

Signs and symptoms that develop during or after

an infection consistent with COVID-19, continue

for more than 12 weeks and are not explained by

an alternative diagnosis; it usually presents with

clusters of symptoms, often overlapping, which

can fluctuate and change over time and can

affect any system in the body; post-COVID-19

syndrome might be considered before 12 weeks

while the possibility of an alternative underlying

disease is also being assessed

Guideline COVID-19

rapid guideline:

managing the long-

term effects of COVID-

19 (nice.org.uk)

Note: Adapted from the Table titled, “Commonly used terminology in the research of COVID-19 sequelae” in Munblit

D, O’Hara M, Akrami A et al. Long COVID: aiming for a consensus. Lancet Respir Med. 2022; S2213-2600(22)00135-

7. https://www.thelancet.com/action/showPdf?pii=S2213-2600%2822%2900135-7. Accessed June 21, 2022.

*United Kingdom National Institute for Health and Care Excellence (NICE)

National Research Action Plan on Long COVID

**NICE also states that: “In addition to the clinical case definitions, the term ‘long COVID’ is commonly used to

describe signs and symptoms that continue or develop after acute COVID-19. It includes both ongoing

symptomatic COVID-19 (from 4 to 12 weeks) and post-COVID-19 syndrome (12 weeks or more).”

National Research Action Plan on Long COVID

Appendix D: Highlights of Current U.S.

Government Research Portfolio on Long

COVID

The U.S. government is currently conducting and supporting many studies that will contribute

to the successes of the National Research Action Plan. This table contains a comprehensive list

of the most prominent projects in the Long COVID federal research portfolio, including the

research described in Chapter 3. This is not an exhaustive list of all Long COVID research or U.S.

government supported research. The list is in alphabetical order based on the study title.

Agencies that are leading and collaborating in the research are also listed. Finally, for each

research study, research areas corresponding to the topic areas highlighted in Chapter 3 of this

report are listed.

Study Title Agency* Research Areas

Advancing the epidemiological and

mechanistic understanding of the

neurological complications of COVID-19

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

All of US Research Program NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

Applied Research to Address the

Coronavirus (COVID-19) Emerging Public

Health Emergency

CDC

Surveillance and Epidemiology

Long COVID and Overall Well-Being

Behavioral Risk Factor Surveillance System

(BRFSS) 

CDC

rveillance and Epidemiology

Characterization of host immune responses

to SARS-CoV-2

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

National Research Action Plan on Long COVID

Cognitive sequelae of the biological effects

of COVID-19 on the nervous system in a

health disparity population

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Cohort study of effects of SARS-CoV-2

infection, vaccination, and immunology on

gut tissue and clinical symptoms

NIH

linical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

COVID-19 Neuro Databank Biobank NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

COVID-19 Observational Research

Collaboratory Long-term Outcomes Study

(CORC-LTO)

mpacts of Illness

Surveillance and Epidemiology

COVID-19 patient registry DOD

linical Spectrum of Long COVID and Diagnostic

Strategies

COVID-19: Predictive Immune and Airway

Monitoring in Healthcare workers and

Hospitalized COVID-19 patients

NIH, VA

linical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

Surveillance and Epidemiology

COVID–Standardized Evaluation of Long-

term Effects (COVID-SELECT)  

CDC Surveillance and Epidemiology

COVID-19: Understanding the Post-Viral

Phase (COVID-UPP)

CDC

rveillance and Epidemiology

Clinical Spectrum of Long COVID and Diagnostic

Strategies

COVID-19 within American Indian

Communities at High Risk in the Southwest

U.S.

CDC

rveillance and Epidemiology

CSP #2028 (Epidemiology, Immunology and

Clinical Characteristics of COVID-19 [EPIC3])

Surveillance and Epidemiology

Clinical Spectrum of Long COVID and Diagnostic

Strategies

National Research Action Plan on Long COVID

Descriptive and Analytical Study of Post-

acute Sequelae of COVID-19 (Long COVID)

among U.S. Veterans

FDA, VA

rveillance and Epidemiology

Effects of Long COVID on inflammatory

processes in the central nervous system

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

Effects of Long-COVID on Maintenance and

Incidence of ME/CFS

NIH

linical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

Pathophysiology

Effects of Long COVID on Topological

Mapping of Immune, Microbiota,

Metabolomic and Clinical Phenotypes to

Reveal ME/CFS Disease

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Employer Assistance and Resource Network

on Disability Inclusion

ODEP Human Services, Supports, and Interventions

Epidemiology, Immunology, and Clinical

Characteristics of Emerging Infectious

Diseases with Pandemic Potential (EPICC)

DOD

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Exploratory Analysis of Long COVID service

use among Medicare beneficiaries

CMS, ASPE Health Services and Health Economics Research

FindCOVID CDC

linical Spectrum of Long COVID and Diagnostic

Strategies

Formative Evaluation of Long COVID care

delivery models in the VA

ealth Services and Health Economics Research

Health+ HHS, OASH Long COVID and Overall Well-Being

National Research Action Plan on Long COVID

Household Pulse Survey

CDC,

Commerce

Surveillance and Epidemiology

Identifying Long COVID algorithms to

operationalize for use in the FDA Sentinel

system and other administrative claims or

electronic health records data sources.

FDA, CDER Therapeutics

Immune Response to SARS-CoV-2 among

patients in Louisiana

CDC Surveillance and Epidemiology

Immunophenotyping in a COVID-19 Cohort

(IMPACC)

NIH

Surveillance and Epidemiology

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

Immunotherapy for Neurological Post-Acute

Sequelae of SARS-CoV-2 (IN-PASC)

NIH

athophysiology

Therapeutics

Impact of Long COVID on return-to-work

efforts for people with disability

ACL Human Services, Supports, and Interventions

Innovative Support for Patients With SARS-

CoV-2 Infections (INSPIRE)

CDC

linical Spectrum of Long COVID and Diagnostic

Strategies

Leveraging the power of VA data to

understand Long COVID

VA Surveillance and Epidemiology

Long COVID and Fatiguing Illness Recovery

Program (LC&FIRP) 

CDC Surveillance and Epidemiology

Long COVID Needs Assessment of Health

Professionals (2022 DocStyles Survey)

CDC Health Services and Health Economics Research

Long COVID Practice Based Research

Network

VA Therapeutics

Long COVID supplement to the National

Survey on Health and Disability

ACL

ealth Services and Health Economics Research

National Research Action Plan on Long COVID

Longitudinal Study of COVID-19 Antibody

Response in Children in Seattle, WA

CDC Surveillance and Epidemiology

Longitudinal At Home Smell Testing to

Detect Infection by SARS-CoV-2

NIH

linical Spectrum of Long COVID and Diagnostic

Strategies

Longitudinal Study of COVID-19 Sequelae

and Immunity

NIH

rveillance and Epidemiology

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

Longitudinal study of immune memory in

COVID-19 patients with mild to moderate

symptoms

NIH

linical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

Multi-site Study of Post-COVID Conditions

(MPCC)

CDC

Surveillance and Epidemiology

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Multi-state Long COVID Survey  CDC Surveillance and Epidemiology

National COVID Cohort Collaborative (N3C) NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

Long COVID and Overall Well-Being

Pathophysiology

Therapeutics and Other Health Interventions

National Health Interview Survey CDC Surveillance and Epidemiology

National Research Action Plan on Long COVID

National Patient-Centered Clinical Research

Network (PCORnet)

PCORI

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

Long COVID and Overall Well-Being

Pathophysiology

Therapeutics and Other Health Interventions

National Survey of Children’s Health

Longitudinal Cohort Study (NSCH-LC)

HRSA,

rveillance and Epidemiology

Health Services and Health Economics Research

NIH Epidemiologic Study of Diabetes

Incidence and Severity and Its Potential

Association with COVID-19

NIH

rveillance and Epidemiology

Occurrence of post-COVID-19 conditions and

symptoms among adults seen in primary

care practices by sociodemographic

factors—American Board of Family Medicine

PRIME Registry, American Family Cohort

CDC

rveillance and Epidemiology

Office of Workers Compensation Program DOL Impacts of Illness

Pediatric COVID Outcomes Study (PECOS) NIH

linical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

Pathophysiology

Impacts of Illness

Pediatric Research Immune Network on

SARS-CoV-2 and MIS-C (PRISM)

NIH

rveillance and Epidemiology

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

National Research Action Plan on Long COVID

Pediatric Learning Health System

consortium of PCORnet (PEDSnet

consortium)

PCORI

linical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

Long COVID and Overall Well-Being

Therapeutics and Other Health Interventions

Planning workshop: Long-Term Health

Effects from COVID-19 and Implications for

the SSA

SSA

uman Services, Supports, and Interventions

Population-based study of long-term

impacts of COVID-19 infection (including

subset of Veterans with Long COVID)

ealth Services and Health Economics Research

Post COVID Collaborative Merit Program VA

linical Spectrum of Long COVID and Diagnostic

Strategies

Project ECHO (Extension for Community

Healthcare Outcomes)

AHRQ Health Services and Health Economics Research

RADx Radical program NIH

linical Spectrum of Long COVID and Diagnostic

Strategies

Rapid olfactory tools for telemedicine-

friendly COVID-19 screening and

surveillance

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Researching COVID to Enhance Recovery

(RECOVER)

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Surveillance and Epidemiology

Long COVID and Overall Well-Being

Pathophysiology

Therapeutics and Other Health Interventions

Research on COVID Long-Term Illness,

Effects, and Risk Factors (COVID-RELIEF)

CDC Surveillance and Epidemiology

Retaining Employment and Talent After

Illness/Injury Network (RETAIN)

DOL

mpacts of Illness

National Research Action Plan on Long COVID

Risk Factor Assessment Study for Post-Acute

Sequelae of COVID-19 (Long COVID) in the

Medicare Population

FDA, CBER,

CMS

Surveillance and Epidemiology

Risk of developing post-COVID-19 conditions

among younger and older adult COVID-19

survivors—Cerner Real World Data

CDC Surveillance and Epidemiology

SCENTinel: A Rapid Smell Test for COVID-19

Surveillance

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Survey of Occupational Injuries and Illnesses

(SOII)

DOL Impacts of Illness

TLC Trial (Treatment of Long COVID). 

FDA, CDER,

NIH,

NCATS

Therapeutics and Other Health Interventions

Understanding the Pathophysiology and

Clinical Course of New-Onset Diabetes

Following COVID-19

NIH

Clinical Spectrum of Long COVID and Diagnostic

Strategies

Pathophysiology

VA COVID-19 Observational Research

Collaboratory Long-term Outcomes Study

(CORC-LTO)

VA Surveillance and Epidemiology

Qualitative study Long COVID-19 impact on

return-to-work efforts for people with

disability

ACL Human Services, Supports, and Interventions

COVID-19 pandemic-related experiences of

working-age adults with disabilities

ACL Human Services, Supports, and Interventions

Analysis of disability claims with report of

Long COVID

SSA Human Services, Supports, and Interventions

*Agency abbreviations, in alphabetical order

CL: Administration for Community Living

AHRQ: Agency for Healthcare Research and Quality

ASPE: Office of the Assistant Secretary for Planning and Evaluation

CBER: Center for Biologics Evaluation and Research

CDC: Centers for Disease Control and Prevention

National Research Action Plan on Long COVID

CDER: Center for Drug Evaluation and Research

CMS: Centers for Medicare & Medicaid Services

DOD: Department of Defense

DOL:

Department of Labor

FDA: Food and Drug Administration

HHS: Department of Health and Human Services

HRSA: Health Resources and Services Administration

NCATS: National Center for Advancing Translational Sciences

NIH: National Institutes of Health

OASH: Office of the Assistant Secretary for Health

ODEP: Office of Disability Employment Policy

PCORI: Patient-Centered Outcomes Research Institute

SSA: Social Security Administration

VA: Department of Veterans Affairs

National Research Action Plan on Long COVID

Appendix E: U.S. Government Long

COVID Research, Interim

Implementation Plan

As the U.S. government is standing up the new Office of Long COVID Research and Practice,

there is a need for an interim implementation plan. The following tables demonstrate the

actions that the U.S. government will take over the next six months to implement the strategies

and priorities of this Plan. At a high level, this interim plan will guide federal efforts until the

Department of Health and Human Services develops the first annual implementation plan,

including performance and progress metrics, to execute the strategic priorities and coordinate

the activities of federal agencies and private partners. Efforts described in these tables are new

or enhanced activities, above and beyond the research described in Chapter 3 and Appendix

D, almost all of which is ongoing. These two tables correspond to the two main sections in

Chapter 4. The first table below, U.S. Government Research Priorities for Long COVID, describes

specific research that U.S. government will undertake to respond to the broad call to action

described in Chapter 4 for the U.S. government as well as the private research community. The

second table below, Strategic U.S. Government Actions, are the new structures and processes

in U.S. government to drive the research.

U.S. Government Research Priorities for Long COVID

Characterizing the Full Clinical Spectrum of Long COVID and Diagnostic

Strategies

Host a convening of public and private partners to better align interim definitions of

Long COVID for clinical, surveillance, and research

Augment use of existing chronic disease initiatives (e.g., the Serological Sciences

Network (SeroNet)) to better understand the increased risk of chronic disease and

clinical course among persons with Long COVID

Surveillance and Epidemiology

Establish a framework for a multipronged approach to Long COVID surveillance to

coordinate and enhance existing efforts in the context of broader data modernization

efforts

Leverage existing research on post-infectious chronic illness to support identification of

commonalities and differences with Long COVID, accelerate research and innovation, as

well as prepare for the long-term consequences of future pandemics

National Research Action Plan on Long COVID

Long COVID and Overall Well-Being

Publish findings from Health+ Long COVID patient-centered research, qualitative

studies of patients experiencing Long COVID and associated conditions, caregivers,

frontline workers, and those with lived experience

Assess existing cohort studies as well as studies conducting qualitative interviews with

persons with Long COVID, to expand consideration of outcomes such as behavioral

health, employment, education, caregiving, care utilization, and experience with care,

especially among groups who are disproportionately affected

Therapeutics and Other Health Interventions

Implement additional strategies to accelerate and enhance enrollment into RECOVER

studies

Human Services, Supports, and Interventions

Identify existing national surveys related to human services, supports and interventions

that could be amended to include modules for data collection about Long COVID

Health Services and Health Economics Research

Build on current studies to evaluate the economic costs and outcomes of Long COVID,

across the full range of economic costs and outcomes, and at all levels-- patient and

family, health system, state, federal (including Medicare and Medicaid), and national

Strategic U.S. Government Actions

Establish an Office of Long COVID Research and Practice

Support ongoing meetings of the Long COVID Coordination Council

Develop first annual implementation plan

Establish the Secretary’s Advisory Committee on Long COVID

Develop and contribute to best practices to collect detailed information on age, gender, race,

ethnicity, rurality, economic disadvantage, insurance coverage, pregnancy status, and

disability status in all USG-conducted and sponsored research on Long COVID, in line with

OMB and other U.S. government policies

Facilitate development of comprehensive and equitable Long COVID diagnosis, care and

treatment guidance and compile existing guidance

National Research Action Plan on Long COVID

Develop and immediately begin implementation of a strategic communications plan to share

findings from Long COVID research widely with partners and stakeholders to coordinate and

enhance current efforts

Leverage existing platforms and resources for clinical trial, genetic data, and literature

(e.g., , GenBank, Sequence Read Archive, and PubMed Central) to provide

broad access to information about U.S. Long COVID research and the results.

ClinicalTrials.gov

Host a convening of research partners, including government, academia, public health,

pharmaceutical industry, national pharmacy chains, and health systems to initiate

collaborations.