The Neuropsychiatry of Long COVID and Post-Acute COVID-19 Syndrome: A Review

LONG COVID & POST-ACUTE COVID-19 SYNDROME DEFINITIONS

Long – COVID:

• The term “long COVID” was introduced in May 2020. [Yong & Liu, 2021]
• Long COVID is characterised by ongoing symptomatic COVID-19 beyond 4 weeks post-infection.
• The National Institutes of Health (NIH) use the US Centers for Disease Control and Prevention (CDC) definition of long COVID as ‘sequelae that extend beyond four weeks after initial infection.’ [Datta et al., 2020]
• Different terms are used worldwide to describe the persistent effects of COVID-19. In Spain it is Covid persistente, in Germany it is mit Corona leben (living with coronavirus). In the United States, it is commonly referred to as “long-hauler” COVID-19. [Sigal, 2021]

Post-COVID-19 Syndrome: 

• Post-COVID-19 syndrome is defined as ongoing COVID-19-related symptoms from 12 weeks post-infection. [Nalbandian et al., 2021]
• The World Health Organization (WHO) and SNOMED international now use the term Post COVID-19 condition to classify all clinical variations of Post COVID-19 infection. [Nurek et al., 2021]
• Over 1 million people in the UK are now estimated to suffer from long COVID. The disease pattern is commonly unpredictable, with significantly associated illnesses occurring weeks or months following the onset of COVID-19 infection. [Nurek et al., 2021]
• People with long COVID may exhibit impairments in the structure and functions of multiple organs. [Raman et al., 2021]; [Sollini et al., 2021]  [Greenhalgh, 2020]

I was diagnosed with this after having covid. The fatigue is frightening. I have a hard time getting through my work day and my life has changed dramatically. Prior I had no health issues, worked long hours, studied for graduate degrees full-time, and walked 5 miles a day. Now I work as an accountant and can’t do anything else except rest and sleep. I had EBV a long time ago. Now I have long covid. I have done the research for 2 years with no secrets found for recovery. 

She suddenly felt a stabbing pain in her chest. It just got worse and worse and worse, to the point I was crying from the pain,” she recalled in a recent interview. At 3 am, the pain sent her to the emergency department. “I had developed a dry cough, maybe a mild fever. I don’t remember.

I joke, ‘Well, COVID has eaten my brain, because I can’t remember how to remember words, keep track of medication,’” she said. “My brain just feels like there’s a fog. [Rubin, 2020]

LONG COVID - PATHOPHYSIOLOGY

Multiple mechanisms underpin the pathophysiology of the symptoms of Long-COVID.

Understanding these mechanisms can help clinicians target the underlying pathophysiology, where possible, to address symptoms.

FATIGUE:                                                  

Fatigue is the most common symptom of long COVID, regardless of the severity of the original COVID-19 infection. [Crook et al., 2021]

The Office of National Statistics (ONS) estimates the 5-week prevalence of fatigue to be 11.9% in patients with long COVID.

Risk factors include female sex, pre-existing anxiety and depression, smoking and obesity.

Pathophysiology of Fatigue: 

Impaired waste clearance resulting in CNS toxicity: [Wostyn, 2021]

• Congestion in the glymphatic system [CNS transport pathway mainly active during sleep involved in waste clearance, and, potentially, brain immunity].
• Poor cerebrospinal fluid (CSF) drainage.

Cerebral Hypometabolism:

• Frontal lobe and general cerebral hypometabolism are associated with cell-mediated immune mechanisms and systemic inflammation as opposed to a direct viral attack. [Delorme et al., 2020]; [Guedj et al., 2021]
• Reduced Cerebral blood flow (CBF) and orthostatic intolerance are associated with abnormal vascular regulation.
• The reduced CBF may arise from excessive sympathetic vasoconstriction in the presence of dysfunctional Beta-2 adrenergic receptors (β2ADRs) and vascular or endothelial dysfunction.
• This impairs the vasodilator component of vascular regulation leading to a predominance of vasoconstrictor mechanisms in skeletal muscle and brain, reducing perfusion (mediated by alpha-1 receptors). [Wirth and Scheibenbogen, 2020]

Direct SARS-CoV-2 infection in skeletal muscles: 

• Damage, weakness and inflammation in muscle fibres and neuromuscular junctions. [Ferrandi et al., 2020]
• Muscle mitochondrial dysfunction.

Dopamine (DA) imbalance hypothesis:

• Inflammatory cytokines can decrease the expression or function of the vesicular monoamine transporter 2 (VMAT2) and/or increase the expression or function of the dopamine transporter (DAT), reducing dopamine levels.
• Reduced dopamine levels are associated with reduced connectivity in the mesocorticolimbic regions resulting in anhedonia, reduced cognitive capacity and fatigue. [Dobryakova et al., 2015]

Psychological and environmental factors: 

• Stress
• Insomnia
• Reduced activity
• Psychiatric disorders

• Patients with long-COVID show a significantly higher rate of insomnia than subjects who never had COVID-19. [Orrù et al., 2021]
• While psychological and environmental factors such as psychological stress, pain and the impact of illness due to other symptoms can impact sleep, it is also essential to recognise that sleep dysfunction also has biological underpinnings due to inflammation and immune dysregulation.
• Inflammation and immune dysregulation directly impact sleep architecture, with the relationship being bidirectional.
• Disrupted sleep can result in decreased quality of life and fatigue, exacerbating symptoms such as pain and discomfort, which, in turn, further decreases sleep quality.

Pathophysiology of Sleep Dysfunction:

The two main sleep-mediating areas affected by inflammation are the Nucleus tractus solitarius (NTS) in the Hypothalamus and the Suprachiasmatic nucleus (SCN).

Insomnia – Neurobiology | Pathophysiology | Assessment and Management

Neurons in the nucleus tractus solitarius (NTS) enhance NREM sleep by stimulating the ascending reticular activating system and are closely involved in autonomic regulation [Liu and Dan., 2019]

The SCN is the ‘master circadian clock’ that generates and regulates the body’s circadian rhythms and synchronises them to the environmental 24-h light-dark cycle. Each tissue and cell has its molecular clock, known as the peripheral clock.

Immune cells also have peripheral clocks which are synchronised daily and coordinated by the SCN via the hypothalamic pituitary adrenal (HPA) axis and the autonomic nervous system (ANS)  [Comas et al., 2017]

Inflammatory cytokines (IL-1 beta (IL-1β), Tumor necrosis factor-alpha (TNF-α) and IL-6) are increased after infection with COVID-19.

Inflammatory signals between the brain and periphery are mediated by vagal afferents to the NTS (Hypothalamus), while vagal efferents have anti-inflammatory actions mediated by acetylcholine receptor activation.

Inflammation also affects circadian rhythms by impacting the Suprachiasmatic nucleus (SCN). The circadian firing rhythms of the SCN neurons are differentially affected by various cytokines. [Zielinski and Gibbons., 2022]

Neuroinflammation in Psychiatry Simplified – The Link Between the Immune System and The Brain- Dr Sanil Rege

Effects of cytokines on sleep architecture:

• IL-1β and TNF-α are two pro-inflammatory cytokines that regulate sleep and interact with the circadian system.
• IL-1β and TNF-α flatten the diurnal rhythm of activity.
• IL-6 reduces slow wave sleep (SWS).
• The NLRP3 inflammasome is somnogenic and promotes NREM sleep during inflammation.
• In animal studies, TNF promotes NREM sleep in higher doses suppressing REM.
• Alterations in sleep architecture (REM suppression and NREM increase) might facilitate fever: energy is spared through long NREM, whereas shorter time spent in REM allows for shivering.
• IL-6 may lead to sleep disorders such as Restless legs syndrome(RLS). It induces hepcidin production in hepatocytes, which decreases iron absorption in the intestines and inhibits iron release from the macrophage, leading to hypoferremia, which is associated with fatigue, irritability, and RLS.

Pre-existing conditions such as Obstructive sleep apnoea (OSA) are associated with adverse outcomes post covid infection, which may involve multiple mechanisms such as nocturnal hypoxemia, exacerbating or causing endothelial dysfunction, inflammation, oxidative stress, microaspiration and cardiac dysfunction. [Miller and Cappuccio., 2021]

OSA also independently shifts the balance towards an immune response via intermittent hypoxia, increasing hypoxia-inducible factor 1 (HIF-1), which:

• Inhibits Treg production and promotes the formation of pro-inflammatory Tregs-producing interferon-gamma (INF-ɣ)
• Stimulates the production of Th17 (and subsequently interleukin-17 (IL-17).

HYPERAROUSAL AND AGITATION:

A high frequency of post-COVID PTSD was observed in patients with a moderate-to-severe course of COVID-19.

Post-COVID Stress Disorder links to PTSD and comprises of [Szepietowska et al., 2022]

• Hyperarousal
• Avoidance
• Intrusions/ruminations
• Dysphoric and anxious arousal associated with memories of the COVID-19 pandemic or related events.

While hyperarousal, irritability and agitation are usually part of psychiatric disorders, multiple other neurobiological changes as part of post-COVID may be aetiologically related. Understanding these mechanisms may have therapeutic implications.

Moreover, untreated hyperarousal and agitation exacerbate several psychiatric and physical symptoms (pain, ANS dysfunction, fatigue, insomnia etc.).

Pathophysiology of Hyperarousal and Agitation: 

Role of the Amygdala: 

• The amygdala is a critical area involved in acquiring, storing, and expressing learned fear associations. [See neurobiology of PTSD]
• The amygdala & hypothalamus are connected with the Locus coeruleus (LC), where Corticotrophin releasing hormone (CRH) and noradrenaline (NA) interact to modulate fear conditioning, encoding of emotional memories and enhancing arousal and vigilance. [Ross, 2021].
• The amygdala expresses adrenoreceptors and D2 receptors. There are direct projections onto amygdalae nuclei from the ventral tegmental area (VTA) and Locus Coeruleus (LC), brainstem areas responsible for the synthesis and release of DA and NA, respectively.
• Increased catecholamines due to stress or insomnia can increase amygdala excitation, exacerbating conditioned fear responses, paranoia and agitation.
• Excess amygdala activation also impairs PFC functioning, which can manifest as cognitive symptoms (e.g. brain fog) and fatigue. [Arnsten, 2009]

GABA dysfunction:

• Post-Covid-19 infection is also associated with intracortical GABAergic dysfunction, a key inhibitory neurotransmitter, the reduction of which is associated with agitation. [Versace et al., 2021]
• Pro-inflammatory cytokines reduce GABA and increase glutamate excitation contributing to mood dysregulation and hyperarousal states.

DYSPNOEA: 

Dyspnea (breathlessness) has been identified as a common symptom after contracting COVID-19. [Mandal et al., 2021]

Prevalence at 5 weeks post-infection is at 4.6% but in one study, approximately 43.4% of the 143 patients assessed at 60 days post-COVID-19 onset still experienced breathlessness. [Carfi et al., 2020]

Lung function in hospitalised patients a month after COVID-19 infection can take time to recover, with abnormalities found in total lung capacity, carbon monoxide diffusion capacity, first-second expiratory volume, forced vital capacity and small airway function, causing varying degrees of impairment. [Mo et al., 2020]

SARS-Cov-2 infection can also cause substantial endothelial damage via cell replication, and those overcoming an initial infection may develop long-term respiratory complications [Wei et al., 2020]

Pathophysiology of Dyspnoea: 

• SARS-CoV-2 replication inside endothelial cells results in endothelial damage and an intense immune and inflammatory reaction.
• Inflammatory reaction: complement activation, the release of pro-inflammatory cytokines.
• Hypercoagulability: platelet activation, platelet-leukocyte interactions, disruption of normal coagulant pathways increasing the risk of thrombosis.
• Hypoxia
• Relationship between respiratory impairments and dysregulated iron metabolism, possibly involved in organ damage.

Pulmonary Fibrosis: 

• Pulmonary fibrosis in patients with ongoing dyspnea may be linked to the IL-6 cytokine, often raised in COVID-19.
• Older people and those with existing underlying lung conditions such as acute respiratory distress syndrome are most at risk of developing longer-term conditions post covid-19 infection. [McElvaney et al., 2020]
• Endothelial damage triggers the activation of fibroblasts, which deposit collagen and fibronectin resulting in fibrotic changes.

CARDIOVASCULAR INVOLVEMENT: 

• Ongoing myocardial inflammation and elevated serum troponin levels are seen in many patients with COVID-19 at 71 days after diagnosis [Puntmann et al., 2020]
• Chest pain, possibly owing to myocarditis, was also common in patients 60.3 days following the onset of COVID-19 symptoms, with 21.7% of the 143 patients assessed in a case series [Carfi et al., 2020]
• Young, competitive athletes among those considered least at risk from COVID-19 have been found to have residual myocarditis long after recovery. [Rajpal et al., 2021]
• In addition to cardiac complaints, an emerging trend in recent studies is the development of new-onset POTS due to autonomic dysfunction following COVID-19 infection. [Kanjwal et al., 2020]; [Johansson et al., 2021]
• Viral infection has previously been shown to precede POTS, and with the ACE2 receptor expressed on neurons, viral infection by SARS-CoV-2 may lead to dysfunction of the autonomic nervous system. [Goldstein 2021]

Pathophysiology of Cardiovascular Involvement: 

• Invasion of cardiomyocytes by SARS-CoV-2 through ACE2 receptors.
• Chronic inflammation of cardiomyocytes can result in myositis and cardiomyocyte death.
• Dysfunction of the afferent autonomic nervous system may lead to POTS.
• Prolonged inflammation and cellular damage prompt fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis.
• Fibrotic changes are accompanied by increased cardiac fibromyoblasts, while damage to desmosomal proteins results in reduced cell-to-cell adhesion.
• Microvascular endothelial dysfunction within the heart and vessels could provoke microthrombi impairing appropriate vascularisation.

PAIN: 

Several pain syndromes are associated with Long COVID. [Fiala et al., 2022]

Persistent chest pain

• One of the most common long-term symptoms in patients who have recovered from SARS-CoV-2.

Testicular pain:

• High concentrations of ACE-2 receptors in kidney and testicular tissue may help explain long-term testicular pain prevalence in COVID-19 patients.

Chronic pain:

• PICS (persistent inflammation, immunosuppression, and catabolism syndrome) is a potential risk factor in post-COVID pain syndromes.

Fibromyalgia:

• Individuals with post-COVID-19 report a symptom phenotype similar to Fibromyalgia and CFS, negatively impacting cognitive and physical function but with less severe pain and fatigue overall. [Haider et al.,2022]
• Clinical features of FM are common in patients who recovered from COVID-19.
• Obesity and male gender are risk factors for developing post-COVID-19 FM. [Ursini et al., 2021]
• The Neuropsychiatry of Fibromyalgia – Etiology and Management

Pathophysiology of Pain:

Neurotransmitter Dysfunction:

ACE2 receptors are highly expressed in dopamine neurons. ACE2 receptor involvement by SARS-COV-2  may occur with a Dopa Decarboxylase DDC dysfunction, leading to altered neurotransmitter levels in COVID-19 patients. [Attademo and Bernardini, 2021]

• In fibromyalgia, dysfunctional dopaminergic neurotransmission is associated with patients’ pain symptomatology.
• Dopamine activity is attenuated in fibromyalgia as evidenced by reduced CSF levels of dopamine, reduced presynaptic dopamine function and reduced dopamine responses to acute pain.
• Inflammation also affects serotonin and noradrenaline levels which are linked to nociception.

Autonomic Nervous System Involvement

• Blunted autonomic reactivity to nociceptive or stressful stimuli and excessive sympathetic activity can increase pain sensitivity.

Central Sensitisation

• Inflammation is associated with neuronal excitability mediated by microglia and the release of proinflammatory cytokines resulting in pain hypersensitivity. [Latremoliere and Woolf, 2009]
• This central sensitisation can occur centrally and peripherally, resulting in widespread chronic pain (e.g. fibromyalgia). [Ji et al., 2018]

POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS):

Long COVID is associated with orthostatic intolerance (OI), including orthostatic hypotension (OH) and POTS.

POTS is defined by a heart rate increment of 30 beats/min or more within 10 minutes of standing or head-up tilt (HUT) in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher.

Post-COVID-19 tachycardia syndrome, characterised by persistent tachycardia, may present as inappropriate sinus tachycardia or POTS. [Chadda et al.,2022]

Pathophysiology of POTS: 

Hypovolaemia, Inflammation/autoimmunity and Neurotropism are involved in the pathophysiology of POTS.

There are two types of POTS: [Benarroch, 2012].

• Central hyperadrenergic POTS
• Neuropathic POTS (dysautonomia)

Central hyperadrenergic POTS

• Some patients with POTS have elevated levels of plasma NA, suggestive of a hyperadrenergic state. This is most commonly secondary to partial dysautonomia or hypovolemia.
• A specific single-point mutation causing loss of function in the noradrenaline transporter (NAT) has been identified. The resultant diminished NA clearance leads to a hyperadrenergic state in response to sympathetic nerve activation.

Neuropathic POTS (Dysautonomia)

• Neurotropic effects of the virus may damage the sympathetic nervous system ganglia resulting in impaired sympathetic vasoconstriction leading to venous pooling, hypovolemia, deconditioning and compensatory tachycardia.
• COVID-19 infection is associated with antibodies against the β2AdR and M1 AChR, which may be linked to POTS, vasomotor, gastrointestinal symptoms and increased pain sensitivity. These antibodies are also elevated in CFS. [Chadda et al.,2022]
• Due to the suspected dysfunction of β2AdR and endothelial dysfunction, the heart rate may not rise proportionally to sympathetic activity (“chronotropic incompetence”), masking the true extent of sympathetic activation and α1-adrenergic activation.

MAST CELL ACTIVATION (MCA)

• The hyperinflammatory responses seen in Long COVID have been hypothesised to be partly mediated by mast cell activation (MCA) [Weinstock et al., 2021]
• MCA releases vasoactive mediators and histamine, leading to vasodilation (responsible for flushing) and subsequent reflex sympathetic activation, central volume contraction, NA release, and orthostatic intolerance. [Shibao et al., 2005]
• Mast cells also contain dopamine, and activation causes DA depletion. [Rönnberg et al, 2012]. 
• Since DA is a potent vasodilator in arteries, indicative of an endogenous source of dopamine in the vascular wall, DA depletion can contribute to excessive vasoconstriction. [Iadecola, 1998], [Krimer et al., 1998] 
• A novel syndrome of chronic hyperadrenergic orthostatic intolerance associated with episodes of MCA has been described. This syndrome should be considered in POTS patients with a history of flushing. [Shibao et al., 2005]

DERMATOLOGICAL INVOLVEMENT: [McMahon et al, 2021].

• Morbilliform, urticarial, and papulosquamous lesions are associated with Long Covid.
• Pernio lesions and livedo reticularis were reported to last longer than the other lesions.

Pathophysiology of Dermatological Involvement: 

• Leukocyte infiltration
• Microthrombi
• Vasculitis
• Histamine intolerance [Llana et al., 2022]

OLFACTORY AND GUSTATORY DYSFUNCTION: 

• Loss of smell and taste are very common in COVID-19 infection, with the ONS estimating the 5-week prevalence at 7.9% and 8.2%, respectively. [ONS 2020]
• In some study cohorts, olfactory and gustatory dysfunction ranges from 11% to 45.1%, indicating a much higher general prevalence. Sensory neurons may be impaired by the inflammatory response caused by SARS-Cov-2 infection, thereby causing a reduced sense of smell and taste.

Pathophysiology of Olfactory and Gustatory Dysfunction: 

• Retrograde neuronal transport via the olfactory pathway (across the cribriform plate of the ethmoid bone to the olfactory bulb situated in the forebrain) is a likely route given the proximity to the brain but also due to the presence of ACE2 receptors on olfactory cilial cells.
• The virus can reach the CSF and brain through the olfactory nerve and bulb within 7 days and can cause inflammation and a demyelinating reaction.  [Bohmwald K et al., 2018]
• Intact CoV particles and SARS-CoV-2 RNA have been found in the olfactory mucosa and in neuroanatomical areas receiving olfactory tract projections. They may suggest SARS-CoV-2 neuroinvasion occurring via axonal transport. [Meinhardt J et al., 2020]
• Direct cellular injury linked to high expression of ACE2 receptors in the oral mucous membrane, particularly on the tongue [Xu et al., 2020], or that SARS-Cov-2 may bind to sialic acid receptors, thereby increasing the gustatory threshold and degrading gustatory particles even before their exposure to infection. [Pushpass et al., 2019]

ENDOCRINE INVOLVEMENT: 

• ACE2 is expressed on the pancreatic β cell, and SARS-CoV-2 could damage these cells, thereby precipitating diabetes.
• Pancreatitis was observed in some acute cases [Hadi et al., 2020] with higher serum amylase and lipase levels, more elevated in severe illnesses compared with mild cases [Hamming et al., 2021], and pancreatic injury showing on computed tomography (CT) scans. [Liu et al., 2020]
• A cross-sectional study of COVID-19 patients at low risk of severe disease showed that 40% had mild pancreatic impairment 141 days following infection. [Dennis et al., 2020]
• Diabetic ketoacidosis [DKA] has been observed in patients without known diabetes mellitus weeks to months after the resolution of COVID-19 symptoms. [Suwanwongse and Shabarek, 2020]
• Other endocrine effects include subacute thyroiditis and bone demineralisation. [Nalbandian et al., 2021]

RENAL, HEPATIC AND HAEMATOLOGICAL COMPLICATIONS: 

• The long-term effects of COVID-19 on the liver and kidneys are not yet fully understood. In one study assessing kidney function in patients with COVID-19, approximately 35% had decreased kidney function 6 months post-discharge. [Huang et al., 2021]
• Several kidney cell types, like podocytes or cells from the proximal tubule, express ACE2 on their surface and are thus susceptible to SARS-COV-2 damage.
• Endothelial damage and dysregulation of the renin-angiotensin-aldosterone system are other factors for renal involvement.
• COVID-19 has also been shown to significantly impact the spleen, with lymphoid follicle atrophy, thrombotic events such as infarcts, and a decrease in T and B lymphocytes, leading to lymphocytopenia in some cases. [Xu et al., 2020]; [Ihlow et al., 2021]

NEUROPSYCHIATRIC SYMPTOMS: 

• Neuropsychiatric symptoms such as anxiety, depression, post-traumatic stress disorder (PTSD), and sleep disturbances have been reported in 30 and 40% of COVID-19 survivors. [Nalbandian et al., 2021]
• SARS-CoV-2 can take two pathways to involve the brain; direct and indirect. [Wu Y et al., 2020] The virus can enter the brain through the haematogenous or neuronal route.
• The neuronal route involves olfactory, respiratory pathways and the Gut-brain axis (GBA).
• We have covered the neuropsychiatry of COVID-19 in detail here.

Pathophysiology of CNS involvement:

• Cytokine dysregulation
• Neuroinflammation
• Post-infectious autoimmunity
• Hypoxic injury
• Immunomodulatory treatment
• Gut microbiome translocation
• ACE2 receptor involvement
• Hypercoagulability

The following ‘Psych Scene Hub’ resources review the neuropsychiatric impacts of COVID-19 in detail:

1. Psychiatric and Neuropsychiatric Manifestations of COVID-19 – SARS-CoV-2 and the Brain (Video)
2. COVID-19 and the brain – Pathogenesis and Neuropsychiatric Manifestations of COVID-19 (article)
3. Mental Health challenges for healthcare workers during the COVID-19 pandemic – Psychological Impact and Management strategies (article)

MULTISYSTEM INFLAMMATORY SYNDROME (MIS-C): 

• Multisystem inflammatory syndrome (MIS-C) has been identified as a possible delayed immune-mediated complication of SARS-CoV-2 infection.
• Clinical and laboratory features of MIS-C are similar to Kawasaki disease and Toxic Shock Syndrome.
• MIS-C can cause severe acute respiratory syndrome (SARS) and can be life-threatening if not detected early enough. [Radia et al., 2021]
• Symptoms in children are usually mild, but the pathophysiology of MIS-C is still unclear, so caution during the assessment is vital. [Radia et al., 2021]

Risk factors for lack of recovery

• Age ( ≥50 years) and the number of pre-existing medical conditions, with a higher number of conditions associated with chronicity. [Tenforde et al., 2020]
• Of the pre-existing conditions, hypertension, obesity, psychiatric condition or an immunosuppressive condition were associated with the highest risk of chronicity.  [Tenforde et al., 2020]
• In January 2021, NICE reviewed its guidance on assessing, treating, and managing patients with COVID-19 by including a new chapter on the treatment and management of long COVID.
• Data remains limited, but the evidence base grows as new research is published. NICE’s evidence-based management guideline for post-infection care is the most up-to-date thus far. Still, due to criticism from the ME association on its recommendations for self-care and management, the guidance required updating in November 2021. [NICE, 2021]

Psychological factors associated with Long COVID: 

• Psychological factors may play a part in the chronicity of the illness. It is, however, essential to avoid diagnostic overshadowing, i.e. attributing physical symptoms to psychological factors only.
• Long COVID is a medical illness; thus, a thorough medical and psychiatric evaluation should be the norm.
• Patients with post-COVID syndrome tend to show higher levels of neuroticism with lower scores on emotional stability, equanimity, positive mood, and self-control. These personality traits are predictive of the presence of depression and anxiety but not cognitive function, sleep quality, or fatigue, in the context of the post-COVID syndrome. [Delgado-Alonso et al., 2022]
• Patients with COVID-19 have a higher risk of developing Somatic symptom disorder (SSD) and show high levels of alexithymia and perfectionism, known risk factors for SSD.
• A fear of dying during the first days of COVID-19, features of posttraumatic stress disorder and past history of trauma were associated with a significant excess risk of developing SSD. [Kachaner et al., 2022]
• Many patients with unexplained long-lasting neurological symptoms after mild COVID meet diagnostic criteria for SSD. [Horn et al., 2021]
• Similar findings are present in Chronic fatigue syndrome (CFS), which is associated with perfectionist, conscientious, hardworking, individuals with higher levels of introversion and neuroticism with high personal standards, a great desire to be socially accepted and a history of continuously pushing themselves past their limits. [van Geelen et al.,2007]

INVESTIGATIONS IN POST-COVID SYNDROME

Red flag symptoms should prompt emergency attention:

• Tachycardia > 100 bpm at rest or on minimal exertion
• Chest pain on exertion
• Desaturation> 3% on exertion

The following investigations are outlined as a range and are not meant to be used generically. They are a guide to be used based on clinical needs.

Haematological Investigations:

• Complete blood count and differential
• ESR and CRP
• Iron studies – Serum Iron, Iron Binding capacity and Ferritin
• Vitamin B12 and folate
• Fasting Glucose
• Vit D
• Clotting screen

Urinary

• Electrolytes : Na, K, Ca, Po4, Mg
• Creatinine Clearance
• Urea
• Glomerular Filtration rate (eGFR)
• Albumin / Globulin Ratio
• Urine Analysis
• CPK (myositis suspected)
• Urine Drug screen
• Cystoscopy

Immunological:

• ANA, DsDNA, Anti-ENA
• Thyroid antibodies
• Total and subclass immunoglobulins, lymphocyte subsets
• Screen for HIV, Lyme disease, Q fever
• Microbiology of stools, throat, urine, sputum and genitals

Endocrine:

• Thyroid Stimulating Hormone (TSH), T4, T3
• ACTH
• Prolactin
• Testosterone
• Renin/Aldosterone ratio
• Cortisol (am and pm)
• Short ACTH challenge test or cortisol stimulation test
• Estrogen, FSH, LH

Neurological :

• MRI: Stroke, TIA, White matter involvement
• SPECT or PET

Respiratory:

• Lung function tests
• Exercise tolerance test
• D-dimer
• CXR
• ECG, troponin T

Cardiovascular:

• Pulse oximetry
• ECG
• N terminal BNP

POTS:

• NASA 10-minute lean test
• Tilt table test for autonomic function (Investigations for other causes of autonomic dysfunction/POTS if positive)
• 24-hour ECG and BP

Fatigue and Brain fog:

• Psychiatric evaluation
• Brief cognitive screening test
• CRP
• MRI  /SPECT / PET (if indicated) due to abnormal neuropsychiatric symptomatology

GI:

• Bilirubin
• Alkaline Phosphatase (ALP)
• Gamma Glutamyl Transaminase (GGT)
• Alanine Transaminase (ALT)
• Aspartate Transaminase (AST)
• Amylase

Sleep:

• Polysomnogram
• Multiple sleep latency test (MSLT)
• Assess daytime somnolence (e.g., using Epworth sleepiness scale); exclude underlying causes (e.g., obstructive sleep apnoea using STOP-Bang questionnaire)

TREATMENT IN POST-COVID SYNDROME [Crook et al., 2021]

Management of Pulmonary symptoms:

• Multidisciplinary management involving respiratory specialists.
• Patients with continuing respiratory symptoms should have a CXR by 12 weeks after infection.
• Limiting factors that exacerbate dyspnoea include stopping smoking, avoiding pollutants, avoiding extremes in temperature, and exercising.

Non-pharmacological interventions for dyspnoea:

• Breathing exercises
• Pulmonary rehabilitation
• Maintaining optimal body positioning for postural relief

Pharmacological treatment:

• Oral opioids (morphine and dihydrocodeine) may help treat dyspnoea in people with long COVID.

Possible mechanisms of action of opioids include: [Jennings et al., 2002]

• Reduction in the central perception of dyspnoea (similar to the decrease in the central perception of pain)
• Reduction in anxiety associated with dyspnoea
• Decrease in sensitivity to hypercapnia
• Reduction in oxygen consumption and improved cardiovascular function.

Treatments showing promise for respiratory involvement

• Hyperbaric oxygen
• Montelukast (cysteinyl leukotriene receptor antagonist, which inhibits leukotrienes which are potent mediators of inflammation leading to contraction of bronchiolar smooth muscle, increased mucous production etc.)
• Deupirfenidone (an anti-fibrotic and cytoprotective agent)

Management of  Cardiovascular symptoms:

• Post-COVID chest pain: rule out pulmonary emboli, pericarditis, myocarditis, and other cardiac abnormalities
• Pain medication for chest pain.
• β blockers may be helpful in angina, cardiac arrhythmias, and acute coronary syndromes. They may also help reduce palpitations.
• Myocarditis may resolve over time.
• Supportive and/or immunomodulatory therapy may improve recovery. [Sinagra et al., 2016]
• Anticoagulants may be used to reduce the risks associated with hypercoagulability.
• Since NETosis is associated with hypercoagulability, agents that attenuate NETosis may reduce hypercoagulability. Vitamin C is an antioxidant that significantly attenuates NETosis in healthy neutrophils by scavenging ROS and may be beneficial in Long COVID. [Zhu et al., 2022]. 

Management of Fatigue and ‘Brain Fog’: 

Cognitive impairment in long COVID, sometimes called “brain fog”, has been compared to “chemobrain”. 

Brain fog is also a common symptom of CFS.

Strategies that are effective in CFS or “chemobrain” may be repurposed for Long COVID.

• Repeating exercises
• Cue detection – Tracking cues that exacerbate fatigue
• Stress relief and coping strategies.
• Pacing is recommended as a treatment for PEM.[Davis et al, 2023].
• Hyperbaric oxygen therapy (HBOT) and enhanced external counterpulsation (EECP).
• Physical therapy course (8 weeks biweekly) comprising aerobic training, strengthening exercises, diaphragmatic breathing techniques, and mindfulness training improved muscle strength and physical function. [Joli et al., 2022]
• Recent guidance from NICE recommends against the routine use of GET or CBT in treating CFS, and these recommendations would also apply to Long COVID as they may pose potential harm in some instances. [Yong, 2021]

Do not advise people with ME/CFS to undertake exercise that is not part of a programme overseen by an ME/CFS specialist team, such as telling them to go to the gym or exercise more, because this may worsen their symptoms.

An individualised approach should be taken for people with ME/CFS who choose to undertake a physical activity or exercise programme…

The committee wanted to highlight that cognitive behavioural therapy (CBT) has sometimes been assumed to be a cure for ME/CFS. However, it should only be offered to support people who live with ME/CFS to manage their symptoms, improve their functioning and reduce the distress associated with having a chronic illness. [NICE guidelines]

Supplements for Fatigue and Cognitive Impairment:

Luteolin:

• Luteolin is a natural flavonoid that may alleviate cognitive impairment by inhibiting mast cell and microglial activation. [Theoharides et al., 2021]

Vitamin C

• High-dose intravenous vitamin C could be a beneficial treatment option. [Vollbracht and Kraft, 2021]

Nicotinamide Riboside

• May reduce cognitive symptoms and fatigue by modulating pro-inflammatory cytokines.

Probiotic supplementation:

• Probiotic supplements normalise the gut microbiome’s composition and reduce inflammation in long COVID.

Coenzyme Q10 and D-ribose may help address fatigue through improving mitochondrial function. [Davis et al, 2023].

Medications: [Crook et al., 2021]

• Methylphenidate
• Donepezil
• Modafinil
• Memantine

Dopaminergic agents, e.g. psychostimulants or dopaminergic antidepressants 

• Dopamine directly affects cerebral blood vessels and, thus, the control of local cerebral cortical blood flow.
• Amphetamine results in both vascular and microvascular responses, increasing cerebral blood flow and reducing the diffusion distance for oxygen. [Russo et al., 1991].

Clinical tips: 

• Since DA plays an important role in the pathophysiology of cognition, brain fog, fatigue, pain, mood, sleep, postural tone, and top-down control of emotional arousal, dopaminergic potentiation can provide multiple benefits in patients.
• Dopaminergic potentiation requires a stepwise approach, usually with augmentation strategies to manage emotional arousal and hyperarousal, which can be exacerbated with DA potentiating agents.

Antidepressants:

• Serotonin-noradrenaline reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) reduce peripheral inflammatory markers and cytokines.
• Thus, they may reduce the impact of long COVID.

Clinical tips:

• Duloxetine and Milnacipran are valuable agents in treating fibromyalgia symptoms such as pain and allodynia in Long COVID. The Neuropsychiatry of Fibromyalgia – Etiology and Management
• SSRIs at higher doses can reduce dopamine in the ventral striatum, worsening cognitive deficits or brain fog.
• Consider dopaminergic antidepressants (Bupropion, SNRIs, Vortioxetine, Armodafinil, Modafinil or Psychostimulants).

Antipsychotics:

Antipsychotics also have anti-inflammatory and immunomodulatory effects. [Mondelli & Howes,2014]

Low dose aripiprazole has been recommended in fatigue, unrefreshing sleep, brain fog. The evidence is drawn from ME/CFS.  literature. [Davis et al, 2023].

Clinical tips:

• Antipsychotics are valuable agents in managing agitation (low doses are needed).
• Higher doses can increase the likelihood of side effects (due to a possible dopamine deficit state induced by inflammation).
• Reduction of agitation improves response to antidepressants.
• Reduction of agitation improves cognitive function and reduces pain.

Management of Sleep Disturbances:

• Sleep hygiene measures (e.g., structured routines, exercise based on ability, avoiding shift work if possible, avoiding caffeine, alcohol and short daytime naps)
• Melatonin should be considered a first-line agent to treat sleep-wake rhythm disorders. [Hosseini et al, 2022]
• Melatonin may help restore circadian rhythms in some cases.
• Melatonin may act as an immune buffer with immunomodulatory effects, which can improve several inflammation-related symptoms. [Carrillo-Vico et al., 2013]
• Evidence suggests Melatonin can improve insomnia, depression, fatigue, and “brain fog”, but not tachycardia. [Jarrott et al., 2022]
• High melatonin doses of up to 10 mg have been administered to COVID-19 ICU patients to prevent and treat delirium and sleep disturbances. [Pataka et al, 2021].
• Fluvoxamine has shown benefits in limiting disease progression in mild to moderate COVID-19 illness in a randomised trial, and besides its action via sigma-1 agonism, increased melatonin is another postulated mechanism as fluvoxamine almost tripled the plasma levels of melatonin. [Hashimoto et al, 2022].

Clinical tips: 

• If insomnia is present due to hyperarousal indicated by nightmares, vivid dreams or sweats, then α-2 agonists such as clonidine or guanfacine can be effective. Reduction of hyperarousal can improve cognition and reduce pain.
• Doses of clonidine required are often in the range of 100-200 mcg nocte.
• A recent case series showed benefits of guanfacine (1 mg nocte bedtime for the first month, increased to 2 mg after 1 month, if well-tolerated) and 600 mg NAC daily.  The combination showed benefits for “brain fog” including difficulties in executive functions. Those who stayed on guanfacine plus NAC reported improved working memory, concentration, and executive functions, including a resumption of normal workloads. [Fesharaki-Zadeh,,2022].
• Prazosin or clonidine may be beneficial in insomnia due to nightmares in Post-COVID PTSD-like symptoms.
• Insomnia with agitation may need low-dose antipsychotic agents with sedative properties (e.g. quetiapine or olanzapine)
• Benzodiazepines may provide relief in the short term but may worsen ‘brain fog’ with long-term use.

Pain:

• NSAIDs.
• Mobilisation within personal limits.
• Neuropathic agents (amitriptyline, gabapentin, pregabalin) in chronic cases, especially if neuropathic symptoms.
• Noradrenergic agents such as Duloxetine, Milnacipran and Levomilnacipran can benefit patients with pain syndromes.

Fibromyalgia: see the article

Management of POTS:

Multidisciplinary input from a cardiologist is essential.

Midodrine: 

• Peripheral α-1 agonist that serves as a vasoconstrictor.
• Most useful in patients with “neuropathic POTS”, associated with a failure of vascular resistance.

EMERGING TREATMENTS

Treatment for long COVID should be delivered locally and within integrated healthcare systems where possible, with GPs playing a vital role in the multidisciplinary team. [Nurek et al., 2021]

Fundamental principles of treatment: [Nurek et al., 2021]

• Holistic care pathways
• Investigation of specific complications
• Management of potential symptom clusters
• Tailored rehabilitation

Those at high risk for post-acute COVID-19, including those with a severe illness during acute COVID-19/required care in an ICU, those most susceptible to complications and those with the highest burden of persistent symptoms must be prioritised for treatment and follow-up. Even recovered patients may have persistently increased cardiometabolic demand, as observed in the long-term evaluation of SARS survivors. [Wu et al., 2017]

While similarities have also been drawn between post-COVID-19 fatigue and ME/CFS, with overlapping symptoms involving reduced daily activity, long symptom length and post-exertional malaise, there also exist differences between the two. [Wong et al., 2021]

Differences between CFS/ ME and Long COVID: 

COVID-19 is associated with elevated levels of virus-specific antibodies in the saliva (At 3-6 months after mild/asymptomatic SARS-CoV-2 infection), signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K).

In patients with ME/CFS, antibody responses were significantly stronger, particularly for EBV, indicating an altered immune response that may be responsible for the prolongation of symptoms in some individuals. [Apostolou et al, 2022]

• In long COVID, the infection as a trigger was generally documented. In CFS /ME, the infectious trigger is not always known.
• Long COVID patients were initially more symptomatic than CFS / ME patients with respect to the immune (respiratory symptoms, fever and lymph nodes) and orthostatic domains.
• ME/CFS patients displayed more gastrointestinal and neurocognitive symptoms.
• Long COVID patients reported an improvement in most symptoms over time except for neurocognitive symptoms.
• The illness duration was longer in CFS / ME patients. [Castanares-Zapatero et al.,2022]

Research on long COVID may also help to unlock some of the mysteries surrounding ME/CFS. [Crook et al., 2021]

Immunomodulation: [Crook et al., 2021]

Tocilizumab blocks IL-6 receptors and has shown efficacy in a small trial of patients with COVID-19.

Adjuvant treatments, such as adaptogens, are being explored.

Paxlovid a co-packaged combination of nirmatrelvir, a second generation protease inhibitor, and ritonavir shows promise in prevention. [Davis et al, 2023].

BC007, potentially addresses autoimmunity by neutralising G protein-coupled receptor autoantibody levels. [Davis et al, 2023].

Sulodexide, an orally administered highly purified mixture of glycosaminoglycan that includes fast-moving heparin and dermatan sulfate reduced symptom severity in individuals with endothelial dysfunction. [Davis et al, 2023].

Sulodexide is postulated to have  beneficial effects on the fibrinolytic system, platelets, endothelial cells, and inflammation.

Because of the global scale of the pandemic and the severity of systemic inflammatory responses in people who have had COVID-19, healthcare models and services will require scaling up at pace, with many GP clinics now offering Long COVID clinics. [Nurek et al., 2021]

Patient advocacy groups have also become instrumental in identifying persistent symptoms and influencing research and clinical development. Active engagement with these group members, many of whom identify as long haulers, is crucial for effective management, monitoring and future policymaking. [Nature 2020]

Prognosis: 

Complete recovery is uncommon in long COVID

One study showed that 85% of patients who had symptoms 2 months after the initial infection reported symptoms 1 year after symptom onset. [Davis et al, 2023].

CONCLUSION

With a growing number of people infected and continuing to be infected with COVID-19, the long-term implications of long COVID and post-COVID-19 illness are of increasing concern [Nalbandian et al., 2021].

The range of possible conditions is vast, with multiple organs and structures at risk [Nurek et al., 2021].

Pre-existence of asthma has also been significantly associated with long covid complications. [Sudre et al., 2021]

The plethora of recent research provides early evidence for clinicians to identify those at the highest risk of post-acute COVID-19 illness [Nalbandian et al., 2021].

Future research should include identifying and classifying clinical, serological, imaging, and epidemiological features of COVID-19 in the acute, subacute and chronic phases of the disease to help us better understand the history and pathophysiology of post-COVID-19 conditions.

This will ultimately facilitate safe and effective treatment strategies and help build solid interdisciplinary healthcare networks. [Radia et al., 2021]; [Nalbandian et al., 2021]