Inflammation may induce or aggravate damage in various tissues such as joints and muscle, triggering pain-related symptoms

4) Glymphatic-lymphatic system congestion hypothesis. Damages to olfactory sensory neurons, may lead to a reduced outflow of cerebrospinal fluid through the cribriform plate, causing a congestion of the glymphatic system with secondary cranial hypertension and subsequent toxic build-up within the central nervous system.

6 Su S¹³⁷ et al Bolay H¹¹⁵ et al Attal N¹²⁶ et al Wostyn P¹¹² et al Low RN¹⁰⁰ et al Yong S¹¹³ et al

Neurologic Persistent fatigue Several potential mechanisms are proposed:

• Neuro-inflammation and subsequent neurotransmission disorders

(neurotransmitters concentration, intrinsic excitability, inflammation, changes in axonal conduction due to demyelination)

• Psychological factors (neurotransmitters levels can vary after COVID-19 and give rise to psychological disorder accounting for fatigue worsening)

• Peripheral factors (musculoskeletal impairment) in chronic fatigue

• Environmental factors (social isolation temperature, humidity)

• Associated comorbidities

• Glymphatic-lymphatic system congestion hypothesis: reduced outflow of cerebrospinal fluid following olfactory sensory neurons damages leading to a certain level of intracranial pressure and accumulation of toxins accumulation within the brain

• Bioenergetic disorders (muscle) due to mitochondria dysfunction

6 Wostyn P¹¹² et al Islam M⁹⁸ et al Rudroff T¹⁰⁶ et al Low RN¹⁰⁰ et al Wood E¹¹¹ et al Korompoki E et al¹²⁴

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System Involved

symptom(s) Mechanisms N Studies

Neurologic Olfactory

dysfunction Olfactory dysfunction due to viral invasion and subsequent inflammation and cells injury:

ACE2 present in epithelial cell of olfactory mucosa (sustentacular cells). Mechanism still unclear: no clear evidence of ACE2 on olfactory sensory neurons.

2 Gasmi A¹³¹ et al Iadecola C⁹⁷ et al Cardiorespiratory Cardiorespiratory

dysautonomic symptoms (palpitations, post-exertional malaise, exercise

intolerance, breathlessness, chest pain)

Dysautonomy hypothesis

Virus- or immune-mediated disruption of the autonomic nervous system (autoimmunity, microcirculation disorders): intrathoracic chemo and mechanoreceptors involved in the cardiovascular and respiratory reflexes or brainstem and cortical regions involved in the cardiorespiratory control, that may lead to various symptoms such as dizziness and other cardiovascular symptoms.

• Consecutive ionic changes and neuro-hyperexcitability ensues

• Increased smooth muscle cells tone (vasoconstriction) could lead to hypoperfusion of different organs

5 Dani M⁹⁵ et al Low RN¹⁰⁰ et al Yong S¹¹³ et al Motiejunaite J⁹¹ et al Korompoki E¹²⁴ et al

Cardiovascular Thromboembolic complications

(stroke, pulmonary embolism)

Endothelial dysfunction (endotheliitis) and subsequent activation of coagulation are the mechanisms for cardiovascular complications.

These cardiovascular issues can lead to chronic symptoms, associated with organ damages. Thrombo-inflammation can affect large blood vessels. Microcirculation impairment can also lead to tissue ischaemia.

• Endothelial invasion (ACE2 receptor) and consecutive dysfunction with coagulation activation and platelets/leucocytes attraction and activation

• Coagulation activation through the systemic cytokines release

• Direct viral-induced activations of platelets (ACE2 receptor) leading to inflammation and coagulation activation

• Inflammatory reaction-platelets and leucocytes attraction and thrombogenicity

• Neutrophil extracellular traps (NETs): inflammation-coagulation (factor XII)

• Direct complement activation (inflammation)

• Pericytes invasion and endothelial cells injury (loss of endothelial homeostasis and integrity)

• Antiphospholipids antibodies (endothelial/coagulation activation)

6 Ostergaard L¹⁰⁴ et al Moschonas I¹³³ et al Roberts K¹³⁶ et al Evans P¹³⁰ et al Andrade B¹²² et al Korompoki E¹²⁴ et al

Cardiovascular Heart disorders (impaired contractility,

Cardiomyocyte impairments and endothelial cells within the heart are the mechanisms proposed for cardiac complications.

These mechanisms can predispose for cardiac problems and/or symptoms after recovery and predispose them to late complications (arrythmia, cardiac insufficiency):

8 Ostergaard L¹⁰⁴ et al Evans PC¹³⁰ et al Mitrani R¹³² et al

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System Involved

symptom(s) Mechanisms N Studies

dyspnoea,

arrythmia) • Direct cardiomyocyte viral invasion (through ACE2 receptor) that may contribute as a trigger for heart tissue inflammation and account for contractility impairment:

acute or subacute myocarditis

• Coronary endothelial cells dysfunction hypothesis: inflammatory role of

endothelium (viral invasion through ACE2 receptor) with subsequent leucocytes recruitment and coagulation activation (micro-thrombi)

• Residual inflammation could lead to subsequent cardiac remodeling (fibrosis)

• Interaction with adipose tissue of epicardium (positive for ACE2) could be a mechanism of long-term arrythmia and coronary disease (adipokines release)

Moschonas I¹³³ et al Roberts K¹³⁶ et al Evans P¹³⁰ et al Orinsky B¹³⁸ et al Korompoki E¹²⁴ et al

Respiratory

system Dyspnoea

Cough Chest pain Exercise limitation

• Lung fibrotic remodeling after severe pneumonia can manifest in respiratory symptoms. Unlike functional respiratory disorders potentially associated with autonomic nervous system dysfunction, the mechanisms leading to fibrosis are associated with long-term lung injuries and occur mainly in severely-ill patients at the initial phase of infection:

o Pulmonary alveolar inflammation after viral invasion

o Degeneration of alveolar epithelial lining with emergence of hyaline membranes

o Excessive cytokines production (host inflammatory response) and enhanced influx of inflammatory cells

o Severe lung tissue scarring and fibrosis due to collagen deposition following aberrant fibroblast proliferation and differentiation (myofibroblasts; TGF-β1, transforming growth factor beta 1 pathway)

o Decreased expression of ACE2 receptor and angiotensin 1,7 peptides o Exposure to high supplemental oxygen concentration may result in a greater

oxidative and contribute to inflammation and fibrosis stress

• Unresolved (micro-) vasculature damages that can account for persistent respiratory symptoms which may be a potential precursor to chronic thromboembolic disease and pulmonary hypertension.

• Dysautonomy hypothesis (See above Cardiorespiratory system)

8 Murthy K¹³⁵ et al Ojo A¹³⁴ et al Dhawan R¹²⁸ et al Yong S¹¹³ et al Oronsky B¹³⁸ et al Andrade B¹²² et al Korompoki E¹²⁴ et al Tanni S¹⁴⁰ et al

Immune system Wide range of

symptoms • Chronic dysregulated immune system activation with subsequent cytokine release and chronic low grade inflammation leading to multiple organ dysfunction. This hypothesis suggests that inflammation could be responsible for persistent symptoms (no specificity on the type of symptoms):

6 Galeotti C¹¹⁶ et al Low RN¹⁰⁰ et al Afrin B⁹² et al Kazama I⁹⁹ et al

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symptom(s) Mechanisms N Studies

o Autoimmunity phenomena would result from inflammation and dysregulated immune responses. It could also result of a molecular mimicry with viral and self- antigens.

o Genetic polymorphism in the cytokine genes' regulatory regions could explain a predisposition to present symptoms and account for inter-individual

differences in the severity and occurrence of symptoms

• Mast cell activation syndrome hypothesis suggested as aetiology of persistent symptoms (multisystem disorder with inflammatory and allergic issues). The mast cell would be activated via the cytokines release. This could lead to lung fibrosis via a stimulation of fibroblast activity.

• Persistent smoldering infection: the natural down-regulation of the strong initial inflammatory response could allow the virus to persist and replicate in the body with ongoing inflammation and autoimmunity phenomena as a consequence

Yong S¹¹³ et al Jacobs J ¹²⁰ et al

Gastro-intestinal and hepato-biliary system

Gastro-intestinal symptoms:

anorexia, dyspepsia, nausea/vomiting diarrhoea abdominal pain

Several potential mechanisms are suggested to persistent digestive symptoms.

• Post-infection gastro-intestinal dysfunction:

o Viral invasion-local inflammation followed by leucocytes infiltration in the digestive mucosa generating a local inflammation

o Role of persistent gut microbiome for maintaining a status of chronic low grade intestinal inflammation (motility disorders, mucosal hyperpermeability, bile acid malabsorption)

o Hypothesis of gut as undetected virus reservoir

o Contributions of genetic predisposition and interaction between gut and environmental and psychological factors

• Autonomic nerve system disorder hypothesis: virus- or immune-mediated disruption of the autonomic nervous system (vague nerve) leading to gut motility disorders

5 Schmulson M¹¹⁴ et al Abdel-Moneim A¹²⁵ et al Yong S¹¹³ et al

Andrade B ¹²² et al Korompoki E ¹²⁴ et al

Musculoskeletal

system Muscular weakness Bone and joint disorders (pain, mobility)

• Muscle:

o Pro-inflammatory cytokines-induced disruption of myocytes o Cytokines-induced muscle fibroblast activation leading to fibrosis o Neuronal demyelination

• Bone:

4 Disser N¹²⁹ et al Andrade B ¹²² et al Ahmed S ¹²¹ et al Korompoki E ¹²⁴ et al

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o Microvascular blood flow impairment secondary to hypercoagulability, leukocyte aggregation, and vessel inflammation that contribute to the development of osteonecrosis

• Joints:

o Autoimmunity (virus persistence, dysregulated immune response, triggering of connective tissue diseases) and NETs activation

Endocrine system Thyroid disorders

Diabetes Thyroid

• Direct damage on the thyroid gland

• Low-T3 syndrome in hospitalised subjects (inflammation due to severe COVID-19)

• Subacute thyroïdis Diabetes

• Possible viral invasion of the pancreatic β cell that precipitates new-onset diabetes

3 Gentile S¹⁴³ et al Trimboli P¹⁴⁴ et al Korompoki E¹²⁴ et al

Renal system Alteration of renal

function Several mechanisms potentially involved in renal dysfunction:

• Consequence of the severity of acute infection: critical illness and mechanical ventilation and toxic effects (rhabdomyolysis, medications)

• Viral invasion (podocytes and proximal tubular cells express ACE2)

• Microangiopathy and intra-renal activation of the coagulation

• Alterations of the renin-angiotensin-aldosterone pathway

• Glomerulopathy as rare complication (as observed with other viral infections)

• Possible genetic susceptibility

4 Andrade B ¹²² et al Almaguer-Lopez¹⁴¹ et al Korompoki E¹²⁴ et al Le Stang MB¹⁴² et al

Multisystem Inflammatory Syndrome

in Children (MIS-C)

• Fever

• Multiple organ dysfunction

• Mucocutaneous disorders

• Abdominal symptoms

• Cardiovascular disorders

• Neurological disorders

Several mechanisms proposed to explain MIS-C:

• Genetical predisposition host factors

• Uncontrolled T-cell immune response (triggered by SARS-CoV-2)

• Complement activation

• Molecular mimicry between antigens and host tissues (autoimmunity)

4 Buonsenso D¹²³ et al Korompoki E¹²⁴ et al Andrade B¹²² et al Ahmed S¹²¹ et al

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Table 8 – Articles approaching the hypothetical pathophysiology of symptoms in patients

System Involved

symptom(s) Mechanisms N Studies

Neurology Smell disorders

Cognitive disorders Pain Insomnia

Functional brain disturbances

• In comparison with matched subjects, identification of hypometabolic activity in various cerebral zones by using [18F]FDG PET/CT: olfactory bulb,

limbic/paralimbic structures, thalamus, orbito-frontal cortex, cerebellum, and brainstem.

• Significant associations are observed between hypometabolism and long-term functional complaints: hyposmia/anosmia, memory/cognitive impairment, pain and insomnia.

• Absence of significant brain hypermetabolism, suggesting the absence of brain inflammation (in both studies).

• Reduced activity of the GABA inhibition by transmagnetic stimulation

4 Sollini M¹⁵⁸ et al

Neuro-inflammation and brain microstructural modifications

• In comparison to healthy subjects, micro-structural and volumetric and vascularisation disorders are evidenced through magnetic resonance imaging (MRI) patients who recovered from COVID-19.

• Neurochemical signs of neurons injury and microglia activation: several proteins markers of neuronal dysfunction, higher levels of cytokines (IL-4, IL-6), higher levels of IgG

• Indirect signs suggesting the role of neuro-inflammation on mood disorders symptoms: patients treated by interleukin inhibitors (IL-1β and IL-6) at the initial phase of COVID-19 had less signs of depression (but not PTSD)

• In patients who died from COVID-19, an association was found between MRI abnormalities and brain vascular lesions (congestion, clotting, vessel wall abnormalities, signs of activated microglia)

• In patients who died from COVID-19, identification of neuroinvasion (cortical neurons and endothelial cells) and neuronal damages with ischaemic zones.

8 Lu H¹⁵⁷et al

Structural lesions in the olfactory and taste system at imaging and histology

• Olfactory nerve morphological abnormalities at imaging (tomodensitometry, magnetic resonance imaging) suggesting direct/indirect injury to olfactory neuronal pathways

• Brush cytological sampling: neuroepithelium remains inflamed (high levels of cytokines including IL-6, myeloids cells) with persistent SARS-CoV-2 RNA.

• In biopsy of taste buds in the tongue: invasion and replication of SARS-CoV-2 in taste buds type II cells.

3 Kandemirli S¹⁶¹ et al De Melo G¹⁶² et al Doyle M¹⁶⁷ et al

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System Involved

symptom(s) Mechanisms N Studies

Cardiovascular

system Fatigue

Dyspnoea Chest pain Headache Joint pain Ocular disorders

Persistent vascular inflammation

• Signs of macrovascular vascular inflammation (vasculitis):

o Using [18F]FDG PET/CT, in comparison with age/sex-matched controls, evidence of increased [18F]FDG uptake in several vascular regions (thoracic aorta, right iliac artery, and femoral arteries).

• Signs of microvascular inflammation (endothelial dysfunction) in comparison with control subjects, using blood sample analysis:

o Identification of microvascular retinal impairment assessed by optical coherence tomography (compared to control group).

o Persistent cytokine-driven endothelial cells dysfunction (compared to control group):

 Increased number of circulating endothelial cells

 Pro-coagulant and pro-inflammatory phenotype in patients with cardiovascular risks

 Increased level of cytokines

 Signs that endothelial cells could be targeted by cytotoxic leucocytes) o At autopsy, evidence of endothelial cells and cardiomyocytes viral invasion

with signs of structural alterations

Auto-antibodies able to modulate the cardiac frequency and vascular tone

• G protein-coupled receptor antibodies acting as receptor agonists on the β2-adrenoceptor, the α1- β2-adrenoceptor,angiotensin II AT1-receptor, angiotensin 1,7 and endothelin receptors.

Persistent alteration of coagulation (sustained increased of D-dimer levels)

9 Sollini M¹⁷⁴ et al Savastano A¹⁷³ et al Chioh F¹⁷² et al Varga Z¹⁵³ et al Bulfamante G¹⁵⁴ et al Lindner D¹⁴⁹ et al Roshdy A¹⁵⁰ et al Wallukat G et al¹⁷⁵ Towsend L¹⁷⁶ et al

Respiratory Dyspnoea Chest pain Cough Fatigue Breathlessness

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). Biomarkers were significantly higher in patients who needed intensive care.

• Compared with healthy subjects, [18F] FDG PET/CT abnormalities suggesting persisting inflammation in lungs, mediastinal lymph nodes, spleen, and liver.

• Correlation of iron metabolism disorders with persisting respiratory symptoms suggesting an involvement of iron homeostasis disturbances in end-organ damage:

8 Chun H¹⁶⁹ et al Sonnweber T¹⁷⁰ et al Bai Y¹⁶⁸ et al De Michele S¹⁴⁷ et al Schaller T¹⁵¹ et al Ackermann M¹⁴⁵ et al Carsana L¹⁴⁶ et al Xu J¹⁷¹ et al

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System Involved

symptom(s) Mechanisms N Studies

o Persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status (6 minutes walking test)

• Relationship between metabolic abnormalities and lung sequelae (DLCO)

• At autopsy, signs of fibrosis, endothelial injury, microangiopathy, coagulation activation (microthrombi) and angiogenesis

Gastro-intestinal

system Gut microbiota modifications after recovery

• Decreases gut commensals with known immunomodulatory potential

• Perturbed composition of microbiota correlated with plasma inflammatory

cytokines and chemokines concentrations and blood markers (C- reactive protein, lactate dehydrogenase, aspartate aminotransferase, gamma-glutamyl transferase)

1 Yeoh Y¹⁷⁷et al

Immune system Multi-system

symptoms Persistent immune inflammatory response impairing organ functioning

• In comparison with healthy subjects, signs of remaining inflammation in blood samples analysis (increased levels of proteins involved in mitochondrial function, leucocytes function, urea cycle, protease inhibitors).

• In comparison with healthy subjects, identification of long-lasting phenotypic and functional disorders of lymphocytes: persistence of a cytotoxic program in CD8⁺ T cells and elevated production of cytokines that could impact tissue integrity and cytokines responsiveness. Decreased amount of dendritic cells and persisting alterations of markers of activation.

• Magnetic resonance imaging suggests signs of mild organ impairment (even in low risk patients): heart, lungs, kidneys, liver, pancreas, spleen. Correlation between the extent of extra-pulmonary MRI abnormalities and exercise

intolerance (cardiopulmonary exercise test, six-minute walk test) and markers of inflammation

• Abnormalities at [18F] FDG PET/CT suggesting persisting inflammation in several organs (lungs, mediastinal lymph nodes, spleen, liver, adrenal glands)

• No association between vitamine D levels with persistent symptoms nor CT-abnormalities, or impaired pulmonary function testing.

Autoimmunity

• Auto-antibodies against the nociception-like opioid receptor

• Auto-antibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins) and against tissues (vascular cells, coagulation factors and platelets, connective tissue,

12 Doykov I¹⁸² et al Dennis A¹⁸¹ et al Shuwa H¹⁸³ et al Bai Y¹⁶⁸ et al Sollini M¹⁵⁸ et al Pizzini A¹⁸⁴ et al Raman B¹⁸⁵ et al Wallukat G¹⁷⁵ et al Wang E¹⁸⁷ et al Gaebler¹⁸⁸ et al Richter A¹⁸⁶ et al Perez-Gomez A¹⁸⁹ et al

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System Involved

symptom(s) Mechanisms N Studies

extracellular matrix components and various organ systems, including lung, the central nervous system compartment, skin, gastrointestinal tract)

Persistence of the SARS-CoV-2 in tissues

• Persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel several months after initial infection

Dermatological

system Various skin

disorders Potential immune or inflammatory mechanisms in skin lesions.

On skin biopsy, description of:

• Lymphocytic or neutrophilic infiltrates

• Endotheliitis

• Microangiopathy

• Microthrombosis

• Leucocytoclatsic vasculitis

3 Genovese G¹⁷⁸ et al Sharma S¹⁷⁹ et al McMahon D¹⁸⁰ et al

Multisystem Inflammatory Syndrome

in Children (MIS-C)

Comparisons of inflammatory characteristics in children with Kawasaki disease, children infected with COVID-19 and children presenting with MIS-C:

• More pronounced lymphopenia was more pronounced in MIS-C than in children with mild SARS-CoV-2 infection, Kawasaki disease

• Higher CRP and ferritin levels and lower platelet counts in MIS-C compared to Kawasaki disease and children with COVID-19

• Difference in cytokines profiles (Interleukins 7 and 8)

• Specific differences between immune cell responses in MIS-C and patients with Kawasaki disease

• IL-17 significantly lower in MIS-C than in Kawasaki patients

• Identification of plasma proteins distinguishing MIS-C from Kawasaki

• Presence of auto-antibodies could be involved in the pathogenesis of MIS-C

1 Consiglio C et al¹⁹⁰

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Central nervous system

The long-term symptoms related to central and peripheral nervous systems can arise from early neurological complications such as stroke, encephalitis, Guillain Barré syndrome or from factors related to the hospitalisation (delirium in ICU, immobilization, exposure to sedative agents, sepsis, sequelae of the initial disease severity).^{124, 139}

The other long-term neurological symptoms include neurocognitive problems, mental health diseases, smell and taste disorders and dysautonomia. Those symptoms entails several overlapping mechanisms.

Reported hypothetical mechanisms:

• Twenty-two publications elaborated on the putative mechanisms that could contribute to neurocognitive disorders (difficulty of concentration, memory and executive functions disorders, ‘brain fog’) and psychiatric impairment (mood disorders, post-traumatic stress syndrome, anxiety, insomnia).93, 94, 96, 97, 100-105, 107-110, 117-119, 122, 124, 127, 131, 139 Mechanisms are numerous and mainly encompass neuroinflammatory disorders (See Table 7).

According to this hypothesis, brain dysfunction is secondary to inflammatory phenomena following viral invasion of the brain, or to proinflammatory cytokines that reach the central nervous system.

Microglia, which is a network of cells scavenging neurons and involved in homeostasis and brain immune defense, can secondarily be activated. Once activated, microglia can perpetuate neuro-inflammation through a dysregulated release of cytokines and reactive oxygen species. Microglia impairment has been associated with a large number of neuropsychiatric disorders.¹⁹¹

As a consequence of inflammation, hypercoagulation could lead to the formation of microthrombosis impairing correct vascularization, neurotransmission and potentially inducing neuron injury (through ischaemia or excitotoxicity). On the other hand, a bioenergetics failure due to mitochondrial dysfunction has also been proposed as a consequence of inflammatory reaction or viral invasion.

In that way, symptoms could be related to the impaired cerebral region.

For example, the limbic system or cortical areas dysfunction could account for psychiatric and cognitive disorders. Besides, brain damages can also be secondary to the severity and complications of the acute infection.¹⁰⁷

• Six articles proposed that autoimmune manifestations against the central nervous system could be triggered, via a molecular mimicry with viral proteins or via a dysregulation of inflammatory processes as a consequence of the acute phase of the infection. This relationship between COVID-19 and autoimmunity has been suggested because autoimmune complications have been reported in the early course of infection.107, 110, 116, 122, 124, 127

• Three articles speculated that the gut-brain axis could be modified and involved in central nervous system dysfunction100, 110, 122 and 3 other articles elaborated on the indirect nervous system damage via the complications of acute illness.101, 122, 139

• Regarding the persistent smell and taste disorders, 2 studies reported on the role of neuroepithelial viral invasion and subsequent inflammation as mechanisms contributing to olfactory dysfunction.^{97, 131}

• Six articles suggested mechanisms contributing to pain and headache100, 112, 115, 117, 126, 137 and six articles proposed mechanisms involved in chronic fatigue.98, 100, 106, 111, 112, 122 Peripheral and central neuro-inflammation could play a role for both symptoms. Muscle mitochondrial dysfunction could take part in the physical dimension of fatigue while other pluridimensional factors (psychological, environmental, comorbidities) could also be involved. Interestingly, one article proposed for both symptoms, a dysfunctional brain glymphatic drainage leading to cerebrospinal fluid congestion (intracranial hypertension) and toxins accumulation within the brain.¹¹²

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Findings reported in clinical studies:

Clinically, studies gave contrasting results:

• Three studies evaluated brain metabolism using the uptake of [18F]FDG PET/CT in symptomatic patients 3 to 4 months after infection.158, 160, 164 In comparison with matched subjects, hypometabolic activity was underscored in various cerebral areas involved in the symptoms (cognitive symptoms, headache, pain, sleep and smell disorders). Interestingly, zones with hypermetabolism were not identified in both studies. Such hypermetabolic zones would have suggested brain inflammation.

• Conversely, by using magnetic resonance imaging (MRI), 3 months after infection, one study evidenced brain micro-structural, volumetric

• Conversely, by using magnetic resonance imaging (MRI), 3 months after infection, one study evidenced brain micro-structural, volumetric

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