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Table 2.

Pathophysiological mechanisms identified in patients with long COVID symptoms.

SystemInvolved symptom(s)Mechanisms
Neurology

  • Cognitive and mental health disorders

  • Pain

  • Headache

  • Fatigue

  • Anosmia/Agueusia

  • Neuropathy

Functional brain disturbances

  • Hypometabolic activity in various cerebral zones

  • Reduced activity of the GABA inhibition


Neuro-inflammation and brain microstructural modifications

  • Micro-structural, volumetric and vascularization disorders

Smell and tasteAnosmia/AgueusiaStructural lesions in the olfactory and taste system at imaging and histology

  • Injury in olfactory neuronal pathways

  • Persistent inflammation of the neuroepithelium and with SARS-CoV-2 RNA identification

  • Invasion and replication of SARS-CoV-2 in taste buds type II cells

Cardiovascular system

  • Fatigue

  • Dyspnoea

  • Chest pain

Persistent vascular inflammation

  • Macrovascular vascular inflammation

  • Microvascular inflammation: increased level of cytokines, circulating endothelial cells, coagulation activation microvascular retinal impairment (at autopsy, evidence of endothelial cells and cardiomyocytes viral invasion with signs of structural alterations)


Auto-immunity: auto-antibodies able to modulate the cardiac frequency and vascular tone (acting as receptor agonists on the β2-adrenoceptor, the α1- adrenoceptor, angiotensin II AT1-receptor, angiotensin 1,7 and endothelin receptors)
Persistent alteration of coagulation (sustained increased of D-dimer levels)
Respiratory

  • Dyspnoea

  • Chest pain

  • Cough

Persistent inflammation and dysregulated host response of lung repair

  • Increased plasma biomarkers of lung inflammation and fibrosis (Lipocalin 2, Matrix metalloproteinase-7, Hepatocyte growth factor)

  • Persisting inflammation in lungs, mediastinal lymph nodes, spleen, and liver

  • Involvement of iron homeostasis disturbances in end-organ damage

  • Relationship between metabolic abnormalities and lung sequelae

Gastro-intestinal systemNo specific symptomGut microbiota modifications after recovery

  • Decreases gut commensals with known immunomodulatory potential

  • Perturbed composition of microbiota correlated inflammation biomarkers

Immune systemMulti-system symptomsPersistent immune inflammatory response impairing organ functioning

  • Remaining inflammation in blood samples analysis, long-lasting phenotypic and functional disorders of lymphocytes, decreased amounts of dendritic cells and persisting alterations of activation markers

  • Signs of mild organ impairment at magnetic resonance imaging and [18F] FDG PET/CT


Autoimmunity: auto-antibodies against the nociceptive receptors, immunomodulatory proteins (including cytokines, chemokines, complement components, and cell-surface proteins) and tissue components
Persistence of the SARS-CoV-2 nucleic acids in tissues
Multisystem Inflammatory syndrome in children (MIS-C)
Dermatological systemSkin disordersAt biopsy, presence of lymphocytic or neutrophilic infiltrates, endothelitis, microangiopathy, and microthrombosis