Could Long COVID Research Lead to Breakthroughs in Understanding Fibromyalgia and CFS? - PracticalPainManagement.com
Editor's Note: This is the first in a series of articles presenting crucial topics on post-COVID syndrome (or post-acute sequelae of SARS-CoV-2 infection [PASC]) and chronic pain syndromes. These topics are addressed, in greater detail, in the author's book, Unravelling Long COVID, by Don Goldenberg and Marc Dichter, to be released in September 2022 by Wiley Publishers. Subsequent PPM features will address chronic pain and long COVID, and the impact of long COVID clinics on pain treatment models.
Current Long COVID Criteria
Between 50 million and 200 million people worldwide have persistent medical symptoms long after recovering from COVID-19 infection. Termed "long COVID" by patients, and post-acute sequelae of SARS-CoV-2 (PASC) by some investigators, this condition has been considered by many to be the next global public health disaster.
Criteria for Defining Long COVID
Although there is no uniform definition for long COVID, most working case definitions include persistent symptoms, lasting for at least 3 months, following SARS-CoV-2 infection, that cannot be explained by another medical disorder. Criteria include:
Symptom duration > 3 months
No other medical condition causing the symptoms
More than 3 of the following symptoms:
Long COVID Disease vs Long COVID Syndrome
Long COVID can be broadly subdivided into:
What is Long COVID Disease?
Individuals who, following SARS-CoV-2 infection, developed chronic symptoms that can be attributed to initial lung, heart, or CNS damage should be considered to have long COVID disease. The presence and persistence of their symptoms correlates with the severity of the initial infection. Most of these patients were hospitalized and their symptoms and clinical course were often indistinguishable from patients with post-ICU syndrome.
Discussing long COVID disease in a BMJ paper, Anthony David, MD, professor at the Institute of Mental Health, University College, London, wrote:
"If a patient recovers from the acute respiratory illness, but remains short of breath and is found to have pulmonary fibrosis or pericarditis by accepted criteria, or, experiences brain fog and mental slowing, later linked to microvascular infarcts on MRI – can they be removed from the post-COVID-19 cohort? I would say yes…. These conditions add to the tally of morbidity caused by COVID-19, but not to post-COVID-19 syndrome."¹
What is Long COVID Syndrome?
Many people with long COVID have no evidence of organ damage and their chronic symptoms do not correlate with the severity of the initial infection. Such individuals were usually not hospitalized and had mild symptoms or may even have been asymptomatic. These individuals should be classified as having long COVID syndrome.
Long COVID syndrome has many similarities to other poorly understood illnesses, such as fibromyalgia and chronic fatigue syndrome (CFS), that cause widespread musculoskeletal pain, chronic fatigue, and neurocognitive symptoms. Like fibromyalgia and CFS, there are no biomarkers yet identified in long COVIDs syndrome, and it is defined solely by its subjective symptoms. These similarities have prompted enthusiasm that breakthroughs in understanding long COVID will lead to a better understanding and therapy for certain chronic pain and fatigue syndromes.
Comparing Long COVID Disease and Syndrome Characteristics
The demographic and clinical characteristics of long COVID disease are very different from those of long COVID syndrome (see Table I). Long COVID disease follows the same clinical trajectory of other respiratory diseases requiring hospitalization. It occurs more often in older patients with multiple comorbidities and its clinical course is determined largely by the initial disease severity.
In contrast, long COVID syndrome appears to be more common in young, healthy women, does not correlate with initial hospitalization or disease severity and is not associated with organ damage.
| Characteristics | Disease | Syndrome |
|---|---|---|
| Average Age | 50 to 60 years | 30 to 50 |
| Percent Female | 45% to 50% | 60% to 75% |
| General health | Comorbidities | No Comorbidities |
| Hospitalized | Most patients | Seldom |
| Organ impact | Damage | Dysfunction |
| Correlates with initial severity | Yes | No |
Long COVID Research Impact on Understanding Fibromyalgia, CFS
Three distinct themes underlie important research advances in long COVID that may improve our understanding of fibromyalgia and CFS:
Growth of patient-centric research
Greater appreciation of chronic, poorly understood syndromes
Better understanding of neuroimmune mechanisms
The Growth of Patient-Centric Research
Patient Symptom Reports in Rheumatology
During the past two to three decades, there has been much greater acknowledgment of the importance of patient experience in clinical research. I have witnessed this first-hand in my rheumatology career, most evident in our initial definitions of fibromyalgia, which were based solely on patients' descriptions of their symptoms.² In syndromes such as fibromyalgia, there are no diagnostic or biologic markers. We make the diagnosis and determine illness severity and treatment response based only on patients' accounts of symptoms.
Patient experience has also become essential in the diagnosis and treatment of rheumatic diseases with well-established disease markers. Early in my career, when assessing response to therapy in individuals with rheumatoid arthritis (RA), for example, we would rely primarily on objective disease markers, including the ESR or CRP, and evidence of radiologic joint damage. Assessing patients' response to therapy was not included.
During the past few decades, every therapeutic study of rheumatoid arthritis has included the patient's subjective response, typically exploring symptom severity, such as pain and fatigue, ability to function, and quality of life.
Patient Symptom Reports in COVID-19 Care
The term coined by patients, long COVID, has been called "the first illness created through patients finding one another on Twitter."³ Patients have been involved in many of the research studies to characterize long COVID symptoms. The ZOE COVID app in the UK and US was used by nearly 5 million individuals during 2000 and 2001, providing in-depth patient self-reporting in real time with questions that were modified based on patients' experiences.⁴
Long COVID has sparked a greater appreciation of chronic, poorly understood syndromes.
Clinicians have embedded patient experience in long COVID research in innovative ways. For instance, Nisreen Alwan, MBChB, MPH, PhD, a scientist-clinician at the University of Southampton, UK, one of the first to strongly advocate for patient involvement in long COVID research, described the lessons she learned:
"An important one is how much better we can do in health research if our understanding and questions are enriched by the lived experiences of patients right from the start of the research cycle…patients must have a central role in conceptualizing and phrasing the research question, shaping the study design, and co-producing innovative ways to capture real-life experiences, as well as defining and labelling their conditions in a way that serves their wellbeing."⁵
Appreciation of Poorly Understood, Chronic Syndromes
As the authors of an NEJM opinion piece stated, long COVID syndrome, like fibromyalgia, CFS, and other "invisible" illnesses is, "not a condition for which there are currently accepted objective diagnostic tests or biomarkers. It is not blood clots, myocarditis, multisystem inflammatory disease, pneumonia, or any number of well-characterized conditions caused by COVID-19. No one knows what the time course of long COVID will be or what proportion of patients will recover or have long-term symptoms. It is a frustratingly perplexing condition."⁶
Often, the absence of objective signs of disease has led to the misconception that there is no physiological basis for chronic symptoms, such as exhaustion or widespread pain. Patients with long COVID syndrome, like those with fibromyalgia or chronic fatigue syndrome (CFS), also termed chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), are subsequently not considered to have a "real" disease.
Twenty years ago, rheumatologists still voiced their opinion that fibromyalgia was not a "legitimate medical condition, in contrast to rheumatoid arthritis."² One neurologist wrote, "fibromyalgia is not just overdiagnosed, it downright does not exist. There is no empiricism to fibromyalgia. Just wild speculation. People with fibromyalgia do not have a specific medical disorder and they are harmed by giving them a name or treating them medically. It makes them feel crippled."⁷
Fibromyalgia, CFS/ME, and related poorly, understood disorders, such as irritable bowel syndrome (IBS), are still often thought of as psychological, rather than physical, illnesses. Now, the same skepticism may plague long COVID syndrome.
Long COVID syndrome, like fibromyalgia and CFS, is considered likely only after excluding diseases that may be causing the symptoms. The symptoms should be persistent and severe enough to interfere with normal activity.
Overlapping Features of Long COVID Syndrome, Fibromyalgia, and CFS
considered syndromes, not diseases
no evidence of organ damage
diagnosed after excluding other conditions that may cause the symptoms
severe enough to interfere with normal activities and last at least 3 to 6 months
primary symptoms include exhaustion, pain, and cognitive, sleep, and mood disturbances
more common in women, age 30 to 50 years
may become a chronic illness
Burke and del Rio discussed the parallels of long COVID to illnesses such as fibromyalgia and CFS:
"Long COVID might exemplify the category of mysterious, unexplained, chronic symptoms (either post-infectious or not), and could operate via similar mechanisms to symptoms seen in other patients. The major problem in teasing this out is that the latter, despite a long history of high numbers of patients, has remained very poorly understood and constitutes one of medicine's largest blind-spots."⁸
Indeed, the vast majority of people with long COVID syndrome would meet the current diagnostic criteria for fibromyalgia and CFS. In one international patient survey of patients with persistent symptoms after COVID, fatigue was present in 98%, post-exertional malaise in 89%, musculoskeletal pain in 94%, and cognitive dysfunction in 85%.⁹ In another report, one-third of 616 people who had COVID-19 infection met the criteria for fibromyalgia at an average of 6 months after COVID infection.¹⁰ The authors forecast a sharp rise in post-COVID chronic pain, what they called "FibroCOVID."
The medical community has also been skeptical about any relationship of fibromyalgia, CFS/ME, and other post-viral syndromes to a specific infection. There is no such doubt with long COVID syndrome, which clearly is initiated by SARS-CoV-2. We can trace its infectious origin and subsequent clinical course, allowing for prospective, controlled studies. Individuals enrolled in long COVID research can be stratified to include suspected, probable, and confirmed SARS-CoV-2 infection, and compared to non-infected controls and to infected subjects who did not have long COVID.
COVID-19 as a Boon for CFS/ME Research?
The US has earmarked $1.15 billion over the next 4 years for long COVID research under the NIH's Researching COVID to Enhance Recovery (RECOVER) program. The RECOVER research program has included queries regarding patient experience throughout its initial rollout. However, patients and patient advocacy groups have been concerned about the slow nature of patient-centered research and the absence of treatment studies of long COVID in research funding.
Public health experts have suggested that the Biden Administration appoint a point person to chair a long COVID task force and create a centralized agency to unify government response, accountability, and to better engage the public.¹¹ They recommend that the NIH launch a unified, open-access platform with a public database listing all funded long COVID projects and a nationwide messaging campaign to encourage patient enrollment in research. The worldwide research attention on long COVID will likely have profound effects on fibromyalgia and CFS, as well as other post-viral syndromes. These public health experts directed the NIH to draw from the experience of investigators in related conditions, such as fibromyalgia, CFS, and post-ICU syndrome and to attain financial support for clinical treatment trials.¹¹
Long COVID and Neuroimmune Mechanisms
Moving forward, how can clinicians account for the characteristic long COVID symptoms of chronic fatigue, widespread pain, and cognitive disturbances in the absence of organ damage? This same question has perplexed researchers in fibromyalgia, CFS, and related medical conditions for years. Many investigators believe that the answer will be found in an understanding of, "How the brain connects within itself and to the body via complex neural, neurohormonal, and neuroimmune axes, one of the final frontiers of science and medicine."⁸
Neuroimmune mechanisms trigger aberrant brain network reorganization.¹² These neuroplastic changes can explain why patients with long COVID syndrome, fibromyalgia, and CFS experience chronic pain when there is no external cause of the pain, feel short of breath when lung function tests are normal, and severely fatigued when muscle function is normal.
Fibromyalgia is the prototype of centralized pain, and most investigators now accept the role of the CNS in fibromyalgia and related conditions.¹³ Imaging in people with fibromyalgia demonstrates reorganization in brain pain pathways and activation of neurochemicals that promote pain transmission, such as glutamate.
Functional and structural changes in the brain's pain matrix fluctuate with pain severity and with effective therapy. Brain imaging studies have also mapped out characteristic patterns of chronic pain rewiring, and such neural signature maps may provide better diagnostic and treatment measures in the near future.¹³ Similar brain network reorganization has been found in people with CFS, depression, cognitive disturbances, and sleep disturbances. In these conditions, there is evidence of chronic low-level CNS inflammation and brain microglial activation.¹²
Brain imaging studies of people with long COVID have demonstrated structural and functional alterations as well, even in mild cases with no obvious neurologic symptoms.¹⁴ People experiencing long COVID with cognitive disturbances, fatigue, apathy, and executive dysfunction have shown evidence of cortical impairment of inhibitory GABAergic neurotransmission.¹⁵ At 3 and 10 months following both mild and severe SARS-CoV-2 infection, a variety of brain structural changes were found, including multiple areas of reduced gray matter volume, reduced blood flow, and reduced white matter volume.¹⁶
Is Long COVID an Autoimmune Disease?
Many investigators have suggested that long COVID is an autoimmune disease. However, people with systemic, autoimmune diseases, such as RA, systemic lupus erythematosus (SLE), and multiple sclerosis (MS), typically have evidence of organ damage, including in the brain in those with SLE and MS (see Table IV). Systemic autoimmune diseases are characterized by high levels of autoantibodies in the blood, and immune deposits with intense inflammation at specific organ sites. Such inflammatory-related organ damage is a hallmark of acute SARS-CoV-2 infection, features of so-called cytokine storm.
These characteristics of systemic autoimmune diseases are not found in long COVID syndrome. There is no organ damage in long COVID syndrome, but rather evidence of organ dysfunction, specifically in the central and peripheral nervous system. Inflammatory markers, such as elevated CRP or D-dimer, are not present in long COVID syndrome and autoantibodies are primarily localized to the central nervous system (see Table II).
| Characteristics | Systemic Autoimmune Disease | Neuroimmune Disease |
|---|---|---|
| Organ damage | Brain, other sites | Dysfunction |
| Autoantibodies | Multiple, targeted | Localized |
| Inflammatory markers | CRP, D-dimer | Not present |
| Disease | SLE, RA, MS Long COVID disease | Fibromyalgia, CFS Long COVID syndrome |
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