What is Long COVID?
Long COVID is a multi-system syndrome characterized by one or more symptoms persisting or relapsing for more than 12 weeks after acute COVID-19 infection, without an alternative explanation, affecting any individual regardless of their initial disease severity. 1
Formal Definition and Diagnostic Criteria
Long COVID is defined as symptoms persisting beyond 12 weeks from acute COVID-19 diagnosis that cannot be explained by another condition. 1 The WHO and CDC provide similar definitions, specifying persistent symptoms lasting at least 2 months and persisting beyond 12 weeks from the acute disease. 1
The syndrome can be classified as:
- Definite: When acute COVID-19 was laboratory-confirmed 1
- Probable: When typical symptoms occurred with negative laboratory results but suggestive epidemiology 1
- Possible: When typical symptoms occurred without laboratory confirmation or epidemiological link 1
A related entity, post-acute COVID, describes symptoms persisting from 4 to 12 weeks after confirmed acute infection, including specific complications like thyroiditis, myocarditis, and venous thromboembolism. 1
Most Common Symptoms and Their Prevalence
The symptom profile is remarkably consistent across multiple systematic reviews and meta-analyses:
Primary symptoms include:
- Fatigue (31-58%) - the most prevalent symptom 1
- Dyspnea/shortness of breath (24-40%) 1
- Cognitive impairment or "brain fog" (12-35%) 1, 2
- Sleep disturbances (11-44%), including insomnia affecting approximately 22% of patients 1, 3
- Musculoskeletal pain (9-19%) 1
- Cough (7-29%) 1
- Anosmia/dysgeusia (10-22%) 1
- Chest pain (6-17%) 1
Importantly, only 22.9% of patients are completely symptom-free at 12 months post-infection. 4 The most frequently reported symptoms at one year include reduced exercise capacity (56.3%), fatigue (53.1%), dyspnea (37.5%), concentration problems (39.6%), word-finding difficulties (32.3%), and sleep problems (26.0%). 4
Impact on Quality of Life and Function
Long COVID substantially impairs quality of life, with 57% of patients reporting decreased quality of life beyond 12 weeks, and 12.5% unable to envision coping with their symptoms long-term. 1, 5 The syndrome considerably affects patients' ability to return to daily activities and work. 1
Patients with at least one long-COVID symptom at 12 months have significantly reduced physical and mental quality of life compared to those without symptoms. 4
Underlying Pathophysiological Mechanisms
The mechanisms driving long COVID remain incompletely understood but involve multiple interconnected pathways:
Primary mechanisms include:
- Viral persistence in tissue reservoirs across various organs, evading immune clearance 1, 6
- Immune dysregulation with cytokine imbalances and T-cell exhaustion 1, 6
- Autoimmunity, with 43.6% of patients showing elevated antinuclear antibody titers (≥1:160) at 12 months, significantly associated with neurocognitive symptoms 4
- Neuroinflammation and neurotropism of SARS-CoV-2 affecting brain regions 1, 6
- Endothelial dysfunction contributing to cardiovascular complications 6
- Metabolic disturbances including mitochondrial dysfunction, leading to impaired energy production and post-exertional malaise 6
- Activation of the kynurenine pathway with metabolites associated with cognitive and sleep disturbances 3
For critically ill patients, post-intensive care syndrome may explain prolonged symptoms, encompassing physical, cognitive, and psychiatric abnormalities after critical illness, making it difficult to distinguish from SARS-CoV-2-specific effects. 1
Risk Factors for Developing Long COVID
The two most consistent risk factors are acute COVID-19 severity and female sex. 1 Women have an estimated two-fold increased risk of developing long-COVID symptoms. 1
Additional risk factors include:
- Older age 7
- Cigarette smoking 7
- Pre-existing medical conditions 7
- Lack of COVID-19 vaccination 7
- Infection with pre-Omicron SARS-CoV-2 variants 7
- Number of acute phase symptoms (more than five early symptoms) 8
- Higher viral load 7
- Invasive mechanical ventilation 7
Evidence for other risk factors like obesity and comorbidities shows mixed results. 1
Clinical Course and Persistence
Long-COVID symptoms can persist for 12 months or longer after acute disease, with some symptoms documented to persist for at least 2 years. 1, 3, 2 The prevalence of certain symptoms, particularly brain fog, increases over time—from 16% at 2 months to 26% at 12 months post-infection. 2
The frequency and burden of symptoms at 12 months correlate with initial disease severity, with patients experiencing moderate or severe acute illness reporting symptoms more frequently (82.6% vs 38.6%) and having an average of 6.8 more symptoms than initially asymptomatic participants. 5
Multi-System Nature and Clustering
Long COVID is not a single clinical entity but rather consists of multiple subcategories with symptoms that tend to cluster. 5 The syndrome affects multiple organ systems including respiratory, cardiovascular, nervous, gastrointestinal, and musculoskeletal systems. 8
Neurological and cardiovascular symptoms frequently cluster together, as do gastrointestinal symptoms, suggesting distinct pathophysiological subtypes. 5 Brain fog commonly co-exists with insomnia, gastrointestinal symptoms, and mood disturbances. 2
Prevalence
The cumulative global prevalence of long COVID ranges between 9% and 63%, up to 6-fold higher than similar post-viral infection conditions. 7 Among cohort study participants, 59.5% reported at least one symptom at 12 months, with a median of 6 symptoms. 5
Clinical Approach
Long COVID is a diagnosis of exclusion. 1 Before considering long COVID, serious or life-threatening conditions must be ruled out, including previously overlooked conditions (e.g., malignancy) or complications of acute COVID-19 (e.g., thromboembolic events, myocarditis, encephalitis). 1
Any patient with persisting or new symptoms lasting more than 12 weeks after acute COVID-19 should be referred to medical care. 1 For patients with symptoms 4 to 12 weeks after acute infection, assessment should be considered case-by-case according to symptom severity and course. 1