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Long COVID

Complex MONDO:0100233 Post-viral syndrome COVID-19 complications

Long COVID, formally designated as Post-acute Sequelae of SARS-CoV-2 (PASC), is a complex, multisystem condition characterized by persistent symptoms following resolution of acute SARS-CoV-2 infection. The condition can develop following both mild and severe acute illness and affects an estimated 65 million individuals worldwide.

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Mappings
0
Definitions
0
Inheritance
11
Pathophysiology
0
Histopathology
21
Phenotypes
0
Genes
4
Treatments
0
Subtypes
5
Differentials
1
Datasets
1
Trials
⚙

Pathophysiology

11
Viral Persistence
SARS-CoV-2 viral reservoirs may persist in tissues including gut, brain, and other organs for months after acute infection. The gastrointestinal tract has emerged as a particularly significant reservoir site, with viral RNA detected in approximately 30% of intestinal specimens from Long COVID patients.
intestinal epithelial cell link CD8-positive T cell link
Show evidence (1 reference)
PMID:37140960 SUPPORT
"Persistence of SARS-CoV-2 RNA or antigens is reported in some organs, yet the mechanism by which they do so and how they may be associated with pathogenic immune responses is unclear."
Links Long COVID to persistence of SARS-CoV-2 RNA or antigen in tissues and resulting immune responses.
Systemic Immune Activation
Long COVID patients show ongoing systemic inflammation with altered T cell subset distributions and cytokine perturbations, indicating chronic immune activation and dysregulated signaling.
CD4-positive T cell link CD8-positive T cell link
inflammatory response link JAK-STAT signaling link
Show evidence (2 references)
PMID:38212464 SUPPORT
"LC individuals exhibited systemic inflammation and immune dysregulation. This was evidenced by global differences in T cell subset distribution implying ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets."
Demonstrates persistent systemic inflammation and altered immune signaling in Long COVID.
PMID:37748514 SUPPORT
"Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID."
Immune profiling shows broad myeloid/lymphocyte shifts and heightened humoral responses in Long COVID.
T Cell Exhaustion and Tissue Trafficking
SARS-CoV-2-specific CD8+ T cells exhibit exhaustion phenotypes while CD4+ T cells are poised to migrate to inflamed tissues, reflecting sustained antigen exposure and chronic activation in Long COVID.
CD4-positive T cell link CD8-positive T cell link
T cell migration link T cell activation link
Show evidence (1 reference)
PMID:38212464 SUPPORT
"LC individuals displayed increased frequencies of CD4+ T cells poised to migrate to inflamed tissues and exhausted SARS-CoV-2-specific CD8+ T cells"
Documents tissue-trafficking CD4+ cells and exhausted virus-specific CD8+ cells in Long COVID.
Endothelial Dysfunction and Microclots
Persistent endothelial damage and formation of amyloid-like fibrin microclots impair microcirculation. These anomalous fibrin deposits resist normal fibrinolysis and can block capillaries, limiting oxygen delivery to tissues and potentially explaining the diverse symptomatology of Long COVID.
endothelial cell link platelet link
fibrinolysis link
Show evidence (2 references)
PMID:35195253 SUPPORT
"The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies."
Documents the presence and persistence of amyloid fibrin microclots in Long COVID patients.
PMID:35195253 SUPPORT
"the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms"
Explains how microclots may cause Long COVID symptoms through impaired oxygen delivery.
Serotonin Depletion Mechanisms
Long COVID features reduced peripheral serotonin driven by diminished intestinal tryptophan absorption, platelet hyperactivation that depletes stored serotonin, and enhanced monoamine oxidase-mediated serotonin turnover.
tryptophan transport link platelet activation link serotonin metabolic process link
Show evidence (1 reference)
PMID:37848036 SUPPORT
"Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover."
Describes the three mechanistic drivers of serotonin loss in Long COVID.
Vagus-Hippocampal Signaling Impairment
Peripheral serotonin depletion weakens vagus nerve activity, leading to impaired hippocampal responses and memory formation that contribute to cognitive symptoms in Long COVID.
regulation of synaptic plasticity link memory link
Show evidence (1 reference)
PMID:37848036 SUPPORT
"Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory."
Connects serotonin loss to vagal signaling deficits and hippocampal dysfunction.
Autonomic Nervous System Dysfunction
Dysautonomia, particularly postural orthostatic tachycardia syndrome (POTS), develops in many Long COVID patients. This may be related to virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes.
mast cell activation link
Show evidence (2 references)
PMID:33243837 SUPPORT
"We posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes."
Proposes autonomic nervous system disruption as a key mechanism in Long COVID.
PMID:33243837 SUPPORT
"'Post-acute COVID' (known colloquially as 'long COVID') is emerging as a prevalent syndrome. It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
Documents the prevalence of autonomic symptoms in Long COVID.
Impaired Mitochondrial Energy Production
Long COVID is associated with reduced mitochondrial ATP production and impaired oxidative phosphorylation, contributing to fatigue, cognitive disturbances, and exercise intolerance.
oxidative phosphorylation link ATP biosynthetic process link
Show evidence (1 reference)
PMID:38668888 SUPPORT
"Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms."
Links mitochondrial dysfunction and reduced energy production to persistent Long COVID symptoms.
Metabolic Shift and Oxidative Stress
Mitochondrial impairment drives a shift toward glycolysis with associated oxidative stress and metabolic disturbances, further exacerbating systemic symptoms in Long COVID.
glycolytic process link response to oxidative stress link
Show evidence (1 reference)
PMID:38668888 SUPPORT
"This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction."
Describes oxidative stress and metabolic disturbances resulting from mitochondrial dysfunction in Long COVID.
Mast Cell Activation
Mast cell activation syndrome (MCAS) has been implicated in Long COVID pathophysiology. Mast cell degranulation releases pro-inflammatory mediators including histamine, contributing to fatigue, brain fog, cardiovascular symptoms, and gastrointestinal disturbances.
mast cell link
Show evidence (2 references)
PMID:37529714 SUPPORT
"Previous studies have suggested that mast cell activation (MCA) may play a role in the pathophysiology of long-COVID, including in the mechanisms of its cardiovascular manifestations."
Implicates mast cell activation in Long COVID pathophysiology.
PMID:37529714 SUPPORT
"Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms (improved or disappeared) in all treated patients"
Treatment response to antihistamines supports the role of mast cell activation in Long COVID.
Neuroinflammation
Neuroinflammation in Long COVID involves microglial activation, blood-brain barrier disruption, and inflammatory cytokine penetration into the brain parenchyma. This contributes to cognitive dysfunction, memory impairment, and other neurological symptoms.
microglial cell link macrophage link
inflammatory response link
Show evidence (2 references)
PMID:36846556 SUPPORT
"Activation of microglia in response to an immune system challenge can lead to a significant impact on cognitive processes, such as learning, memory and emotional regulation."
Documents microglial activation and its impact on cognitive processes in Long COVID.
PMID:36846556 SUPPORT
"Inflammatory cytokines have been found to play a significant role in reductions in LTP and LTD, a reduction in neurogenesis, and in dendritic sprouting."
Explains how inflammatory cytokines impair neural function in Long COVID brain fog.
●

Phenotypes

21
Cardiovascular(2) Digestive(2) Head and Neck(2) Nervous System(7) Respiratory(3) Constitutional(5)
Cardiovascular 2
Palpitations Palpitations (HP:0001962)
Show evidence (2 references)
PMID:33243837 SUPPORT
"It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
Lists palpitations among the debilitating symptoms of Long COVID.
PMID:37529714 SUPPORT
"Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations."
Confirms palpitations as a cardiovascular manifestation of Long COVID.
Tachycardia Tachycardia (HP:0001649)
Show evidence (1 reference)
PMID:37529714 SUPPORT
"Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations."
Documents high heart rate and postural tachycardia as Long COVID manifestations.
Digestive 2
Diarrhea Diarrhea (HP:0002014)
Show evidence (1 reference)
PMID:34839263 SUPPORT
"curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms"
Gastrointestinal symptoms including diarrhea were among the clinical manifestations mapped in Long COVID.
Nausea Nausea (HP:0002018)
Show evidence (1 reference)
PMID:34839263 SUPPORT
"the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%)"
Nausea was reported across multiple Long COVID cohorts with median prevalence of 3.9%.
Head and Neck 2
Anosmia Anosmia (HP:0000458)
Show evidence (2 references)
PMID:38976065 SUPPORT
"During the acute-phase of COVID-19, 80% of patients reported anosmia, 15% hyposmia, 63% ageusia, and 33% hypogeusia. At two years' follow-up, 53% still experienced smell impairment"
Documents persistent anosmia with 53% still affected at 2-year follow-up.
PMID:38976065 SUPPORT
"Most patients who initially suffered from smell and/or taste disturbance did not reach full recovery after 2 years follow-up."
Demonstrates long-term persistence of olfactory dysfunction in Long COVID.
Ageusia Ageusia (HP:0041051)
Show evidence (1 reference)
PMID:38976065 SUPPORT
"During the acute-phase of COVID-19, 80% of patients reported anosmia, 15% hyposmia, 63% ageusia, and 33% hypogeusia. At two years' follow-up, 53% still experienced smell impairment, and 42% suffered from taste impairment."
Documents persistent ageusia with 42% still affected at 2-year follow-up.
Nervous System 7
Cognitive Impairment Memory impairment (HP:0002354)
Show evidence (2 references)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep"
Documents cognitive problems as a core symptom of Long COVID.
PMID:37848036 SUPPORT
"Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory."
Provides mechanistic explanation for memory impairment in Long COVID.
Headache Headache (HP:0002315)
Show evidence (1 reference)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep"
Lists headaches among the persistent symptoms following COVID-19.
Sleep Disturbance Sleep disturbance (HP:0002360)
Show evidence (1 reference)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep"
Documents disrupted sleep as a symptom that interferes with function.
Anxiety Anxiety (HP:0000739)
Show evidence (2 references)
PMID:38321404 SUPPORT
"The pooled prevalence of depression and anxiety among patients coping with Post COVID-19 syndrome was estimated to be 23% (95% CI: 20%-26%; I2 = 99.9%) based on data from 143 studies with 7,782,124 participants and 132 studies with 9,320,687 participants, respectively."
Meta-analysis establishes 23% prevalence of anxiety in Long COVID patients.
PMID:38231397 SUPPORT
"Patients suffering from post-acute sequelae of COVID-19 (PASC) have a higher prevalence of anxiety and depression than the general population."
Documents higher prevalence of anxiety in PASC patients compared to general population.
Depression Depression (HP:0000716)
Show evidence (2 references)
PMID:38321404 SUPPORT
"The pooled prevalence of depression and anxiety among patients coping with Post COVID-19 syndrome was estimated to be 23% (95% CI: 20%-26%; I2 = 99.9%) based on data from 143 studies with 7,782,124 participants"
Meta-analysis establishes 23% prevalence of depression in Long COVID patients.
PMID:38231397 SUPPORT
"Overall, patients with PASC may have experienced a heavier burden of newly manifest anxiety and depression symptoms compared to patients seen in the GIM clinic."
Documents higher burden of newly manifest depression in Long COVID patients.
Orthostatic Tachycardia Orthostatic tachycardia (HP:0012173)
Show evidence (2 references)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance"
Documents orthostatic intolerance among Long COVID symptoms.
PMID:33243837 SUPPORT
"It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
Documents orthostatic intolerance as a debilitating Long COVID symptom.
Insomnia Insomnia (HP:0100785)
Show evidence (1 reference)
PMID:34839263 SUPPORT
"Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%)"
Insomnia was among the 31 most commonly reported clinical features across Long COVID cohorts.
Respiratory 3
Dyspnea Dyspnea (HP:0002094)
Show evidence (1 reference)
PMID:33243837 SUPPORT
"It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
Lists breathlessness (dyspnea) among the debilitating symptoms of Long COVID.
Cough Cough (HP:0012735)
Show evidence (1 reference)
PMID:34839263 SUPPORT
"curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms"
Systematic review identifying cough among the 287 clinical manifestations mapped to HPO terms in Long COVID.
Pulmonary Opacity Pulmonary opacity (HP:0031457)
Show evidence (1 reference)
PMID:34839263 SUPPORT
"curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms"
Systematic review documenting pulmonary imaging findings including ground glass opacity in Long COVID.
Constitutional 5
Fatigue Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function"
Documents fatigue as a prominent symptom that interferes with function in Long COVID.
Post-exertional Malaise Postexertional symptom exacerbation (HP:0030973)
Show evidence (2 references)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance"
Explicitly identifies post-exertional malaise as a core Long COVID symptom.
PMID:37342500 SUPPORT
"The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)"
Notes the similarity between Long COVID and ME/CFS, which share post-exertional malaise.
Chest Pain Chest pain (HP:0100749)
Show evidence (1 reference)
PMID:33243837 SUPPORT
"It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
Lists chest pain among the debilitating symptoms of Long COVID.
Myalgia Myalgia (HP:0003326)
Show evidence (1 reference)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias"
Lists myalgias as a persistent symptom of Long COVID.
Arthralgia Arthralgia (HP:0002829)
Show evidence (1 reference)
PMID:37342500 SUPPORT
"They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias"
Lists arthralgias as a persistent symptom of Long COVID.
💊

Treatments

4
Pacing and Energy Management
Activity management strategies to avoid post-exertional malaise, similar to approaches used in ME/CFS.
Show evidence (2 references)
PMID:38658496 SUPPORT
"clinical experience has shown that the presence of post-exertional malaise (PEM) is a significant barrier to physical exercise training in people with long COVID."
Documents the importance of addressing PEM through pacing strategies before exercise in Long COVID.
PMID:37342500 SUPPORT
"The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)"
Supports applying ME/CFS management approaches including pacing to Long COVID.
Symptom-directed Pharmacotherapy MAXO:0000058
Medications targeting specific symptoms such as beta-blockers for tachycardia, antihistamines for mast cell activation, and low-dose naltrexone for neuroinflammation.
Show evidence (1 reference)
PMID:37529714 SUPPORT
"Our data confirm that histamine receptors blockade may be an effective target to successfully treat long-COVID."
Demonstrates effectiveness of antihistamine pharmacotherapy for Long COVID symptoms.
Rehabilitation Therapy MAXO:0000011
Physical therapy, occupational therapy, and cognitive rehabilitation tailored to individual tolerance.
Show evidence (3 references)
PMID:38658496 SUPPORT
"impaired exercise performance is a condition that can be recovered in many people through an individualized physical exercise training program."
Documents effectiveness of individualized physical rehabilitation for Long COVID exercise impairment.
PMID:38658496 SUPPORT
"These recommendations may guide allied healthcare professionals worldwide in initiating and adjusting exercise training programs for people with long COVID, stratified according to the presence and severity of PEM."
Provides framework for rehabilitation stratified by PEM severity in Long COVID.
PMID:37061399 SUPPORT
"Rehabilitation is a key element of management to achieve functional improvement... Exercise-based therapy, an essential part of management of long COVID, can be conducted with different modules, including telerehabilitation."
Reviews rehabilitation principles and highlights exercise-based therapy as central to Long COVID management.
Antihistamine Therapy MAXO:0000058
H1 and H2 receptor antagonists (such as fexofenadine and famotidine) to address mast cell activation symptoms.
Show evidence (2 references)
PMID:37529714 SUPPORT
"Patients were treated with fexofenadine (180 mg/day) and famotidine (40 mg/day). Fatigue, brain fog, abdominal disorders, and increased heart rate were evaluated in treated and untreated patients at baseline and 20 days later."
Details the antihistamine treatment protocol used in Long COVID.
PMID:37529714 SUPPORT
"Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms"
Documents significant improvement with antihistamine treatment.
🔬

Biochemical Markers

2
Serotonin Deficiency
Show evidence (1 reference)
PMID:37848036 SUPPORT
"We find that PASC are associated with serotonin reduction."
Directly establishes serotonin reduction as associated with Long COVID.
Elevated Inflammatory Cytokines
Show evidence (1 reference)
PMID:38212464 SUPPORT
"LC individuals exhibited systemic inflammation and immune dysregulation."
Documents systemic inflammation in Long COVID patients.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Long COVID:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome MONDO:0005404
Overlapping Features ME/CFS shares core symptoms with Long COVID, including fatigue, pain, sleep disturbance, and cognitive dysfunction; emerging blood biomarkers can help distinguish these conditions from post-COVID condition.
Distinguishing Features
  • Blood variables including HERV-W ENV, cytokines, and anti-SARS-CoV-2 antibody profiles discriminated post-COVID condition from ME/CFS with high sensitivity and specificity.
  • ME/CFS onset may predate the pandemic or lack confirmed SARS-CoV-2 infection, whereas post-COVID cases follow documented infection.
Show evidence (1 reference)
PMID:40726775 SUPPORT
"some of the measured variables showed a capacity to discriminate post-COVID-19 condition cases from all other participants, with 100 % sensitivity and up to 71.9 % specificity providing a new tool for a differential diagnosis between diseases or syndromes with so many overlapping clinical symptoms."
Demonstrates blood parameter signatures that separate post-COVID condition from ME/CFS despite overlapping symptoms.
Fibromyalgia MONDO:0005546
Overlapping Features Fibromyalgia overlaps with Long COVID on fatigue, pain, sleep disturbance, and cognitive symptoms; biomarker panels can aid differentiation from post-COVID condition.
Distinguishing Features
  • Blood variables including HERV-W ENV, cytokines, and anti-SARS-CoV-2 antibody profiles discriminated post-COVID condition from fibromyalgia with high sensitivity and specificity.
  • Fibromyalgia lacks the post-viral timing linked to confirmed SARS-CoV-2 infection.
Show evidence (1 reference)
PMID:40726775 SUPPORT
"some of the measured variables showed a capacity to discriminate post-COVID-19 condition cases from all other participants, with 100 % sensitivity and up to 71.9 % specificity providing a new tool for a differential diagnosis between diseases or syndromes with so many overlapping clinical symptoms."
Shows biomarker-driven differentiation between post-COVID condition and fibromyalgia.
Narcolepsy Type II Not Yet Curated MONDO:0019371
Overlapping Features Excessive daytime sleepiness after COVID-19 may reflect narcolepsy type II rather than Long COVID; identifying narcolepsy avoids misattribution of hypersomnolence to post-viral fatigue alone.
Distinguishing Features
  • Multiple sleep latency testing with shortened sleep latencies and sleep-onset REM periods indicates narcolepsy.
  • Symptoms can remit with immunomodulatory therapy, differentiating from typical Long COVID fatigue courses.
Show evidence (1 reference)
PMID:39622313 SUPPORT
"A diagnosis of narcolepsy type II was made based on pathologically shortened sleep latencies in polysomnography and multiple sleep latency tests (MSLT) together with several sleep-onset REM-sleep periods (SOREMs)."
Provides diagnostic sleep study criteria distinguishing narcolepsy from Long COVID-related sleepiness.
Post-COVID-19 Vaccination Syndrome
Overlapping Features Mental symptoms such as fatigue, cognitive problems, and sleep disturbance can occur after vaccination without infection, creating overlap with Long COVID symptom profiles.
Distinguishing Features
  • Onset follows vaccination without documented SARS-CoV-2 infection; symptom prevalence varies by dose number and vaccine type.
  • PCVS cases showed similar overall prevalence but different age and vaccination-pattern associations compared with post-infection cases.
Show evidence (1 reference)
PMID:40832032 SUPPORT
"The prevalence of self-reported mental symptoms of PCS was 12.1%... The prevalence of self-reported PCVS was 12.6% among vaccinated individuals"
Shows overlapping mental symptom prevalence after vaccination alone, underscoring the need to distinguish PCVS from infection-related Long COVID.
Persistent SARS-CoV-2 Infection in Immunocompromised Hosts Not Yet Curated MONDO:0100096
Overlapping Features In immunocompromised patients, prolonged fever or symptoms may reflect persistent SARS-CoV-2 infection rather than post-acute sequelae, and should be ruled out before labeling Long COVID.
Distinguishing Features
  • Fever of unknown origin with B-cell depletion or other immunosuppression warrants direct viral testing for ongoing infection.
  • Persistent viral shedding may present without classic acute symptoms but resolves with targeted infection management.
Show evidence (1 reference)
PMID:41384162 SUPPORT
"We report two cases of long-lasting fever in patients with multiple sclerosis and B-cell depletion, finally diagnosed as COVID-19. We suggest the inclusion of SARS-CoV-2 testing in the differential diagnosis of FUO."
Illustrates how persistent infection can mimic post-COVID presentations in immunocompromised patients and must be excluded.
📊

Related Datasets

1
Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients geo:GSE270045
GEO bulk transcriptomic dataset paired with immune and hormonal profiling in long COVID patients meeting ME/CFS criteria, highlighting sex-specific dysregulation.
human BULK RNA SEQ GEO
Conditions: Long COVID with ME/CFS
PMID:41205594
Dataset record: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE270045
Show evidence (1 reference)
PMID:41205594 SUPPORT
"Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS."
Links the dataset to sex-specific transcriptomic and immune profiling in long COVID with ME/CFS.
🔬

Clinical Trials

1
NCT06452082 NOT_APPLICABLE RECRUITING
Retrospective observational study evaluating the effect of vitamin D3 supplementation in reducing the risk of developing Long COVID syndrome after acute COVID-19 illness and in reducing the risk of SARS-CoV-2 infection after vaccination.
Target Phenotypes: Fatigue ↗
Show evidence (1 reference)
clinicaltrials:NCT06452082 SUPPORT
"The aim of this observational retrospective study is to evaluate the effect of supplementation with cholecalciferol D3 in reducing the risk of occurence of Long COVID syndrome after acute COVID-19 illness"
This trial directly investigates interventions to prevent Long COVID development, providing clinical evidence for potential preventive strategies in post-viral syndrome management.
{ }

Source YAML

click to show 
name: Long COVID
creation_date: '2026-01-12T22:00:21Z'
updated_date: '2026-01-20T23:58:45Z'
category: Complex
description: >
  Long COVID, formally designated as Post-acute Sequelae of SARS-CoV-2 (PASC),
  is a complex, multisystem condition characterized by persistent symptoms following
  resolution of acute SARS-CoV-2 infection. The condition can develop following both
  mild and severe acute illness and affects an estimated 65 million individuals worldwide.
disease_term:
  preferred_term: Long COVID
  term:
    id: MONDO:0100233
    label: long COVID-19
parents:
- Post-viral syndrome
- COVID-19 complications
pathophysiology:
- name: Viral Persistence
  description: >
    SARS-CoV-2 viral reservoirs may persist in tissues including gut, brain,
    and other organs for months after acute infection. The gastrointestinal tract
    has emerged as a particularly significant reservoir site, with viral RNA detected
    in approximately 30% of intestinal specimens from Long COVID patients.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: CD8-positive T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:37140960
    supports: SUPPORT
    snippet: "Persistence of SARS-CoV-2 RNA or antigens is reported in some organs, yet the mechanism by which they do so and how they may be associated with pathogenic immune responses is unclear."
    explanation: Links Long COVID to persistence of SARS-CoV-2 RNA or antigen in tissues and resulting immune responses.
- name: Systemic Immune Activation
  description: >
    Long COVID patients show ongoing systemic inflammation with altered T cell
    subset distributions and cytokine perturbations, indicating chronic immune
    activation and dysregulated signaling.
  cell_types:
  - preferred_term: CD4-positive T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  evidence:
  - reference: PMID:38212464
    supports: SUPPORT
    snippet: "LC individuals exhibited systemic inflammation and immune dysregulation. This was evidenced by global differences in T cell subset distribution implying ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets."
    explanation: Demonstrates persistent systemic inflammation and altered immune signaling in Long COVID.
  - reference: PMID:37748514
    supports: SUPPORT
    snippet: "Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID."
    explanation: Immune profiling shows broad myeloid/lymphocyte shifts and heightened humoral responses in Long COVID.
- name: T Cell Exhaustion and Tissue Trafficking
  description: >
    SARS-CoV-2-specific CD8+ T cells exhibit exhaustion phenotypes while CD4+ T
    cells are poised to migrate to inflamed tissues, reflecting sustained antigen
    exposure and chronic activation in Long COVID.
  cell_types:
  - preferred_term: CD4-positive T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell migration
    term:
      id: GO:0072678
      label: T cell migration
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
  evidence:
  - reference: PMID:38212464
    supports: SUPPORT
    snippet: "LC individuals displayed increased frequencies of CD4+ T cells poised to migrate to inflamed tissues and exhausted SARS-CoV-2-specific CD8+ T cells"
    explanation: Documents tissue-trafficking CD4+ cells and exhausted virus-specific CD8+ cells in Long COVID.
- name: Endothelial Dysfunction and Microclots
  description: >
    Persistent endothelial damage and formation of amyloid-like fibrin microclots
    impair microcirculation. These anomalous fibrin deposits resist normal fibrinolysis
    and can block capillaries, limiting oxygen delivery to tissues and potentially
    explaining the diverse symptomatology of Long COVID.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: fibrinolysis
    term:
      id: GO:0042730
      label: fibrinolysis
  evidence:
  - reference: PMID:35195253
    supports: SUPPORT
    snippet: "The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies."
    explanation: Documents the presence and persistence of amyloid fibrin microclots in Long COVID patients.
  - reference: PMID:35195253
    supports: SUPPORT
    snippet: "the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms"
    explanation: Explains how microclots may cause Long COVID symptoms through impaired oxygen delivery.
- name: Serotonin Depletion Mechanisms
  description: >
    Long COVID features reduced peripheral serotonin driven by diminished
    intestinal tryptophan absorption, platelet hyperactivation that depletes
    stored serotonin, and enhanced monoamine oxidase-mediated serotonin
    turnover.
  biological_processes:
  - preferred_term: tryptophan transport
    term:
      id: GO:0015827
      label: tryptophan transport
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
  - preferred_term: serotonin metabolic process
    term:
      id: GO:0042427
      label: serotonin metabolic process
  evidence:
  - reference: PMID:37848036
    supports: SUPPORT
    snippet: "Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover."
    explanation: Describes the three mechanistic drivers of serotonin loss in Long COVID.
- name: Vagus-Hippocampal Signaling Impairment
  description: >
    Peripheral serotonin depletion weakens vagus nerve activity, leading to
    impaired hippocampal responses and memory formation that contribute to
    cognitive symptoms in Long COVID.
  biological_processes:
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
  - preferred_term: memory
    term:
      id: GO:0007613
      label: memory
  evidence:
  - reference: PMID:37848036
    supports: SUPPORT
    snippet: "Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory."
    explanation: Connects serotonin loss to vagal signaling deficits and hippocampal dysfunction.
- name: Autonomic Nervous System Dysfunction
  description: >
    Dysautonomia, particularly postural orthostatic tachycardia syndrome (POTS),
    develops in many Long COVID patients. This may be related to virus- or
    immune-mediated disruption of the autonomic nervous system resulting in
    orthostatic intolerance syndromes.
  biological_processes:
  - preferred_term: mast cell activation
    term:
      id: GO:0045576
      label: mast cell activation
  evidence:
  - reference: PMID:33243837
    supports: SUPPORT
    snippet: "We posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes."
    explanation: Proposes autonomic nervous system disruption as a key mechanism in Long COVID.
  - reference: PMID:33243837
    supports: SUPPORT
    snippet: "'Post-acute COVID' (known colloquially as 'long COVID') is emerging as a prevalent syndrome. It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
    explanation: Documents the prevalence of autonomic symptoms in Long COVID.
- name: Impaired Mitochondrial Energy Production
  description: >
    Long COVID is associated with reduced mitochondrial ATP production and
    impaired oxidative phosphorylation, contributing to fatigue, cognitive
    disturbances, and exercise intolerance.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: ATP biosynthetic process
    term:
      id: GO:0006754
      label: ATP biosynthetic process
  evidence:
  - reference: PMID:38668888
    supports: SUPPORT
    snippet: "Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms."
    explanation: Links mitochondrial dysfunction and reduced energy production to persistent Long COVID symptoms.
- name: Metabolic Shift and Oxidative Stress
  description: >
    Mitochondrial impairment drives a shift toward glycolysis with associated
    oxidative stress and metabolic disturbances, further exacerbating systemic
    symptoms in Long COVID.
  biological_processes:
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:38668888
    supports: SUPPORT
    snippet: "This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction."
    explanation: Describes oxidative stress and metabolic disturbances resulting from mitochondrial dysfunction in Long COVID.
- name: Mast Cell Activation
  description: >
    Mast cell activation syndrome (MCAS) has been implicated in Long COVID
    pathophysiology. Mast cell degranulation releases pro-inflammatory mediators
    including histamine, contributing to fatigue, brain fog, cardiovascular
    symptoms, and gastrointestinal disturbances.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  evidence:
  - reference: PMID:37529714
    supports: SUPPORT
    snippet: "Previous studies have suggested that mast cell activation (MCA) may play a role in the pathophysiology of long-COVID, including in the mechanisms of its cardiovascular manifestations."
    explanation: Implicates mast cell activation in Long COVID pathophysiology.
  - reference: PMID:37529714
    supports: SUPPORT
    snippet: "Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms (improved or disappeared) in all treated patients"
    explanation: Treatment response to antihistamines supports the role of mast cell activation in Long COVID.
- name: Neuroinflammation
  description: >
    Neuroinflammation in Long COVID involves microglial activation, blood-brain
    barrier disruption, and inflammatory cytokine penetration into the brain
    parenchyma. This contributes to cognitive dysfunction, memory impairment,
    and other neurological symptoms.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:36846556
    supports: SUPPORT
    snippet: "Activation of microglia in response to an immune system challenge can lead to a significant impact on cognitive processes, such as learning, memory and emotional regulation."
    explanation: Documents microglial activation and its impact on cognitive processes in Long COVID.
  - reference: PMID:36846556
    supports: SUPPORT
    snippet: "Inflammatory cytokines have been found to play a significant role in reductions in LTP and LTD, a reduction in neurogenesis, and in dendritic sprouting."
    explanation: Explains how inflammatory cytokines impair neural function in Long COVID brain fog.
differential_diagnoses:
- name: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
  description: >
    ME/CFS shares core symptoms with Long COVID, including fatigue, pain,
    sleep disturbance, and cognitive dysfunction; emerging blood biomarkers
    can help distinguish these conditions from post-COVID condition.
  distinguishing_features:
  - Blood variables including HERV-W ENV, cytokines, and anti-SARS-CoV-2 antibody profiles discriminated post-COVID condition from ME/CFS with high sensitivity and specificity.
  - ME/CFS onset may predate the pandemic or lack confirmed SARS-CoV-2 infection, whereas post-COVID cases follow documented infection.
  disease_term:
    preferred_term: Myalgic encephalomyelitis/chronic fatigue syndrome
    term:
      id: MONDO:0005404
      label: myalgic encephalomeyelitis/chronic fatigue syndrome
  evidence:
  - reference: PMID:40726775
    supports: SUPPORT
    snippet: "some of the measured variables showed a capacity to discriminate post-COVID-19 condition cases from all other participants, with 100 % sensitivity and up to 71.9 % specificity providing a new tool for a differential diagnosis between diseases or syndromes with so many overlapping clinical symptoms."
    explanation: Demonstrates blood parameter signatures that separate post-COVID condition from ME/CFS despite overlapping symptoms.
- name: Fibromyalgia
  description: >
    Fibromyalgia overlaps with Long COVID on fatigue, pain, sleep disturbance,
    and cognitive symptoms; biomarker panels can aid differentiation from
    post-COVID condition.
  distinguishing_features:
  - Blood variables including HERV-W ENV, cytokines, and anti-SARS-CoV-2 antibody profiles discriminated post-COVID condition from fibromyalgia with high sensitivity and specificity.
  - Fibromyalgia lacks the post-viral timing linked to confirmed SARS-CoV-2 infection.
  disease_term:
    preferred_term: Fibromyalgia
    term:
      id: MONDO:0005546
      label: fibromyalgia
  evidence:
  - reference: PMID:40726775
    supports: SUPPORT
    snippet: "some of the measured variables showed a capacity to discriminate post-COVID-19 condition cases from all other participants, with 100 % sensitivity and up to 71.9 % specificity providing a new tool for a differential diagnosis between diseases or syndromes with so many overlapping clinical symptoms."
    explanation: Shows biomarker-driven differentiation between post-COVID condition and fibromyalgia.
- name: Narcolepsy Type II
  description: >
    Excessive daytime sleepiness after COVID-19 may reflect narcolepsy type II
    rather than Long COVID; identifying narcolepsy avoids misattribution of
    hypersomnolence to post-viral fatigue alone.
  distinguishing_features:
  - Multiple sleep latency testing with shortened sleep latencies and sleep-onset REM periods indicates narcolepsy.
  - Symptoms can remit with immunomodulatory therapy, differentiating from typical Long COVID fatigue courses.
  disease_term:
    preferred_term: narcolepsy without cataplexy
    term:
      id: MONDO:0019371
      label: narcolepsy without cataplexy
  evidence:
  - reference: PMID:39622313
    supports: SUPPORT
    snippet: "A diagnosis of narcolepsy type II was made based on pathologically shortened sleep latencies in polysomnography and multiple sleep latency tests (MSLT) together with several sleep-onset REM-sleep periods (SOREMs)."
    explanation: Provides diagnostic sleep study criteria distinguishing narcolepsy from Long COVID-related sleepiness.
- name: Post-COVID-19 Vaccination Syndrome
  description: >
    Mental symptoms such as fatigue, cognitive problems, and sleep disturbance
    can occur after vaccination without infection, creating overlap with Long
    COVID symptom profiles.
  distinguishing_features:
  - Onset follows vaccination without documented SARS-CoV-2 infection; symptom prevalence varies by dose number and vaccine type.
  - PCVS cases showed similar overall prevalence but different age and vaccination-pattern associations compared with post-infection cases.
  evidence:
  - reference: PMID:40832032
    supports: SUPPORT
    snippet: "The prevalence of self-reported mental symptoms of PCS was 12.1%... The prevalence of self-reported PCVS was 12.6% among vaccinated individuals"
    explanation: Shows overlapping mental symptom prevalence after vaccination alone, underscoring the need to distinguish PCVS from infection-related Long COVID.
- name: Persistent SARS-CoV-2 Infection in Immunocompromised Hosts
  description: >
    In immunocompromised patients, prolonged fever or symptoms may reflect
    persistent SARS-CoV-2 infection rather than post-acute sequelae, and should
    be ruled out before labeling Long COVID.
  distinguishing_features:
  - Fever of unknown origin with B-cell depletion or other immunosuppression warrants direct viral testing for ongoing infection.
  - Persistent viral shedding may present without classic acute symptoms but resolves with targeted infection management.
  disease_term:
    preferred_term: COVID-19
    term:
      id: MONDO:0100096
      label: COVID-19
  evidence:
  - reference: PMID:41384162
    supports: SUPPORT
    snippet: "We report two cases of long-lasting fever in patients with multiple sclerosis and B-cell depletion, finally diagnosed as COVID-19. We suggest the inclusion of SARS-CoV-2 testing in the differential diagnosis of FUO."
    explanation: Illustrates how persistent infection can mimic post-COVID presentations in immunocompromised patients and must be excluded.
phenotypes:
- name: Fatigue
  description: Persistent, debilitating fatigue that is not relieved by rest.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function"
    explanation: Documents fatigue as a prominent symptom that interferes with function in Long COVID.
- name: Cognitive Impairment
  description: >
    Brain fog, difficulty concentrating, memory problems, and reduced
    executive function. Often referred to as cognitive dysfunction.
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep"
    explanation: Documents cognitive problems as a core symptom of Long COVID.
  - reference: PMID:37848036
    supports: SUPPORT
    snippet: "Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory."
    explanation: Provides mechanistic explanation for memory impairment in Long COVID.
- name: Dyspnea
  description: Shortness of breath and breathing difficulties persisting after acute infection.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:33243837
    supports: SUPPORT
    snippet: "It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
    explanation: Lists breathlessness (dyspnea) among the debilitating symptoms of Long COVID.
- name: Post-exertional Malaise
  description: >
    Worsening of symptoms following physical or mental exertion,
    similar to myalgic encephalomyelitis/chronic fatigue syndrome.
  phenotype_term:
    preferred_term: Post-exertional malaise
    term:
      id: HP:0030973
      label: Postexertional symptom exacerbation
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance"
    explanation: Explicitly identifies post-exertional malaise as a core Long COVID symptom.
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)"
    explanation: Notes the similarity between Long COVID and ME/CFS, which share post-exertional malaise.
- name: Palpitations
  description: Awareness of heartbeat, often associated with POTS or general autonomic dysfunction.
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
  evidence:
  - reference: PMID:33243837
    supports: SUPPORT
    snippet: "It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
    explanation: Lists palpitations among the debilitating symptoms of Long COVID.
  - reference: PMID:37529714
    supports: SUPPORT
    snippet: "Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations."
    explanation: Confirms palpitations as a cardiovascular manifestation of Long COVID.
- name: Tachycardia
  description: Elevated heart rate, often associated with POTS or general autonomic dysfunction.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
  evidence:
  - reference: PMID:37529714
    supports: SUPPORT
    snippet: "Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations."
    explanation: Documents high heart rate and postural tachycardia as Long COVID manifestations.
- name: Chest Pain
  description: Persistent chest discomfort or pain.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:33243837
    supports: SUPPORT
    snippet: "It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
    explanation: Lists chest pain among the debilitating symptoms of Long COVID.
- name: Headache
  description: Chronic or recurring headaches.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep"
    explanation: Lists headaches among the persistent symptoms following COVID-19.
- name: Sleep Disturbance
  description: Insomnia, unrefreshing sleep, or altered sleep patterns.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep"
    explanation: Documents disrupted sleep as a symptom that interferes with function.
- name: Anxiety
  description: Increased anxiety levels and panic symptoms.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:38321404
    supports: SUPPORT
    snippet: "The pooled prevalence of depression and anxiety among patients coping with Post COVID-19 syndrome was estimated to be 23% (95% CI: 20%-26%; I2 = 99.9%) based on data from 143 studies with 7,782,124 participants and 132 studies with 9,320,687 participants, respectively."
    explanation: Meta-analysis establishes 23% prevalence of anxiety in Long COVID patients.
  - reference: PMID:38231397
    supports: SUPPORT
    snippet: "Patients suffering from post-acute sequelae of COVID-19 (PASC) have a higher prevalence of anxiety and depression than the general population."
    explanation: Documents higher prevalence of anxiety in PASC patients compared to general population.
- name: Depression
  description: Depressed mood and emotional dysregulation.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:38321404
    supports: SUPPORT
    snippet: "The pooled prevalence of depression and anxiety among patients coping with Post COVID-19 syndrome was estimated to be 23% (95% CI: 20%-26%; I2 = 99.9%) based on data from 143 studies with 7,782,124 participants"
    explanation: Meta-analysis establishes 23% prevalence of depression in Long COVID patients.
  - reference: PMID:38231397
    supports: SUPPORT
    snippet: "Overall, patients with PASC may have experienced a heavier burden of newly manifest anxiety and depression symptoms compared to patients seen in the GIM clinic."
    explanation: Documents higher burden of newly manifest depression in Long COVID patients.
- name: Anosmia
  description: Loss or alteration of sense of smell persisting beyond acute infection.
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: PMID:38976065
    supports: SUPPORT
    snippet: "During the acute-phase of COVID-19, 80% of patients reported anosmia, 15% hyposmia, 63% ageusia, and 33% hypogeusia. At two years' follow-up, 53% still experienced smell impairment"
    explanation: Documents persistent anosmia with 53% still affected at 2-year follow-up.
  - reference: PMID:38976065
    supports: SUPPORT
    snippet: "Most patients who initially suffered from smell and/or taste disturbance did not reach full recovery after 2 years follow-up."
    explanation: Demonstrates long-term persistence of olfactory dysfunction in Long COVID.
- name: Ageusia
  description: Loss or alteration of sense of taste.
  phenotype_term:
    preferred_term: Ageusia
    term:
      id: HP:0041051
      label: Ageusia
  evidence:
  - reference: PMID:38976065
    supports: SUPPORT
    snippet: "During the acute-phase of COVID-19, 80% of patients reported anosmia, 15% hyposmia, 63% ageusia, and 33% hypogeusia. At two years' follow-up, 53% still experienced smell impairment, and 42% suffered from taste impairment."
    explanation: Documents persistent ageusia with 42% still affected at 2-year follow-up.
- name: Myalgia
  description: Muscle pain and body aches.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias"
    explanation: Lists myalgias as a persistent symptom of Long COVID.
- name: Arthralgia
  description: Joint pain without inflammation.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias"
    explanation: Lists arthralgias as a persistent symptom of Long COVID.
- name: Orthostatic Tachycardia
  description: Excessive heart rate increase upon standing, characteristic of POTS.
  phenotype_term:
    preferred_term: Orthostatic tachycardia
    term:
      id: HP:0012173
      label: Orthostatic tachycardia
  evidence:
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance"
    explanation: Documents orthostatic intolerance among Long COVID symptoms.
  - reference: PMID:33243837
    supports: SUPPORT
    snippet: "It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance)"
    explanation: Documents orthostatic intolerance as a debilitating Long COVID symptom.
- name: Cough
  description: Persistent cough continuing beyond acute infection.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:34839263
    supports: SUPPORT
    snippet: "curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms"
    explanation: Systematic review identifying cough among the 287 clinical manifestations mapped to HPO terms in Long COVID.
- name: Pulmonary Opacity
  description: Ground glass opacification or other pulmonary imaging abnormalities persisting after acute infection.
  phenotype_term:
    preferred_term: Pulmonary opacity
    term:
      id: HP:0031457
      label: Pulmonary opacity
  evidence:
  - reference: PMID:34839263
    supports: SUPPORT
    snippet: "curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms"
    explanation: Systematic review documenting pulmonary imaging findings including ground glass opacity in Long COVID.
- name: Insomnia
  description: Difficulty falling asleep or staying asleep.
  phenotype_term:
    preferred_term: Insomnia
    term:
      id: HP:0100785
      label: Insomnia
  evidence:
  - reference: PMID:34839263
    supports: SUPPORT
    snippet: "Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%)"
    explanation: Insomnia was among the 31 most commonly reported clinical features across Long COVID cohorts.
- name: Diarrhea
  description: Loose or watery bowel movements persisting after acute infection.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:34839263
    supports: SUPPORT
    snippet: "curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms"
    explanation: Gastrointestinal symptoms including diarrhea were among the clinical manifestations mapped in Long COVID.
- name: Nausea
  description: Sensation of unease in the stomach with urge to vomit.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: PMID:34839263
    supports: SUPPORT
    snippet: "the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%)"
    explanation: Nausea was reported across multiple Long COVID cohorts with median prevalence of 3.9%.
biochemical:
- name: Serotonin Deficiency
  notes: >
    Reduced peripheral serotonin levels due to decreased tryptophan absorption,
    platelet hyperactivation, and increased MAO-mediated turnover.
  evidence:
  - reference: PMID:37848036
    supports: SUPPORT
    snippet: "We find that PASC are associated with serotonin reduction."
    explanation: Directly establishes serotonin reduction as associated with Long COVID.
- name: Elevated Inflammatory Cytokines
  notes: >
    Persistently elevated pro-inflammatory cytokines including IL-6, TNF-alpha,
    and type I interferons contribute to systemic inflammation.
  evidence:
  - reference: PMID:38212464
    supports: SUPPORT
    snippet: "LC individuals exhibited systemic inflammation and immune dysregulation."
    explanation: Documents systemic inflammation in Long COVID patients.
treatments:
- name: Pacing and Energy Management
  description: >
    Activity management strategies to avoid post-exertional malaise,
    similar to approaches used in ME/CFS.
  evidence:
  - reference: PMID:38658496
    supports: SUPPORT
    snippet: "clinical experience has shown that the presence of post-exertional malaise (PEM) is a significant barrier to physical exercise training in people with long COVID."
    explanation: Documents the importance of addressing PEM through pacing strategies before exercise in Long COVID.
  - reference: PMID:37342500
    supports: SUPPORT
    snippet: "The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)"
    explanation: Supports applying ME/CFS management approaches including pacing to Long COVID.
- name: Symptom-directed Pharmacotherapy
  description: >
    Medications targeting specific symptoms such as beta-blockers for
    tachycardia, antihistamines for mast cell activation, and low-dose
    naltrexone for neuroinflammation.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:37529714
    supports: SUPPORT
    snippet: "Our data confirm that histamine receptors blockade may be an effective target to successfully treat long-COVID."
    explanation: Demonstrates effectiveness of antihistamine pharmacotherapy for Long COVID symptoms.
- name: Rehabilitation Therapy
  description: >
    Physical therapy, occupational therapy, and cognitive
    rehabilitation tailored to individual tolerance.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:38658496
    supports: SUPPORT
    snippet: "impaired exercise performance is a condition that can be recovered in many people through an individualized physical exercise training program."
    explanation: Documents effectiveness of individualized physical rehabilitation for Long COVID exercise impairment.
  - reference: PMID:38658496
    supports: SUPPORT
    snippet: "These recommendations may guide allied healthcare professionals worldwide in initiating and adjusting exercise training programs for people with long COVID, stratified according to the presence and severity of PEM."
    explanation: Provides framework for rehabilitation stratified by PEM severity in Long COVID.
  - reference: PMID:37061399
    supports: SUPPORT
    snippet: "Rehabilitation is a key element of management to achieve functional improvement... Exercise-based therapy, an essential part of management of long COVID, can be conducted with different modules, including telerehabilitation."
    explanation: Reviews rehabilitation principles and highlights exercise-based therapy as central to Long COVID management.
- name: Antihistamine Therapy
  description: >
    H1 and H2 receptor antagonists (such as fexofenadine and famotidine)
    to address mast cell activation symptoms.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:37529714
    supports: SUPPORT
    snippet: "Patients were treated with fexofenadine (180 mg/day) and famotidine (40 mg/day). Fatigue, brain fog, abdominal disorders, and increased heart rate were evaluated in treated and untreated patients at baseline and 20 days later."
    explanation: Details the antihistamine treatment protocol used in Long COVID.
  - reference: PMID:37529714
    supports: SUPPORT
    snippet: "Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms"
    explanation: Documents significant improvement with antihistamine treatment.
notes: >
  Long COVID shares substantial clinical and biological overlap with myalgic
  encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic
  tachycardia syndrome (POTS). Risk factors for developing Long COVID include
  female sex, type 2 diabetes, pre-existing autoimmune conditions, and evidence
  of EBV reactivation during acute infection. The condition can occur following
  both mild and severe acute illness and may present as a relapsing-remitting
  course with new symptoms emerging months to years after initial infection.
datasets:
- accession: geo:GSE270045
  title: Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients
  description: >
    GEO bulk transcriptomic dataset paired with immune and hormonal profiling
    in long COVID patients meeting ME/CFS criteria, highlighting sex-specific
    dysregulation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  conditions:
  - Long COVID with ME/CFS
  platform: GEO
  publication: PMID:41205594
  evidence:
  - reference: PMID:41205594
    supports: SUPPORT
    snippet: "Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS."
    explanation: Links the dataset to sex-specific transcriptomic and immune profiling in long COVID with ME/CFS.
  notes: "Dataset record: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE270045"
clinical_trials:
- name: NCT06452082
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Retrospective observational study evaluating the effect of vitamin D3 supplementation in reducing the risk of developing Long COVID syndrome after acute COVID-19 illness and in reducing the risk of SARS-CoV-2 infection after vaccination.
  target_phenotypes:
  - preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: clinicaltrials:NCT06452082
    supports: SUPPORT
    snippet: "The aim of this observational retrospective study is to evaluate the effect of supplementation with cholecalciferol D3 in reducing the risk of occurence of Long COVID syndrome after acute COVID-19 illness"
    explanation: This trial directly investigates interventions to prevent Long COVID development, providing clinical evidence for potential preventive strategies in post-viral syndrome management.