Long COVID Part 1: Definition, Pathophysiology, Symptoms, and Root Causes

At a Glance

• Long COVID (post-COVID-19 syndrome):
  
  • is a complex, multisystem syndrome defined by symptoms lasting 3+ months after an acute SARS-CoV-2 infection. [1]
  • represents a constellation of post-acute and long-term health effects that can affect nearly every organ system. [2]
  • may occur in 10–36% of all SARS-CoV-2 infections, depending on the virus variant, with more than 200 symptoms identified across multiple organ systems. [3]
  • is currently estimated to affect 65 million individuals worldwide. [4]
• This article is for patients and clinicians navigating unexplained chronic symptoms after COVID-19, such as persistent fatigue, cognitive impairment ("brain fog"), dysautonomia, digestive dysfunction, and exercise intolerance.
• Six interconnected pathophysiological processes drive Long COVID, which may also contribute to individual pre-COVID-19 predisposition to it. 1. Viral persistence: SARS-CoV-2 parts remaining in tissues long after acute infection. 2. Immune dysregulation: chronic activation and/or exhaustion of immune pathways. 3. Microclot formation: abnormalities of coagulation that impair microcirculation. 4. Endothelial dysfunction: damage to blood vessel linings that disrupts normal vascular regulation. 5. Mitochondrial dysfunction: impaired cellular energy production. 6. Gut dysbiosis: disruption of the intestinal microbiome and barrier integrity. [4, 3, 5] These mechanisms interact with and reinforce each other, creating a self-sustaining cycle of illness that targets multiple organ systems simultaneously. [2] 
• Since PASC is an active area of research, these 6 mechanisms may not be an exhaustive list.
• Identifying individual root causes and predispositions may be the necessary first step toward selecting interventions that resolve the illnesses rather than merely managing individual symptoms.
• The existence of Long COVID as a distinct clinical entity with defined pathophysiological mechanisms is supported by large-scale systematic reviews and multi-cohort studies across international populations. [1,2,3,4]

What Is Long COVID? Defining a Complex, Multisystem Disease

Long COVID, also called post-COVID-19 condition, is generally defined as symptoms persisting for 3 months or more after acute SARS-CoV-2 infection that cannot be explained by an alternative diagnosis. [1] It is a complex, multisystem disorder that can affect nearly every organ system. Researchers have identified more than 200 distinct symptoms with impacts on multiple organ systems. [2,3]

A Global Crisis, Not a Rare Complication

The scale of long COVID is staggering. Approximately 65 million individuals worldwide live with the condition. Acute COVID-19 infection is followed by prolonged symptoms in at least one in ten cases. [4]

Long COVID can occur after mild, moderate, and severe acute infections. The lasting symptoms can be debilitating or mild. Hospitalization is not a prerequisite. An international cohort study (N=3,762) of primarily non-hospitalized patients found that a significant number experienced prolonged, multi-system symptoms lasting 7 months or longer, confirming that outpatient cases carry substantial Long COVID risk. [6,3]

Key Takeaway: Long COVID is not limited to people who were severely ill. Even mild infections can trigger a debilitating, months-long illness affecting dozens of organ systems.

Active Disease, Not Slow Recovery

Long COVID is not simply a prolonged convalescence. It involves ongoing pathological processes, including persistent viral components and chronic immune activation. [7] Many symptoms persist or newly appear after the acute phase, constituting a distinct syndrome rather than a gradual resolution of the original infection. [8]

The illness is often relapsing-remitting in nature. Symptoms fluctuate unpredictably and frequently worsen with physical or cognitive exertion, a hallmark feature known as post-exertional malaise. [3] This pattern distinguishes long COVID from typical post-illness fatigue and places it alongside other complex chronic conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). [9] 

Like ME/CFS, post-infection syndrome is not unique to COVID-19 infections; it can also happen after other infections, including West Nile virus, enteroviruses, and Borrelia. [10] 

If you or a patient is navigating long COVID, understanding the underlying mechanisms is the first step toward targeted intervention. 

This content is for educational purposes and does not constitute medical advice or treatment recommendations.

Signs of COVID That Don't Go Away: The Full Symptom Landscape

Long COVID produces more than 200 documented symptoms across nearly every organ system. [3] Rather than a single illness, it presents as overlapping symptom clusters that vary in severity, duration, and combination from patient to patient. Understanding these clusters is the first step toward identifying the underlying mechanisms driving them.

The Core Symptom Clusters

1. Fatigue and post-exertional malaise (PEM) dominate the clinical picture. A systematic review and meta-analysis of 81 studies (N=12,032) by Ceban et al. identified fatigue and cognitive impairment as the most common persistent symptoms following COVID-19. [11] A separate global modeling study confirmed that persistent fatigue, cognitive, and respiratory symptom clusters account for the largest share of long COVID disability worldwide. [12]

PEM, the hallmark feature shared with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), involves a disproportionate worsening of symptoms after physical or cognitive exertion that can last days or weeks. [13] [STRONG]

2. Cognitive impairment, often called "brain fog," includes memory problems, difficulty concentrating, and slowed processing speed. These deficits persist even in patients whose initial infections were mild. [14] Neurological and psychiatric complications of Long COVID extend well beyond subjective complaints, with documented impairments across multiple cognitive domains. [15] [STRONG]
3. Respiratory and cardiovascular symptoms round out the core cluster. Persistent dyspnea, chest pain, and heart palpitations are frequently reported in follow-up studies. [16,17] These symptoms reflect potential endothelial dysfunction, cardiomyopathy, and autonomic dysregulation that persist long after viral clearance. [18] [MODERATE]

Key Takeaway: Fatigue, cognitive impairment, and cardiorespiratory symptoms form the three most prevalent and disabling long COVID symptom clusters, confirmed across multiple large-scale studies and meta-analyses.

Neurological, Psychiatric, and Autonomic Symptoms

1. Dysautonomia, or dysfunction of the autonomic nervous system, is increasingly recognized in long COVID patients. It manifests as postural orthostatic tachycardia syndrome (POTS), blood pressure instability, temperature dysregulation, and exercise intolerance. [19] These autonomic disturbances can cause variable symptoms ranging from isolated impairment of a single autonomic function to multisystem failure. [19]

Dysautonomia overlaps significantly with fatigue and cognitive symptoms, suggesting shared pathophysiological roots in neuroinflammation and immune dysregulation. [5,20]  [MODERATE]

2. Depression, anxiety, and sleep disruption are common psychiatric consequences. COVID-19 affects the brain, resulting in psychiatric and neurological complications that persist for months or longer. [15] An online survey (N=2,550) of long COVID patients found that these symptoms significantly impair daily functioning and quality of life. [21] These psychiatric symptoms likely reflect underlying neuroinflammation rather than purely psychological responses to chronic illness. [22] [MODERATE]

Gastrointestinal, Hormonal, and Systemic Symptoms

1. Gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, and appetite changes, persist in a significant subset of long COVID patients. [3] These digestive complaints are often linked to gut dysbiosis and persistent viral reservoirs in the gastrointestinal tract. [5,20] [MODERATE]
2. Hormonal imbalances and changes add another layer of complexity. Long COVID is associated with disruption of the hypothalamic-pituitary-adrenal (HPA) axis, which governs the body's stress response, cortisol production, and energy regulation. [23] Multi-organ dysfunction in long COVID extends to endocrine systems, with evidence of altered hormone signaling contributing to fatigue, mood disturbance, and metabolic disruption. [5, 20] [PRELIMINARY]

Key Takeaway: Long COVID is not a single symptom. It is a multisystem condition spanning neurological, psychiatric, gastrointestinal, and endocrine domains, often occurring simultaneously in the same patient.

This content is for educational purposes and does not constitute medical advice, diagnosis, or treatment recommendations.

Long COVID Pathophysiology Explained: The Root Causes

Long COVID is not a single disease. It is the downstream result of several overlapping biological disruptions triggered by SARS-CoV-2 infection. Current research has identified at least six interconnected mechanisms that sustain symptoms long after the acute phase resolves. Since this is an active area of research, it’s possible that they may identify more pathophysiologic contributors in the future.

Persistent Viral Reservoirs

[MODERATE EVIDENCE]

One of the most compelling explanations for long COVID is that the virus never fully clears. SARS-CoV-2 RNA and spike protein have been detected in the gut, brain, and lymph nodes months after acute infection, potentially stimulating continuous immune activation. [7,20,24]

The gut appears to be a particularly important site. Viral antigens detected in intestinal biopsies months post-infection drive systemic inflammation through ongoing immune stimulation. [3,5,24] These tissue reservoirs help explain why symptoms persist in the absence of detectable virus on standard nasal antigen or PCR tests.

Key Takeaway: A negative nasal swab does not mean the virus is completely gone. SARS-CoV-2 can persist in deep tissue compartments for months, continuously provoking the immune system.

Immune Dysregulation and Chronic Inflammation

[STRONG EVIDENCE]

Long COVID is characterized by elevated inflammatory cytokines and T-cell exhaustion, reflecting an immune system stuck in a state of chronic activation. [25,3,26] This is not simply lingering inflammation from the acute phase but a fundamental shift in immune regulation that can persist indefinitely.

A deep multi-omic study by Su et al. (N=309) identified that the presence of specific autoantibodies at the time of initial infection is a quantifiable risk factor for developing persistent symptoms. [27] This finding suggests that SARS-CoV-2 can trigger autoimmune processes, where the immune system begins attacking the body's own tissues, a mechanism that sustains symptoms independently of any remaining virus.

Endothelial Dysfunction

[MODERATE EVIDENCE]

Endothelial dysfunction is a distinct and central pathophysiological driver of both acute and long COVID, extending beyond its role in microclot formation. The endothelium, the single-cell layer lining all blood vessels, regulates vascular tone, immune cell trafficking, and barrier permeability. SARS-CoV-2 directly infects endothelial cells via ACE2 receptors, triggering inflammation of the vessel lining (endotheliitis) that persists long after the acute infection resolves. [23,5,4]

This persistent endothelial injury impairs nitric oxide signaling, the primary mechanism by which blood vessels dilate to match oxygen delivery to tissue demand. [5] The result is a vascular system that cannot properly regulate blood flow, contributing directly to exercise intolerance, cognitive impairment, and the widespread, multi-organ nature of long COVID symptoms. [20]

Damaged endothelium also becomes prothrombotic, creating a permissive environment for the microclot formation described below. [4]

Microclots and Impaired Microcirculation

[MODERATE EVIDENCE]

A growing body of evidence points to the vascular system as a central site of long COVID pathology. Abnormal, breakdown-resistant fibrin amyloid microclots have been identified in longLong COVID patients. These microclots obstruct capillaries and reduce oxygen delivery to tissues, offering a plausible explanation for the fatigue and brain fog that dominate the symptom picture. [7,5,4]

The combination of endothelial dysfunction and microclot formation creates a "double hit" to oxygen delivery: capillaries are physically blocked while the vessels themselves lose the ability to regulate blood flow properly. [4,5]

Key Takeaway: Microclots and endothelial damage work together to starve tissues of oxygen. This vascular "double hit" helps explain why longLong COVID fatigue and brain fog are so resistant to rest alone.

Mitochondrial Dysfunction

[MODERATE EVIDENCE]

At the cellular level, SARS-CoV-2 damages mitochondria, the organelles responsible for producing the energy currency (ATP) that every cell needs. This mitochondrial dysfunction is a key mechanism underlying the profound fatigue and post-exertional malaise that distinguish longLong COVID from ordinary tiredness. [28,5,20]

Critically, this damage is self-reinforcing. Damaged mitochondria release damage-associated molecular patterns (DAMPs) that further stimulate immune activation, creating a vicious cycle where energy failure and inflammation feed each other. [28,7]

Gut Dysbiosis and Microbiome Disruption

[MODERATE EVIDENCE]

SARS-CoV-2 infection significantly disrupts the intestinal microbiome, and this disruption persists well beyond the acute phase. The virus infects enterocytes in the gut lining via ACE2 receptors, causing direct epithelial damage that alters the composition and diversity of gut microbial communities. [5,20]

The resulting dysbiosis, characterized by loss of beneficial commensal bacteria and overgrowth of pathogenic species, compromises intestinal barrier integrity and increases intestinal permeability ("leaky gut"). [3,5]

A permeable intestinal barrier allows bacterial products such as lipopolysaccharide (LPS) and other microbial metabolites to translocate into the bloodstream, fueling systemic inflammation and immune activation. [20,5] This gut-derived inflammation connects directly to the immune dysregulation and neuroinflammation observed in long COVID patients. The gut also serves as a major reservoir for persistent viral antigens. [3,24,29]

Predisposing Factors: Who Gets Long COVID and Why?

Long COVID does not strike randomly. A growing body of research identifies specific biological, environmental, and demographic factors that increase an individual's vulnerability to persistent post-infection symptoms.

Sex, Age, and Biological Demographics

[STRONG EVIDENCE]

Female sex is one of the most consistently identified risk factors for long COVID. A large community-based analysis of 1.2 million individuals (N=1,200,000) across 10 UK longitudinal studies and electronic health records confirmed that women develop long COVID at significantly higher rates than men. [30] A prospective observational study (N=4,182) by Sudre et al. similarly identified female sex as a key predictor of persistent symptoms, along with the number of symptoms experienced during the first week of illness. [31] Global modeling data corroborate this pattern, estimating higher proportions of persistent fatigue, cognitive, and respiratory symptom clusters among females compared to males. [12]

Older age independently increases long COVID risk. The Thompson et al. multi-cohort analysis found older age to be a significant predictor alongside female sex. [30] However, long COVID is not exclusively a disease of the elderly. Younger and middle-aged adults, particularly women of working age, represent a large proportion of affected individuals. [3,23]

Clinical Pearl: The combination of female sex and older age creates a compounding risk profile. Clinicians should maintain a high index of suspicion for long COVID in women over 40 presenting with new-onset fatigue, cognitive complaints, or autonomic symptoms after any severity of SARS-CoV-2 infection.

Severity of Acute COVID-19 Infection

[STRONG EVIDENCE]

The severity of the initial SARS-CoV-2 infection is a correlating risk factor for long COVID. Patients who required hospitalization or intensive care during acute COVID-19 develop persistent symptoms at substantially higher rates than those managed as outpatients. [32,23,9] A UK observational cohort (N=384) by Sykes et al. documented a lasting symptom burden that correlated with acute illness severity. [18]

However, acute COVID severity alone does not determine long COVID risk. Mild and even asymptomatic infections can trigger persistent post-acute sequelae. [3,6] The number of symptoms during the first week of acute illness, rather than hospitalization status alone, is a strong independent predictor of long COVID development. [31] 

Key Takeaway: Hospitalization increases long COVID risk, but a mild acute infection does not protect against it. The breadth of early symptoms matters as much as their severity.

Pre-existing Comorbidities

[STRONG EVIDENCE]

Multiple pre-existing medical conditions elevate long COVID risk. The Thompson et al. analysis (N=1,200,000) identified asthma and high body mass index (BMI) as significant independent risk factors. [30] Type 2 diabetes is another major predisposing condition. The Su et al. multi-omic study (N=309) found that pre-existing Type 2 diabetes, alongside specific autoantibody profiles and high viral load, is among the strongest early biological predictors of post-acute COVID-19 sequelae. [27]

Broader reviews confirm that obesity, cardiovascular disease, respiratory conditions, and mental health disorders all increase the likelihood of developing persistent symptoms. [23,9] These comorbidities share a common thread: they are associated with baseline systemic inflammation, endothelial dysfunction, or immune dysregulation, the same pathways that drive long COVID pathophysiology.

Clinical Pearl: Comorbidities do not simply add risk. They prime the same biological pathways (inflammation, endothelial damage, immune dysregulation) that long COVID exploits. Patients with metabolic syndrome, obesity, or pre-existing autoimmune conditions enter SARS-CoV-2 infection with less physiological reserve to prevent the transition from acute illness to chronic disease.

Smoking

[MODERATE EVIDENCE]

Smoking is an independent risk factor for long COVID. The Thompson et al. multi-cohort analysis identified smoking status as a significant predictor of persistent post-COVID symptoms alongside female sex, older age, and high BMI. [30] Smoking causes chronic endothelial injury, upregulates ACE2 receptor expression in the airways, and maintains a state of low-grade systemic inflammation, all of which overlap directly with the pathophysiological mechanisms that sustain long COVID. [23] Smokers enter SARS-CoV-2 infection with already compromised pulmonary function and vascular health, reducing their capacity to recover fully from the acute insult.

Socioeconomic Factors

[MODERATE EVIDENCE]

Long COVID risk is not distributed equally across populations. Lower socioeconomic status, including reduced access to healthcare, higher occupational exposure risk, crowded living conditions, and greater prevalence of pre-existing comorbidities, contributes to both higher rates of SARS-CoV-2 infection and higher rates of persistent post-infection illness. [3,2] The Thompson et al. analysis found that deprivation indices correlated with long COVID burden in the UK population. [30]

These socioeconomic disparities compound biological risk. Individuals in lower-income settings are more likely to have untreated comorbidities, limited access to early medical intervention during acute infection, and fewer resources for rehabilitation and ongoing care. [2,23]

Key Takeaway: Long COVID risk is shaped by the intersection of biology and circumstance. Female sex, older age, severe acute illness, pre-existing comorbidities, smoking, and socioeconomic disadvantage all converge to determine who develops persistent symptoms and who recovers.

Pre-existing Inflammation and Environmental Triggers

Individuals who enter a SARS-CoV-2 infection with an already elevated inflammatory baseline face a higher risk of developing long COVID. Systemic inflammation from environmental exposures, such as chronic mold exposure, can prime the immune system toward a dysfunctional, hyperactivated response that fails to resolve after the acute infection clears. [3,7] 

A history of chronic or recent viral infections compounds this risk. Pre-existing infectious burden creates a persistent inflammatory milieu that amplifies the immune dysregulation characteristic of long COVID, including T-cell exhaustion and aberrant cytokine signaling. [27,20] 

Pre-existing Dysbiosis and Intestinal Permeability

Individuals with pre-existing gut dysbiosis or compromised intestinal barrier function before SARS-CoV-2 infection face elevated risk for developing long COVID. A disrupted microbiome and increased intestinal permeability prior to infection mean the gut's immune and barrier defenses are already weakened when the virus arrives. [5,20]

Because SARS-CoV-2 directly infects gut epithelial cells, a pre-compromised intestinal lining facilitates greater viral entry, more extensive tissue damage, and a larger persistent viral reservoir in the gastrointestinal tract. [3,24]

Pre-existing leaky gut also means that bacterial translocation and systemic endotoxemia are already occurring before infection, priming the immune system toward the chronic inflammatory state that characterizes long COVID. [5,20] Conditions associated with baseline dysbiosis, including irritable bowel syndrome, inflammatory bowel disease, and chronic antibiotic use,  represent underrecognized predisposing factors for persistent post-COVID illness. 

Clinical Pearl: Patients presenting with long COVID who had pre-existing gastrointestinal complaints or known dysbiosis before their infection warrant particular attention to gut barrier restoration as part of a comprehensive recovery strategy.

Biological Markers During Acute Infection

At the biological level, early markers during acute infection strongly predict who will go on to develop persistent symptoms. The Su et al. deep multi-omic study (N=309) identified four key factors anticipating post-acute COVID-19 sequelae:

• High initial SARS-CoV-2 viral load (RNAemia)
• Reactivation of latent viruses such as Epstein-Barr Virus (EBV)
• Pre-existing Type 2 diabetes
• Specific autoantibody profiles [27,3]

Clinical Pearl: EBV reactivation during acute COVID-19 is one of the strongest early predictors of long COVID. Clinicians evaluating post-COVID patients may consider screening for reactivated herpesviruses as part of a comprehensive workup, as reactivation occurs in nearly 40% of patients with latent herpesviruses. [33]

Reactivation following COVID-19 may also serve as an indicator of systemic immune dysregulation. [34] 

COVID Variant Correlations

[MODERATE EVIDENCE]

The specific SARS-CoV-2 variant responsible for infection also influences long COVID risk. Research estimates that individuals infected during the Omicron wave generally show a lower risk of persistent symptoms compared to those infected with the Delta or Alpha variants. [3,12] This does not mean Omicron infections are benign. Because Omicron infected more cases worldwide, even a lower per-infection risk translates into millions of new long COVID cases. [3]

Understanding these predisposing factors is critical for both clinicians and patients. Risk is not determined by a single variable but by the convergence of sex, age, acute illness severity, pre-existing comorbidities, smoking status, socioeconomic circumstances, environmental exposures, baseline immune status, gut health, biological markers during acute infection, and the viral variant itself.

Study Summary Table

The following table summarizes the key observational and review studies referenced throughout this article. These studies form the evidence base for understanding long COVID pathophysiology, symptom burden, and risk factors. Because long COVID research is primarily descriptive and mechanistic at this stage, none of these studies involve therapeutic interventions, and fields such as dosage and treatment frequency are not applicable.

Key Takeaway: The evidence base for long COVID pathophysiology and symptom characterization is built on large observational cohorts and systematic reviews rather than interventional trials. The largest study (Thompson et al., N=1,200,000) and the most comprehensive meta-analysis (Ceban et al., 81 studies, N=12,032) provide evidence that long COVID is a widespread, multi-system condition with identifiable risk factors. Su et al. stands out for its deep biological profiling approach, linking molecular markers measured during acute infection to later development of persistent symptoms. [27,11,30]

This content is for educational purposes and does not constitute medical advice or treatment recommendations.

Frequently Asked Questions

What is long COVID pathophysiology?

Long COVID pathophysiology involves six interconnected biological mechanisms: persistent viral reservoirs in tissues like the gut and brain, immune dysregulation with chronic inflammation and autoantibody production, endothelial dysfunction impairing blood vessel regulation, fibrin amyloid microclots blocking capillaries, mitochondrial dysfunction reducing cellular energy production, and gut dysbiosis increasing intestinal permeability. These processes interact and reinforce each other, creating a self-sustaining cycle of illness. [3,5,4]

What are the most common long COVID symptoms?

A systematic review and meta-analysis of 81 studies (N=13,232) identified fatigue and cognitive impairment ("brain fog") as the most prevalent persistent symptoms.  [11] Other common symptoms include dyspnea, chest pain, heart palpitations, dysautonomia (including POTS), depression, anxiety, sleep disruption, gastrointestinal complaints, and post-exertional malaise. More than 200 distinct symptoms have been documented across multiple organ systems. [3]

Who is most at risk for long COVID?

The strongest risk factors include female sex, older age, severe acute COVID-19 infection, and pre-existing comorbidities such as asthma, high BMI, and Type 2 diabetes. [30,27] Smoking, lower socioeconomic status, and the number of symptoms during the first week of acute illness are also significant predictors. [31] However, even mild or asymptomatic infections can trigger long COVID. [3]

Can you get long COVID from a mild SARS-CoV-2 infection?

Yes. An international cohort study (N=3,762) of primarily non-hospitalized patients documented prolonged, multi-system symptoms lasting 7 months or longer. [6] While hospitalization increases risk, mild and even asymptomatic SARS-CoV-2 infections can trigger persistent post-acute sequelae. [3]

How many people have long COVID worldwide?

Current estimates place the global burden at approximately 65 million affected individuals. [4] Long COVID occurs in at least 10% of all SARS-CoV-2 infections. [3]

Conclusion

Long COVID is a complex, multisystem disorder affecting an estimated 65 million people worldwide. It is defined by symptoms persisting three months or more after SARS-CoV-2 infection, driven by six interconnected pathophysiological mechanisms: viral persistence, immune dysregulation, endothelial dysfunction, microclot formation, mitochondrial dysfunction, and gut dysbiosis. These processes reinforce each other, creating a self-sustaining cycle of illness that explains why long COVID is so resistant to simple rest or time.

The symptom landscape spans more than 200 documented complaints across neurological, cardiovascular, gastrointestinal, psychiatric, and endocrine systems. Fatigue, cognitive impairment, and cardiorespiratory symptoms form the most prevalent and disabling clusters. Risk factors include female sex, older age, acute illness severity, pre-existing metabolic and inflammatory conditions, smoking, and socioeconomic disadvantage, but even mild infections can trigger the condition.

Understanding these root causes is the essential foundation for any targeted intervention. Without identifying which mechanisms are active in a given patient, treatment remains symptomatic rather than restorative.

This content is for educational purposes and does not constitute medical advice or treatment recommendations.

References: 

1 Greenhalgh, T., Sivan, M., Perlowski, A. and Nikolich, J. Ž. (2024) Long COVID: a clinical update. Lancet, Elsevier BV 404, 707–724

2 Al-Aly, Z., Davis, H., McCorkell, L., Soares, L., Wulf-Hanson, S., Iwasaki, A., et al. (2024) Long COVID science, research and policy. Nat. Med., Springer Science and Business Media LLC 30, 2148–2164

3 Davis, H. E., McCorkell, L., Vogel, J. M. and Topol, E. J. (2023) Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 21, 133–146

4 Turner, S., Khan, M. A., Putrino, D., Woodcock, A., Kell, D. B. and Pretorius, E. (2023) Long COVID: pathophysiological factors and abnormalities of coagulation. Trends Endocrinol. Metab., Elsevier BV 34, 321–344

5 Castanares-Zapatero, D., Chalon, P., Kohn, L., Dauvrin, M., Detollenaere, J., Maertens de Noordhout, C., et al. (2022) Pathophysiology and mechanism of long COVID: a comprehensive review. Ann. Med. 54, 1473–1487

6 Davis, H. E., Assaf, G. S., McCorkell, L., Wei, H., Low, R. J., Re’em, Y., et al. (2021) Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine, Elsevier BV 38, 101019

7 Peluso, M. J. and Deeks, S. G. (2024) Mechanisms of long COVID and the path toward therapeutics. Cell, Elsevier BV 187, 5500–5529

8 Montani, D., Savale, L., Noel, N., Meyrignac, O., Colle, R., Gasnier, M., et al. (2023) Post-COVID-19 syndrome. Bull. Acad. Natl. Med., Elsevier BV 207, 812–820

9 Yong, S. J. (2021) Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect. Dis. (Lond.), Informa UK Limited 53, 737–754

10 CDC. (2025, November 24) About. Chronic Symptoms Following Infections https://www.cdc.gov/chronic-symptoms-following-infections/about/index.html 

11 Ceban, F., Ling, S., Lui, L. M. W., Lee, Y., Gill, H., Teopiz, K. M., et al. (2022) Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav. Immun., Elsevier BV 101, 93–135

12 Global Burden of Disease Long COVID Collaborators, Wulf Hanson, S., Abbafati, C., Aerts, J. G., Al-Aly, Z., Ashbaugh, C., et al. (2022) Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA, American Medical Association (AMA) 328, 1604–1615

13 Arron, H. E., Marsh, B. D., Kell, D. B., Khan, M. A., Jaeger, B. R. and Pretorius, E. (2024) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front. Immunol., Frontiers Media SA 15, 1386607

14 Julide, T., Cigdem, T. and Baris, T. (2024) Cognitive impairment in long-COVID. Ideggyogy. Sz., Ideggyogyaszati Szemle Journal 77, 151–159

15 Zawilska, J. B. and Kuczyńska, K. (2022) Psychiatric and neurological complications of long COVID. J. Psychiatr. Res., Elsevier BV 156, 349–360

16 Aiyegbusi, O. L., Hughes, S. E., Turner, G., Rivera, S. C., McMullan, C., Chandan, J. S., et al. (2021) Symptoms, complications and management of long COVID: a review. J. R. Soc. Med., SAGE Publications 114, 428–442

17 Getzzg. (2022, May 21) Symptoms and signs of long COVID: A rapid review and meta-analysis. JOGH, Journal Of Global Health https://jogh.org/2022/jogh-12-05014/

18 Sykes, D. L., Holdsworth, L., Jawad, N., Gunasekera, P., Morice, A. H. and Crooks, M. G. (2021) Post-COVID-19 symptom burden: What is long-COVID and how should we manage it? Lung, Springer Science and Business Media LLC 199, 113–119

19 Hovaguimian, A. (2023) Dysautonomia: Diagnosis and management. Neurol. Clin., Elsevier BV 41, 193–213

20 Gupta, G., Buonsenso, D., Wood, J., Mohandas, S. and Warburton, D. (2025) Mechanistic insights into Long Covid: Viral persistence, immune dysregulation, and multi-organ dysfunction. Compr. Physiol., Wiley 15, e70019

21 Ziauddeen, N., Gurdasani, D., O’Hara, M. E., Hastie, C., Roderick, P., Yao, G., et al. (2022) Characteristics and impact of Long Covid: Findings from an online survey. PLoS One, Public Library of Science (PLoS) 17, e0264331

22 Koc, H. C., Xiao, J., Liu, W., Li, Y. and Chen, G. (2022) Long COVID and its management. Int. J. Biol. Sci., Ivyspring International Publisher 18, 4768–4780

23 Crook, H., Raza, S., Nowell, J., Young, M. and Edison, P. (2021) Long covid-mechanisms, risk factors, and management. BMJ, BMJ 374, n1648

24 O’Donnell, J. S. and Chappell, K. J. (2021) Chronic SARS-CoV-2, a cause of post-acute COVID-19 sequelae (Long-COVID)? Front. Microbiol., Frontiers Media SA 12, 724654

25 Merad, M., Blish, C. A., Sallusto, F. and Iwasaki, A. (2022) The immunology and immunopathology of COVID-19. Science, Science 375, 1122–1127

26 Altmann, D. M., Whettlock, E. M., Liu, S., Arachchillage, D. J. and Boyton, R. J. (2023) The immunology of long COVID. Nat. Rev. Immunol., Nat Rev Immunol 23, 618–634

27 Su, Y., Yuan, D., Chen, D. G., Ng, R. H., Wang, K., Choi, J., et al. (2022) Multiple early factors anticipate post-acute COVID-19 sequelae. Cell, Elsevier BV 185, 881–895.e20

28 Molnar, T., Lehoczki, A., Fekete, M., Varnai, R., Zavori, L., Erdo-Bonyar, S., et al. (2024) Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches. GeroScience, Springer Science and Business Media LLC 46, 5267–5286

29 Lau, R. I., Su, Q. and Ng, S. C. (2025) Long COVID and gut microbiome: insights into pathogenesis and therapeutics. Gut Microbes, Informa UK Limited 17, 2457495

30 Thompson, E. J., Williams, D. M., Walker, A. J., Mitchell, R. E., Niedzwiedz, C. L., Yang, T. C., et al. (2022) Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat. Commun., Springer Science and Business Media LLC 13, 3528

31 Sudre, C. H., Murray, B., Varsavsky, T., Graham, M. S., Penfold, R. S., Bowyer, R. C., et al. (2021) Attributes and predictors of long COVID. Nat. Med., Springer Science and Business Media LLC 27, 626–631

32 Crook, H., Raza, S., Nowell, J., Young, M. and Edison, P. (2021) Long covid-mechanisms, risk factors, and management. BMJ, BMJ 374, n1648

33 Shafiee, A., Teymouri Athar, M. M., Amini, M. J., Hajishah, H., Siahvoshi, S., Jalali, M., et al. (2023) Reactivation of herpesviruses during COVID-19: A systematic review and meta-analysis. Rev. Med. Virol., John Wiley & Sons, Ltd 33, e2437

34 Chien, M.-H., Wang, J., Lu, K.-C. and Lu, C.-L. (2025) Herpes zoster reactivation following COVID-19 and the risk of renal, infectious, and autoimmune complications: A global propensity-matched cohort study. Biomedicines, MDPI AG 13, 1628