Educational Aims
The reader will come to appreciate:
Our current understanding of what Post Covid Syndrome (PCS) represents.
The presentation and assessment of children and young people (CYP) with PCS.
Management strategies to address symptoms and their impact on functioning.
Abstract
Post Covid Syndrome (PCS) is a complex multi-system disorder with a spectrum of presentations. Severity ranges from mild to very severe with variable duration of illness and recovery. This paper discusses the difficulties defining and describing PCS. We review the current understanding of PCS, epidemiology, and predisposing factors. We consider potential mechanisms including viral persistence, clotting dysfunction and immunity. We review presentation and diagnosis and finally consider management strategies including addressing symptom burden, rehabilitation, and novel therapies.
Introduction
Post COVID syndrome (PCS), also known as Long COVID, was first described in May 2020 in adults following infection with SARS-CoV-2 in the first wave of the pandemic. By October 2020 it was apparent some children and young people (CYP) were also experiencing persistent debilitating symptoms following SARS-CoV-2 infection, with predominance of fatigue, post exertional malaise, brain fog, headache, autonomic dysfunction, and breathlessness.
Studies have sought to describe and define this complex syndrome in an emerging group of CYP, in the absence of a diagnostic test. The available literature, therefore, has limitations, particularly the initial lack of a clear case definition, inclusion of CYP without confirmation of SARS-CoV-2 infection, reliance on self- or parent-reported symptoms without clinical assessment, variable follow-up times, poor response rates, recall bias, and often the absence of a control group .
PCS is now known to be a chronic multi-system disorder affecting adults, children, and young people with a fluctuating course. Its effects can be debilitating, interfering with even basic activities of daily life and has an impact on the whole family. This review aims to summarise our understanding of the syndrome, its pathophysiology, symptoms, prognosis and management options, and the many uncertainties that remain.
What is PCS in Children and Young People (CYP)?
The World Health Organisation(WHO) and UK National Institute for Health and Care Excellence(UK NICE) definitions of PCS in CYP broadly agree on criteria for a clinical diagnosis of Post Covid Condition/syndrome including the persistence of symptoms for more than 2–3 months after the onset of SARS-COV-2 infection, for which there is no alternate explanation, and which has an impact on a young person’s ability to carry out normal daily functioning . The Delphi research consensus established in 2022 concluded the diagnostic criteria were met with at least one persistent impacting symptom provided alternate diagnoses have been ruled out ( Table 1 ).
| Clinical Definition | |
|---|---|
| Post Covid-19 Condition World Health Organisation (WHO) [2] | Post COVID-19 condition in children and adolescents occurs in individuals with a history of confirmed or probable SARS-CoV-2 infection, when experiencing symptoms lasting at least 2 months which initially occurred within 3 months of acute COVID-19. Symptoms generally have an impact on everyday functioning such as changes in eating habits, physical activity, behaviour, academic performance, social functions (interactions with friends, peers, family) and developmental milestones. Symptoms may be of new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. They may also fluctuate or relapse over time. Workup may reveal additional diagnoses, but this does not exclude the diagnosis of a post COVID-19 condition. This can be applied to children of all ages, with age-specific symptoms and impact on everyday function taken into consideration. |
| Post Covid-19 Syndrome UK National Institute for Health and Care Excellence (UK NICE), Scottish Intercollegiate Guidelines Network (SIGN) and Royal College of General Practitioners (RCGP) [3] guideline: | Signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks, and are not explained by an alternative diagnosis. It usually presents with clusters of symptoms which may overlap, fluctuate, change over time, and affect any body system. |
| Research Definition | |
| Post Covid-19 Condition Stephenson et al (2022) by modified Delphi process | Post-COVID-19 condition occurs in young people with a history of confirmed SARS-CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID infection, and may fluctuate or relapse over time. |
Although fatigue is almost universally present, commonly with headaches, post-exertional malaise and brain fog, more than 200 symptoms have been reported affecting every system of the body and impacting both physical and mental health. Symptoms can persist from the initial infection, follow a period of recovery, or occur following initially asymptomatic or pauci-symptomatic infection. Severity of initial SARS-CoV-2 infection has little predictive value for subsequent PCS risk. Symptoms often fluctuate over time with a relapsing and remitting course. Patients report that whilst some symptoms improve others can emerge. Recurrent SARS-COV-2 infection can be problematic for some but may go unnoticed by others.
Diagnostic challenges
Differentiating PCS from other illnesses and post pandemic effects can be challenging (see Fig. 1 ). Symptoms such as headaches and fatigue are common in adolescence with more than 30% of surveyed adolescents reporting fatigue prior to the pandemic . The effect of lockdown, social isolation, limited education and bereavement or illness within close family members had a significant effect on the health of CYP over the same pandemic period and has given rise to a so-called Post/Long Pandemic syndrome . School absence remains higher than pre pandemic levels . Studies using self-assessed symptom reporting of PCS in young people have found that up to 50% of participants with negative SARS-COV-2 antigen and/or antibodies report symptoms linked to PCS , although the severity of symptoms is not compared. A large nationwide cohort study found fatigue, loss of smell and taste, dizziness, muscle weakness, chest pain and respiratory problems were reported more frequently in children with SARS-COV-2 infection than controls, but found concentration difficulties, headache, muscle pain, joint pain and nausea were more frequently reported in controls .
As SARS-CoV-2 has become endemic, with testing not readily available, distinguishing PCS from other post viral fatigue syndromes requires increasingly complex assessments, clinical expertise, and robust diagnostic criteria.
Epidemiology
Early studies suggested prevalence of PCS ranged between 4% and 66% often using self- or parent- reported symptoms, with unconfirmed prior infection and variable time points . Subsequent studies including an uninfected control group narrowed the likely prevalence to 1–16% with a metanalysis showing a prevalence of 4% or less in all but one study . Estimates from large population-based studies suggest around 1–5 % of young people aged 11–24 are affected . Recent data from the UK Office for National Statistics suggests >99% of CYP have been exposed to SARS-CoV-2. Furthermore, the incidence of PCS is now < 1% .
Predisposing Factors
Observational studies have described some possible risk factors for developing PCS. A female preponderance is seen, with older adolescents and those from lower socioeconomic groups more likely to develop PCS. Acute symptomatic infection, requiring hospital admission, increased number of symptoms and pre Omicron variants correlate with increased risk. Co-existing medical conditions such as atopy, obesity , hypermobility and Vitamin D deficiency have also been associated with PCS, whilst a family history of disorders with predominant fatigue is common .
Although a previous psychiatric history has been noted as a risk factor in some studies , others have not found preceding mental health symptoms to be any more common in PCS patients compared to controls . However neurodevelopmental conditions including Attention-Deficit/Hyperactivity Disorder (ADHD) and Autistic Spectrum Conditions (ASC) appear to be overrepresented .
The impact of vaccination remains unclear with evidence to suggest it may reduce the risk of PCS whilst anecdotally some patients have reported onset of PCS or worsening of symptoms post vaccination.
Pathophysiology
Multiple mechanisms for PCS have been proposed ( Fig. 2 ). Theories include persistent viral antigen load, microvasculature or endothelial dysfunction and/or dysregulation of immunological, inflammatory, autoimmune or coagulation pathways . It is likely there is overlap with the spectrum of clinical phenotypes related to variable pathophysiology. A biological marker for PCS has not been found for CYP or adults.
Viral persistence
Persistent SARS-CoV-2 RNA has been found at multiple sites outside the respiratory system at autopsy in adults up to 230 days after symptom onset despite being undetectable in plasma . Viral persistence has also been demonstrated in children with SARS-CoV-2 RNA detected in cardiac, respiratory, gastrointestinal, renal, lymphoid and central nervous system tissues, and persisting for weeks to months regardless of disease severity . Stool samples with persistently positive quantitative PCR for SARS-COV-2 have been frequently reported, but without clear correlation to symptoms, whilst gut biopsies may show a gut viral reservoir more reliably associated with PCS .
A study of 63 adult patients with PCS compared with fully recovered controls found 60% of PCS patients continue to have detectable SARS-CoV-2 spike protein compared to controls, in whom levels quickly become undetectable .
Dysbiosis
Disruption to the normal bacterial composition of the gut, termed dysbiosis, has been investigated in PCS. It is proposed that imbalance of the microbiome can affect the functional and metabolic activities in the surrounding environment. Preliminary data seem to suggest that gut and airway dysbiosis may play a role but the nature of this requires further investigation .
Role of immunity
There is ongoing research to describe the immune responses associated with PCS but marked heterogeneity between studies including differing definitions of PCS, SARS-COV-2 variants, vaccination status, time from onset of symptoms and immune markers included makes conclusions challenging. In addition, the research on immune responses in PCS surpasses that of any preceding post viral syndrome, leading to uncertainty about whether mechanisms are unique to SARS-COV-2 or part of a more widespread post viral response.
A number of mechanisms have been proposed, including dysregulated adaptive immune responses, elevated levels of autoantibodies, impaired antibody responses, reactivation of latent viruses such as Epstein-Barr Virus (EBV) and Human Herpes Virus 6 (HHV6), impaired T cell responses and mast cell activation . Women are less likely to seroconvert and have low antibody levels but are more likely to have autoimmune responses and develop PCS whilst those with strong innate immune responses, reduced expression of angiotensin converting enzyme 2 (ACE2) receptors and active thymic function are at reduced risk [5].
Multi-omic approaches suggest specific immune responses during acute SARS-CoV-2 infection may correlate with later PCS phenotypes. Low cortisol, traditionally associated with fatigue, muscle weakness, dizziness and mood disturbance, has been suggested as a potential biomarker of PCS, whilst CCL11, a chemokine previously identified as a mediator of neurocognitive decline has been found to be higher in male patients with brain fog . A 43 % increased rate of autoimmune conditions post SARS -CoV-2 infection has been noted in adults . Increased detection of anti-nuclear antibodies, lupus-like anti-nuclear antibodies and antiphospholipid antibodies have been associated with PCS and may play a role in endothelial activation and thrombotic risk.
Vascular/endothelial/clotting dysfunction
Endothelial dysfunction in patients with severe acute SARS-CoV-2 infection was apparent early in the pandemic, and pre-existing endothelial disease in conditions such as diabetes, cardiovascular disease and obesity conferred an increased risk for severe illness. Endothelial inflammation results in altered arterial stiffness, vascular reactivity and capillary morphology, and a hypercoagulable state which can persist for many months.
Acute SARS-CoV-2 infection in adults is strongly associated with an increased risk of thrombosis, with an elevated D-dimer being associated with poor outcomes. Thrombotic events are rare in CYP with SARS-CoV-2 infection. In a multicentre retrospective cohort study of 853 paediatric admissions with SARS-CoV-2 infection, 9/138 (6.5%) children with multisystem inflammatory syndrome in children (MIS-C), 9/426 (2.1%) with acute SARS-CoV-2 infection and 2/289 (0.7%) with asymptomatic infection had thrombotic events . Whilst these rates are higher than expected, the results are complicated by associated comorbid conditions such as cancer, obesity and diabetes and additional risk factors such as central venous lines, immobility and multi-organ dysfunction in those hospitalised with acute SARS-CoV-2 infection.
Pretorius reported abnormal amyloid-like fibrin ‘microclots’ in patients with PCS alongside normal coagulation profiles. A subsequent Cochrane review of five laboratory studies reporting amyloid fibrin(ogen) deposits found these were no more frequently observed in PCS patients than healthy controls and furthermore suggested the term ‘microclots’ is a misnomer.
A hypercoagulable state in PCS has been quantified by an increased von Willebrand factor antigen (VWF(Ag))/ADAMTS13 ratio in adults. In a study of adult PCS patients, an elevated VWF(Ag)/ADAMTS13 ratio (≥1.5) was present in nearly one-third of the cohort and was 4 times more likely to be present in patients with impaired exercise capacity , supporting the theory of microvascular/endothelial dysfunction.
Little is known about thrombotic markers in CYP. DiGennaro et al assessed 75 children and found D-dimer levels were more frequently elevated amongst those with PCS,particularly those severely affected compared to controls, but the remainder of the extended clotting profile was normal across both groups. It is possible that endothelial dysfunction and coagulopathy is driven by an inflammatory process similar to that seen in antiphospholipid syndrome . One study assessing the histopathology of paediatric ‘COVID toes’ found SARS-CoV-2 within the endothelial cells at biopsy with lymphocytic vasculitis of varying severity .
Dysautonomia
Moderate to severe dysautonomia has been reported in two thirds of patients with PCS . Many of the symptoms associated with PCS, such as dizziness, palpitations are associated with dysautonomia. Postural Orthostatic Tachycardia Syndrome (POTS) is an increasingly recognised co-morbidity . The relationship between SARS-CoV-2 infection and dysautonomia is unclear, and proposed mechanisms include the presence of autoantibodies against autonomic nerve fibres, directly neurotoxic effects of the SARS-CoV-2 virus or cytokine hyperactivation causing overstimulation of the sympathetic nervous system .
Neuroinflammation
Multiple neurocognitive symptoms have been reported in PCS and are collectively referred to as brain fog. Emerging evidence suggests that dysregulated immune responses may be responsible for alterations to the blood-brain barrier, proinflammatory cytokine release within the central nervous system (CNS) and myeloid cells within the brain parenchyma causing neuroinflammation . However, indirect effects of chronic pain, neurodevelopmental diagnoses and psychosocial factors can complicate presentations. Conventional CNS sampling and imaging are typically normal however longitudinal imaging has demonstrated reduced grey matter thickness and reduced brain volume in patients with PCS as well as higher levels of plasma CCL11 in those with brain fog .
Symptoms & functional impact
Fatigue, post exertional malaise, headaches, sleep disturbance and cognitive difficulties are characteristic of PCS, with fatigue and headache most common .
A wide spectrum of symptoms has been reported and careful assessment is required to ensure alternative diagnoses are not missed. Wacks et al. provide a useful tool in their recent paper .
Symptom onset is highly variable with some patients failing to recover from acute infection and others presenting later. In one study, 64.5 % presented after 4 weeks and 35.5 % presented up to 8 weeks later .
Symptoms have been reported to last a median duration of 4.1 months but over a third of patients experience persistent symptoms beyond six months . Those presenting with multiple or more severe symptoms at onset correlate with an increased risk of persistent symptoms at 6 months . The wide range and large number of reported symptoms, variable onset, fluctuating course and symptom duration make the PCS clinical phenotype particularly difficult to delineate. Overlaps with post viral syndrome and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as functional conditions are commonly noted.
Living with PCS can have a significant impact on the lives of affected CYP. Functional impact can be measured in several ways such as ability to attend education and activities. In one study more than half of patients affected were not attending school full time, whilst 68 % had stopped extracurricular activities .
Assessment and diagnosis
A positive diagnosis is an important first step in the management of PCS. Alternative diagnoses should be excluded and a comprehensive assessment for secondary organ damage, complications and comorbidities completed, including autonomic dysfunction or secondary impact on mood.
Physical examination
This should be undertaken to elucidate comorbidities.
Bedside tests
The active lean test (NASA) should be undertaken to investigate orthostatic intolerance where appropriate. One minute sit to stand test (or 6-minute walk test) should be done to exclude oxygen desaturation in breathless patients or where indicated.
Investigations
Screening blood tests should be done as per the UK NICE guideline for ME/CFS (full blood count, urea and electrolytes, liver function, thyroid function, erythrocyte sedimentation rate, C-reactive protein, calcium, phosphate, HbA1c, serum ferritin, coeliac screening, creatinine kinase and urinalysis for protein, blood and glucose) . Additional tests such as vitamin D, B12, folate, autoimmune screen, VWF(Ag)/ADAMTS-13 ratio, D-dimer and 9am cortisol should be considered , as well as investigations into specific systems such as brain MRI or gastrointestinal investigations where indicated.
Principles of management
Whilst pathophysiological mechanisms are still uncertain, it is important to provide a holistic assessment to ascertain a formulation and provide a feasible biopsychosocial explanation to patients and parents. Care should be taken to avoid any implication that symptoms are psychologically driven or that the patient is responsible for their presentation, however it is important to assess whether the illness has influenced mood.
Management should aim to address the symptoms, performing appropriate investigations to assess for complications and comorbidities and direct further treatment .
Supported self-management is the mainstay of further care. The WHO Rehabilitation: self management of young people with long COVID ( https://www.who.int/europe/publications/i/item/WHO-EURO-2023-8018-47786-70552 ) and NHS ‘Your covid recovery’ websites have useful resources: https://www.yourcovidrecovery.nhs.uk/children-and-young-people-with-covid .
Holistic Rehabilitation
Fatigue can be managed using a routine with a paced approach to activity management, balancing the level of cognitive and physical exertion over the course of the day. ‘Boom and bust’ must be avoided as over exertion can cause worsening of symptoms in the subsequent days.
Care should be taken to address sleep dysregulation, which is common. Sleep hygiene measures should be promoted, and melatonin can serve as a useful adjunct.
A healthy diet is important. Weight loss or gain should be carefully assessed with referral to dietetics where needed. Emphasis should be on a well-balanced diet without exclusion of food groups unless specifically indicated. Meals may need to be smaller and more frequent.
Wellbeing and psychological support are an especially important aspect of care and should be tailored to each individual patient. PCS frequently has a psychological impact, and this should be addressed alongside physical symptoms.
Patients should be supported to return to school. Providing letters for school to allow a flexible reduced timetable is often effective to make school more consistently manageable. Once a manageable baseline timetable has been trialled this should be consolidated for several weeks before slowly increasing.
Symptom Management
Respiratory symptoms
Cough and shortness of breath are described in approximately 16% and 12% of adolescents, respectively, and are the most common respiratory symptoms of PCS. Persistent cough is characterized by a resolution potential of 4‑8 weeks after disease onset and is prevalent in at least 1% of convalescent children, while the risk of persistent dyspnoea was significantly higher in children exposed to SARS‑CoV‑2 than in healthy controls .
Twelve CYP with PCS and exercise induced dyspnoea who had mild SARS-CoV-2 infection were investigated with spirometry, lung volumes, gas transfer and cardiopulmonary exercise testing (CPET). Spirometric indices, gas transfer and lung volumes were normal in all children assessed. No cardiac or pulmonary limitation was seen in any of the patients and the main cause of dyspnoea was noted to be due to breathing pattern disorders as identified on CPET . The pathophysiology of altered breathing mechanics in PCS is largely unknown but has been linked to autonomic nervous system dysregulation , biomechanical and psycho-physiological factors. Several other studies have shown similar findings of normal spirometry and lung volumes .
Another study utilised low-field-strength MRI to identify persistent pulmonary manifestations after SARS-CoV-2 infection. 54 children and adolescents with previous SARS-CoV-2 infection (29 recovered, 25 with long COVID) were compared with nine healthy controls. Using functional parameters, the authors found a reduction in ventilation-perfusion (V/Q) match from 81% ± 6.1 (SD) in healthy controls to 62% ± 19 (p =.006) in the recovered group and 60% ± 20 (p =.003) in the group with PCS . A recent study using lung perfusion in 14 CYP with PCS using 99mTc-MAA SPECT/CT showed perfusion defects in around 40%, allowing the authors to speculate several pathophysiological explanations for these findings including chronic endothelitis secondary to circulating microclots and hyperactivated platelets as described in adults .
Most of the published studies have limited numbers of CYP with PCS and there is a paucity of studies with matched controls. Furthermore, respiratory assessment and management is not standardised, being mostly dictated by physician bias, skills, and resources available. There is a paucity of longitudinal data that would have given us a better understanding of the trajectory of recovery in these CYP.
CYP with breathing pattern disorders are referred to a specialist respiratory physiotherapist for assessment of breathing pattern at rest and exercise and management includes techniques to optimise breathing.
Cardiovascular symptoms
Whilst early adult studies suggested abnormalities on cardiac magnetic resonance imaging in up to 78 % of subjects, more recent studies have found little evidence of prolonged or persistent inflammation even in those with persistent symptoms and PCS . Webster et al evaluated 17 children with symptomatic SARS-CoV-2 infection or MIS-C compared with healthy controls and found no difference in cardiac appearances or biochemical markers at 2 months follow up. One study of 121 children with SARS-CoV-2 infection reported symptoms of chest and back pain, dizziness, headache, palpitations, fatigue, shortness of breath, loss of balance and coughing persisted for at least 1 month after SARS-CoV-2 in 37.2% of cases. Statistically significant differences were found in systolic blood pressure, left ventricular ejection fraction, relative wall thickness, and tricuspid annular plane systolic excursion when compared with a group of 95 healthy controls .
Inappropriate sinus tachycardia (IST), orthostatic intolerance and Postural Orthostatic Tachycardia Syndrome [POTS] are increasingly recognised sequalae of PCS, thought to be driven by autonomic dysfunction in addition to variable degrees of deconditioning .
24-hour ECG monitoring can demonstrate a persistent IST relative to the patient’s age and activity levels whilst a postural heart rate increase of more than 40 with NASA lean testing is suggestive of POTS. Assessment should look to exclude other contributory factors such as weight loss, underweight, or dehydration and examine for other features of autonomic dysfunction.
Non-medical management is first line and should include optimization of fluid intake and additional salt in the diet. Exercises using sustained muscle contraction should be used with attention to minimise triggers such as prolonged hot showers. They should be started recumbent, and at a comfortable baseline to avoid post exertional malaise. Compression stockings can be used whilst patients should be encouraged to spend more time upright and slowly reintroducing paced activity management to avoid additional effects of deconditioning.
After comprehensive assessment, sodium chloride tablets, beta blockers (such as bisoprolol or propranolol) calcium channel blockers (such as midodrine), ivabradine and fludrocortisone can be useful where non-pharmacological measures prove insufficient, usually after advice from cardiologists .
Neurological, cognitive, and psychiatric symptoms
Headaches, sensorimotor symptoms, cognitive impairment (often termed ‘brain fog’ with impaired cognitive function, memory, and concentration), sensitivity to light, noise, smell, touch (allodynia) taste, and audio vestibular symptoms have been frequently seen despite the absence of proven CNS infection. Mood, anxiety, and sleep disturbances are some of the most commonly reported symptoms in PCS whilst less commonly reported are hallucinations and behavioural disturbance, sudden onset tics and obsessive–compulsive symptoms.
Chronic daily or chronic migrainous type headaches are most seen, with standard treatments often ineffective. Treatment of dysautonomia may be helpful. A trial of migraine treatments, amitriptyline, gabapentin, occipital nerve injections and alternative therapies such as acupuncture may also provide some relief.
Difficulties with executive functioning are particularly notable and have significant implications for education. These can be addressed with careful assessment of the areas of difficulty. Strategies to break tasks down into smaller more manageable chunks can help. Pacing should take account of the cognitive load and the need for regular rest breaks.
Gastrointestinal symptoms
Persistent abdominal pain, nausea and loss of appetite occur in a proportion of PCS patients. Symptoms can be compounded by altered smell and taste leading to restricted intake and weight loss and present a treatment challenge in more severely affected cases. In contrast, diarrhoea is considered a relatively common transient symptom of SARS-CoV-2 infection, encountered in approximately 6% of convalescent adolescents .
Dietetic support may be needed to ensure calorie intake and nutritional requirements are met. Probiotics can be helpful. For severe functional abdominal disorders nortriptyline can provide pain management whilst mirtazapine has a secondary benefit of appetite stimulation.
Parosmia
Loss of smell is reported in up to 21 % of patients with PCS and can serve as a useful discriminator from other post viral syndromes. Parosmia, the experience of certain smells becoming altered and unpleasant, typically begins 2–3 months after acute infection. Parosmia has been linked with specific chemicals within food which provoke particularly strong sensations of disgust and these may need to be avoided. Smell retraining ( https://abscent.org/ ) and dietary modifications offer supportive management over a period of prolonged recovery of months to years.
Novel and Experimental Treatments
Antivirals
Xie et al demonstrated a reduced risk of PCS in adults (mean age of 62 years) with a risk of severe disease when treated with nirmatrelvir in the acute phase of SARS-COV-2 infection, thus supporting the role of viral clearance in PCS aetiology. Its applicability to a paediatric population in whom acute severe disease is rare is limited. The role of antivirals in PCS in either adults or children has not been established. Other immune modulatory therapies are being explored and there is some suggestion that vaccination can be helpful .
Aspirin and anticoagulants
As moderately ill hospitalised adults with COVID may benefit from therapeutic anticoagulation and tocilizumab, which directly targets endothelial dysfunction, leads to improved outcomes , the role of antithrombotic therapy has been explored in PCS. However, there is currently little evidence to support prophylactic anticoagulation in adults with PCS, whereas the risk of bleeding is notable.
There is no evidence to date to support antithrombotic therapy in CYP with PCS. Aspirin, clopidogrel, anticoagulation, and plasma apheresis are not recommended. The increased risk of injuries alongside the absence of any proven benefit in this age group makes any blood thinning treatment particularly concerning.
H1 and H2 antihistamines
H1 and H2 antihistamines have been proposed for the treatment of PCS as 72% of 49 adults with PCS treated with histamine receptor antagonists in an observational study reported clinical improvement. Additional research has suggested histamine potentiates SARS-CoV-2 spike protein entry into endothelial cells and that these effects can be blocked by famotidine (an H2 receptor antagonist) . Results from a large randomised control trial are awaited to determine the effectiveness of combined H1/H2 receptor antagonists in adults with PCS. H1 antihistamines are widely available and can be purchased over the counter. These may have a useful, albeit unproven role in patients with PCS and a background of atopic illness. H2 antihistamines are less widely available. Ranitidine was removed from paediatric formularies due to a safety alert in 2019 whilst famotidine, nizatidine and cimetidine are absent from most UK paediatric formularies. Antihistamine diets, whilst popular, are restrictive and difficult to maintain. They risk exacerbating weight loss and nutritional deficiencies and have no proven benefits.
Low dose Naltrexone
Naltrexone is an opioid receptor antagonist thought to have secondary immune modulation properties at low doses with previous uses in chronic pain, fibromyalgia and multiple sclerosis. Large, randomised control trials assessing its use in fibromylagia are awaited. There remains paucity of data with regards to paediatric safety, pharmacokinetics and dosing, but use of higher doses in children with eating disorders and autism have not highlighted any adverse effects . A study of naltrexone use (3–4.5 mg/day) in 218 patients with ME/CFS reported improvement in 74 % of patients but lack of a control group, randomisation or any objective outcome measures are clear limitations of this study.
Hyperbaric oxygen
There is no evidence to support use of hyperbaric oxygen in CYP. A double blinded sham controlled randomised trial of adults with a mean age of 48 years reported improved cognitive functioning, fatigue, psychiatric symptoms and pain, thought to be the result of improved cerebral blood flow. No long-term follow-up data is available to ascertain whether any benefit is sustained and the applicability of these results to a paediatric population is limited.
Breathing retraining programmes
A number of breathing retraining and wellbeing programmes have shown benefit in adults such as the Sing Strong ENO programme . Research on whether these will prove effective for CYP is awaited.
Prognosis
The outcomes for many CYP with PCS are good. Many improve by 6 months from diagnosis with a dramatic improvement seen between 3 and 6 months . Recovery rates after SARS-CoV-2 infection improve with time. In one study at 1–5 month follow up, 4 % had poor recovery, dropping to 1.3 % at 6–9 months and 0.7 % at 12 months with persistence more likely with pre Omicron variants . Morello et al found just 1 in 20 of all children diagnosed with PCS at 3 months had ongoing symptoms at 18 months. Similarly improvements in school attendance have been noted with those attending school more than half the time increased from 29% at initial assessment to 66% at 6 month follow up in one tertiary post covid service However, there is a minority of CYP who are moderately or severely affected who have a protracted course and whose symptoms are more resistant to management.
Longer term outcomes remain uncertain for CYP with PCS, with little data on the lifetime risk of cardiovascular disease, stroke, or diabetes, which are known to occur at increased rates in adults.
Conclusions
Post COVID Syndrome is a complex multi system disorder thought to be caused by a dysregulated immunological response. Various mechanisms are implicated with a wide spectrum of clinical presentations. Research is ongoing to better understand any potential therapeutic targets, but the evidence base for treatment in CYP remains limited. Management approaches involve biopsychosocial assessment and treatment of symptoms and comorbidities such as autonomic dysfunction, as well as multidisciplinary rehabilitation. This approach with attention to symptom management, activity pacing to achieve function goals, and supported return to education have been effective for most. The overall course of PCS in CYP is one of slow improvement with recovery seen in the majority but not all patients.
Future Directions for Research
To establish key pathophysiological mechanisms and possible targeted pharmacological treatment for PCS symptomatology.
To understand the association of PCS with other conditions including neurodevelopmental conditions, hypermobility, and autonomic dysfunction.
To examine the link between PCS and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and whether research from PCS patients offers insights for ME/CFS and other post viral conditions.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Pan London Post COVID service
References
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
