COVID-19 and Multisystem Inflammatory Syndrome in Children

Abstract

Setting: A literature review was undertaken to provide an overview of the evidence of COVID-19 in the paediatric population with special interest in the South African situation.

Key Messages: Children of all ages are susceptible to COVID-19, yet they largely have asymptomatic or mild forms of the disease. Despite most cases not being severe, clinicians should maintain a high index of suspicion for COVID-19 infection in children and monitor for progression of illness, particularly among infants and children with underlying conditions, who may have more severe disease. The serious and life-threatening presentation of multisystem inflammatory syndrome in children is important to recognise, but outcomes are good if referral to an appropriate setting is undertaken and management initiated early.

Conclusions: While the disease itself mostly spares children, measures taken to curb the spread of the virus may have detrimental effects on children, particularly in low-and-middle-income settings. More research is needed into the long-term outcomes of COVID-19 in children.

Main article text

INTRODUCTION

Nearly a year after the World Health Organization declared COVID-19 a Public Health Emergency of International Concern (on 30 January 2020), the worldwide mortality has topped 2.1 million.(1,2) COVID-19, the disease caused by SARS-CoV-2, has swept the world and has had far-reaching effects for everyone.(3)

Children have been relatively spared by the direct effects of the disease, with children making up a small proportion of those infected and those with severe disease. Clinicians, however, should have a high index of suspicion of the most severe presentation related to COVID-19, the multisystem inflammatory syndrome in children (MIS-C), which is discussed in the following.

While children are rarely directly affected by COVID-19, the measures taken to prevent viral transmission, such as nationwide ‘lockdowns’ and school closures, can have unintentional effects on child health, mental state and feeding schemes. The economic consequences of such measures also affect the most vulnerable members of the population, including children.(4)

Despite the burgeoning number of publications pertaining to COVID-19, children remain under-represented in these studies. This review aims to summarise some of the evidence available regarding COVID-19 infection in children. As this is an evolving field with new evidence coming to light daily, this review is not exhaustive, merely an overview with special emphasis on publications pertaining to or available from South Africa.

METHODS

A search of peer-reviewed publications was conducted during December 2020, utilising PubMed, Google Scholar and the World Health Organization COVID-19 database. Search terms used were ‘SARS-CoV-2’ or ‘COVID-19’ or ‘Coronavirus’, or ‘multisystem inflammatory syndrome’ or ‘MIS-C’ or ‘paediatric inflammatory multisystem syndrome’ or ‘PIMS-TS’ and ‘children’, or ‘paediatrics’. The references of each paper were examined for additional relevant articles. Local journals were also examined for publications relating to COVID-19 in children in South Africa since the start of the outbreak. The author then evaluated published studies on the epidemiology, clinical presentation, treatment and outcomes in children with COVID-19 from these sources.

EPIDEMIOLOGY

Since the first published reports, children have been known to be infected with COVID-19, but in much lower proportions than adults.(5,6) In the largest case series from China, 2.2% (965/44,672) of patients with confirmed COVID-19 were <20 years old.(7) Elsewhere, in Italy, children <18 years composed only 1% of the total number of patients, and in the United States (US), 1.7% of cases were among children aged <18 years.(8,9)

A large Korean study reported that the proportion of children with COVID-19 among the confirmed cases to be higher at 4.8%.(10) Subsequently, after the initiation of more widespread testing, Lu et al. conducted a study in China and reported that the incidence of confirmed COVID-19 among children rose to 12.3% (171/1391), indicating the large proportion of asymptomatic patients.(11)

Age

Children of all ages are susceptible to COVID-19. Among 2572 COVID-19 cases in children aged <18 years in the US, nearly one-third of paediatric cases occurred in children aged 15–17 years, followed by 27% in children aged 10–14 years. Among younger children, 15% occurred in infants (<1 year of age), 11% in children aged 1–4 years and 15% in children aged 5–9 years.(8)

There appears to be a bimodal age distribution when it comes to hospitalisations. The Center for Disease Control in the US reported that children <1 and >10 years comprised the highest percentage of COVID-19-associated hospitalisations in the paediatric population.(12) Elsewhere, the proportions of severe and critical cases were greater in the younger age groups and declined gradually in the older age groups.(13) Bialek et al. reiterated that hospitalisation was greatest among infants in whom two-thirds of cases were hospitalised, compared to 4.1% among those aged 1–17 years, leading to suggestions that the infection is more severe among infants.(8,13)

Sex

Patel summarised 10 studies in a systematic review, only including cases with confirmed COVID-19 positive testing.(14) The overall mean percentage of males in the review was 56.4%.(14) Males are slightly, but not significantly, predominant in all paediatric age groups, suggesting that biologic factors may play a role in any differences in COVID-19 susceptibility by sex.(8)

SEVERITY

The initial observational studies from the Wuhan province in China reported that compared to adults, children with COVID-19 do not often experience severe diseases, a claim now supported by further studies.(5,6,8,11,13,15) However, where most COVID-19 cases in children are not severe, serious COVID-19 illness resulting in hospitalisation can still occur.(8)

Dong et al. reported a nationwide case series of 2135 paediatric patients with confirmed or suspected COVID-19 in China.(13) Among laboratory confirmed (n=728) cases, 12.9% were found to be asymptomatic, 43.1% with mild disease, 40.9% with moderate disease and 2.9% were considered to be severe or critical.(13)

Comorbidities and risk factors for severe disease

Bialek et al. reported that 23% of all paediatric cases (80/345) of COVID-19 had at least one underlying condition. The most common underlying conditions were chronic lung disease (including asthma), cardiovascular disease and immunosuppression.(8) The prevalence of underlying medical conditions increased to 77% (28/37) in hospitalised children with COVID-19 and all of the patients requiring admission to an ICU (1.8% of paediatric cases).(8)

In their review of ICU patients, Shekerdemian et al. found comorbidities in more than 80% of paediatric patients with COVID-19 admitted to ICUs. These included ‘medically complex’ (40%), defined as children who had long-term dependence on technological support (including tracheostomy) associated with developmental delay and/or genetic anomalies, immune suppression/malignancy (23%) and diabetes (8%). Obesity, which is considered an important risk factor for adult patients with COVID-19, was also a comorbidity (15%) amongst children.(3)

CLINICAL PRESENTATION

While COVID-19 in adults predominantly presents with respiratory symptoms, children exhibit a range of symptoms, including, but not limited to, respiratory symptoms.(13) Gastrointestinal symptoms are present in approximately 10% of COVID-19 cases involving children.(15)

In a systematic review of individual patient data, fever was the most common symptom (62.4%), followed by cough (32.0%), diarrhoea occurred in 10.4% and vomiting in 4.8%.(16) Furthermore, children <7 years tended to present with fever, diarrhoea and vomiting more than older children who experienced more cough, although the proportion of asymptomatic patients was similar for all ages (11%–21%).(16) Other reported symptoms are listed in Table 1.

Table 1:

Common presenting signs and symptoms in paediatric patients with COVID-19 (8,10,11,14–17)

Common	Less common
Fever	Headache
Cough	Myalgia
Dyspnoea	Diarrhoea
Pharyngitis/sore throat	Nausea/vomiting
Nasal congestion	Abdominal pain or discomfort
Rhinorrhoea	Malaise/fatigue
Tachycardia	Papular rash
Tachypnoea	Peri-oral skin changes

The wide variety of symptoms highlights the challenges of diagnosing COVID-19 and emphasises the importance of having a low threshold for testing children for SARS-CoV-2.(16)

SEVERE PRESENTATION

Multisystem inflammatory syndrome in children (MIS-C)

The most serious paediatric complication of COVID-19 is a syndrome amongst children and adolescents that shows similarities to the clinical entity Kawasaki disease (KD), a rare vasculitis of children with unknown aetiology, that can cause coronary artery aneurysms.(18)

The first reports of a Kawasaki-like disease emerged from Bergamo, Italy, at the peak of the pandemic in that country.(19) Verdoni et al. reported 10 cases of which half had features similar to KD. There was a high proportion of shock (50% required fluid resuscitation and 20% needed inotropic support). Around the same time, clinicians in the United Kingdom reported a cluster of eight previously healthy children with likely exposure to COVID-19 presenting with cardiovascular shock, fever and hyperinflammation, requiring admission to ICU.(20)

This serious and life-threatening illness presenting in previously healthy children and adolescents became known as MIS-C in the USA, or ‘paediatric inflammatory multisystem syndrome – temporally associated with SARS-CoV-2’ (PIMS-TS) in the United Kingdom. There are a range of clinical manifestations associated with MIS-C and currently no pathognomonic findings or diagnostic tests. The features include a fever >38.5°C, single or multi-organ dysfunction, clear evidence of inflammation, with no other clear cause. Importantly, SARS-CoV-2 PCR testing may be positive or negative and serology should be used to aid the diagnosis.(21) MIS-C was included as a notifiable medical condition in South Africa as of 18 September 2020.(22)

The pathophysiology of MIS-C is still unclear, but possible mechanisms include the generation of autoantibodies, recognition of viral antigens expressed on infected cells, formation of immune complexes which trigger inflammatory pathways and viral superantigen sequences which activate the host immune response.(23)

There are slight differences in the case definitions of MIS-C across the world, but the principles of diagnosis and management are similar. Early general management and investigation include treating the patient as possibly infected with COVID-19, considering sepsis as a possibility and treating with appropriate empiric antibiotic early, while performing laboratory investigations to assist diagnosis. Monitoring of cardiorespiratory function is important and early referral to an intensive care centre is advised, as well as other special investigations such as ECG and echocardiogram as required.

Clinical features of MIS-C include prolonged fever, hypotension, tachycardia, confusion, headache, syncope, conjunctivitis, respiratory symptoms, sore throat, oral mucositis, cervical lymphadenopathy, neck swelling, abdominal pain, diarrhoea, vomiting, rash and swollen extremities. Initial targeted therapy should include intravenous immunoglobulins (IVIGs), anticoagulation (with aspirin or heparin/LMWH) and steroids. Further treatment may involve repeat doses of the aforementioned and the addition of biological agents (interleukin-6 or interleukin-1 receptor antagonists) if available.(21)

A study across 26 US states reported on 186 paediatric patients with MIS-C.(24) The majority of patients (70%) had laboratory-confirmed previous or concurrent SARS-CoV-2 infection. The median age was 8.3 (IQR 3.3–12.5) years, 62% (115) were male, and 73% (135) had been previously well. Most patients had gastrointestinal symptoms (92%), cardiovascular involvement (80%), haematologic (76%), mucocutaneous (74%) and respiratory (70%) involvement. The median duration of hospitalisation was 7 days (IQR 4–10), 80% received intensive care, 20% required mechanical ventilation, almost half (48%) required vasoactive support, and four patients (2%) died. Coronary artery aneurysms were found in 15 patients (8%). Most patients (92%) had elevations in at least four biomarkers, indicating inflammation.

Most children with MIS-C had elevated ESR or CRP, lymphocytopenia, neutrophilia, anaemia, thrombocytopaenia, elevated ALT and ferritin level, hypoalbuminaemia, elevated d-dimer, prolonged INR or elevated fibrinogen level. The treatment of MIS-C involved the use of immunomodulators: IVIG in 77%, glucocorticoids in 41%, and interleukin-6 or interleukin-1 receptor antagonists in 20%.(24)

Feldstein et al. highlighted the importance of cardiac compromise in children with MIS-C.(24) Only 5% of children with KD in the USA required vasopressor or inotropic support for cardiovascular shock, compared to 50% of children with MIS-C. Myocardial dysfunction is a prominent extra-pulmonary manifestation of COVID-19, highlighting the importance of performing an echocardiogram in all patients presenting with MIS-C. According to the KD guidelines, long-term cardiac follow-up of children with MIS-C is recommended, since unusual coronary dilatation or aneurysm are possible long-term sequelae.(23,24)

MIS-C in South Africa

The first published report of MIS-C in South Africa appeared in August 2020 from the Cape Town MIS-C team, who reported on the first 23 cases presenting in the Western Cape approximately 6 weeks after the first peak of the disease in that province. The children presented with non-specific features of persistent fever, rash and abdominal pain. The majority (52%) of the children required admission to an intensive care unit, most commonly because of myocardial dysfunction. All 23 children received IVIG, with 15 (65%) children requiring additional drugs (such as methylprednisolone, a second IVIG or tocilizumab).(25)

Given poor availability of serological testing at the time, the Cape Town group recommended a high level of suspicion and a low threshold for diagnosing MIS-C after a careful exclusion of other conditions in regions with evidence of community spread of COVID-19.(25) Close attention to age-inappropriate persistent tachycardia and relative hypotension was highlighted.

RADIOGRAPHIC FINDINGS

Imaging studies play a role in the investigation of children with suspected or confirmed COVID-19, but there appears to be a poor correlation of imaging findings with symptomatic disease since abnormal findings may be present in asymptomatic children.(16) Abnormalities on chest radiograph or CT scan have been described in up to two-thirds of imaged patients.(16) Abnormalities include ground-glass opacities (62.5%), consolidation (11.2%), pneumonia (10.4%), patchy shadows (10.4%), mottling (8%), bronchitis (1.6%) and perihilar opacities (1.6%). Findings may be unilateral or bilateral, patchy or diffuse, including the airspaces and interstitium.(26) As the infection progresses, severe lesions, dense consolidation and nodularity become more prevalent.(15) Lung ultrasound has a role at the bedside and may reveal interstitial syndrome and multiple B-lines.(9,15,16) Xia et al. reported that consolidation surrounded by a halo was found in half of children with severe or moderate COVID-19 lung disease, suggesting that there is some specificity regarding these lesions in children.(17)

TREATMENT

Treatment for COVID-19 infection remains supportive in nature. As yet there are no proven therapies, it is recommended to restrict any proposed therapies for the treatment of COVID-19 infection to the context of formal clinical trials. Careful consideration should be taken in children especially because of continued lack of proven efficacy and concern regarding potential adverse effects.(27)

Treatment protocols for the management of COVID-19 are evolving, and clinical trials are ongoing. Currently, recommendations are largely based on retrospective studies as the best available evidence, with few prospective randomised controlled trials taking place. As is often the case, a lot of paediatric care is extrapolated from adult studies.(28)

One such extrapolation concerns the randomised evaluation of COVID-19 therapy (RECOVERY) trial which showed a decreased mortality among patients who received dexamethasone compared to standard of care.(29) Importantly, the RECOVERY trial did not include a significant number of paediatric patients, so caution must be taken when extrapolating the results to children. Dexamethasone may be beneficial in paediatric patients with COVID-19 respiratory disease who require mechanical ventilation. Use of dexamethasone in patients who require other forms of supplemental oxygen support should be considered on a case-by-case basis only and is generally not recommended.(30)

COVID-19 IN CHILDREN IN SOUTH AFRICA

As of 21 November 2020, children ≤19 years made up 9.0% of laboratory-confirmed COVID-19 cases in South Africa.(31) There were 4042 reported COVID-19-associated admissions in this age group. Where information was available, 17.5% (510/2911) had an underlying condition. Asthma and other chronic pulmonary conditions, diabetes mellitus, HIV infection and tuberculosis were the commonest underlying conditions. Precisely 5.4% of hospitalised patients were admitted into ICU during their stay. There were 100 in-hospital deaths giving an in-hospital case-fatality rate of 2.7% (100/3701). Among all deaths, 47.0% were among adolescents aged 15–19 years and 23.0% were infants. Precisely 76.0% (57/75) of patients who died had an underlying condition. Diabetes, HIV and malignancy were the commonest reported underlying conditions among adolescents ≥15 years who died.(31) Importantly, not all deaths are necessarily due to COVID-19, rather some may be due to the underlying condition with COVID-19 being incidental.

INDIRECT EFFECTS OF COVID-19 PANDEMIC ON CHILDREN

Children have been increasingly impacted by COVID-19, both directly and indirectly.(32) In many instances, children are the victims of measures taken to halt the spread of COVID-19 rather than the disease itself.(33) Despite conflicting data on its role in reducing disease transmission, the COVID-19 pandemic has resulted in school closures implemented by many governments resulting in economic and psychological consequences for children.(33–35) Currently, the evidence to support national closure of schools to combat COVID-19 is very weak and data from influenza outbreaks, and previous coronavirus outbreaks, suggest that school closures have relatively small effects on a virus with COVID-19's high transmissibility and apparently low clinical effect on children. Instead, other school physical distancing interventions (such as staggering classes) are much less disruptive than full school closure and may have the same effect on this pandemic.(34)

‘Lockdown’ has had further unintended consequences for child health. ‘Lockdown’ strategies have increased sedentary screen time and decreased physical activity levels with children not being allowed outdoors.(36) Children with acute and chronic conditions are prevented from accessing health care, leading to a loss of routine immunisation opportunities, access to chronic medication and loss of feeding opportunities that are frequently provided at schools.(33) Food insecurity, leading to an increase in malnutrition, is a very real concern, as is the potential lack of care in homes where parents become ill and require hospitalisation.(35)

A study conducted in KwaZulu-Natal, South Africa, assessed the initial impact of the first wave of the COVID-19 outbreak on routine child health services in the province.(37) They concluded that multiple indicators demonstrated disruption in service access, service delivery and child wellbeing.(37) Children under 5 years suffered most with clinic attendance dropping by 30%–42% and hospital admissions dropping by 47%–54%.(37) Service access was reduced to a greater extent for young children than for adults and adolescents, a finding consistent with the assessment of clinic attendance in rural KwaZulu-Natal.(38) Immunisation indicators demonstrated a one-third decline in the early phases, yet recovered quickly. A significant decline was seen in vitamin A supplementation, deworming treatment and nutrition supplementation with minimal recovery over 3 months.(37) Concerns remain around increased incidence of malnutrition and stunting. Household surveys conducted during the national lockdown period have indicated an extensive impact on food security and hunger.(4)

CONCLUSION

Children are less severely affected by COVID-19 than adults. Although they appear to contract infection at the same rate as adults, they largely have mild or asymptomatic forms of the disease. Children with comorbidities or of younger age are at an increased risk of both COVID-19 infection and severe disease. The clinical entity of MIS-C is a rare presentation related to COVID-19 which requires a high index of suspicion. Outcomes in children are generally good, although deaths have occurred in this age group, albeit in lower proportions than adults. Nevertheless, children represent a vulnerable population that is greatly affected by the pandemic's indirect effects on social determinants of health and the allocation of health resources. Further studies are required to establish the direct long-term impacts of COVID-19 on children, as well as indirect effects of the pandemic on child health.

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