…let’s not be complacent

THE global experience with children in the current COVID-19 pandemic has demonstrated a much milder illness, in this otherwise vulnerable population. The reason for this fortunate difference is open to scientific speculation.

Chemicals (cytokines) are released by the body when exposed to an infection or injury. Adults have a much stronger immune system, often resulting in an exaggerated response (cytokine surge) to infections which can damage various organ systems including the lungs, the heart and the kidneys. It is believed that because of their immature immune system, children cannot mount this “cytokine surge,” resulting in milder disease.

Despite this predominantly mild disease in children, we cannot be complacent since, they can be the potential carriers to the most vulnerable in our population.  We also know that children with certain risk factors can be susceptible to moderate and severe symptoms with increased hospitalisation and deaths.

Multi-system Inflammatory Syndrome in Children (MIS-C) is a new disease entity with a broad spectrum of clinical presentations predominantly seen in children.

The American Academy of Paediatrics (AAP) announced this week that there was a significant increase in cases in children in the past two weeks in the United States. Whether this is a result of school openings is unclear, but it means that there are more kids who can potentially transmit the virus to the more vulnerable in the population.

A number of studies have demonstrated that children with COVID-19 have more viral loads in their nasopharynx. However, there is no conclusive evidence that they are more of less contagious. Special precaution should be taken to avoid exposure to the elderly, such as grandparents.

The symptoms of COVID-19 are similar in children and adults, but the frequency of the symptoms vary. Fever and cough are the predominant presenting symptoms, but vomiting, diarrhoea, abdominal pain, muscle pain, loss of smell and headaches can all be seen in isolation or concurrently. “COVID toes,” characterised by purple blisters on the distil parts of the toes have also been described.

In a systematic review by the Centers for Disease Control and Prevention (CDC) of 7,480 children, less than 18 years of age with laboratory-confirmed COVID-19 infection, information about symptoms and severity was available for 1475.

Among these, 15 percent of cases were asymptomatic, 42 percent were mild, 39 percent were moderate (example, clinical or radiographic evidence of pneumonia without hypoxemia), 2 percent were severe (example, dyspnea, central cyanosis, hypoxemia), and 0.7 percent were critical (example, acute respiratory distress syndrome, respiratory failure, shock).

There were six deaths in the entire study population (0.08 percent). Risk factors for severe disease include but are not limited to obesity, diabetes and asthma.

Since the disease is very mild in most cases, there is no specific treatment except supportive care. Appropriate isolation, contact tracing, handwashing and mask- wearing are the cornerstone to preventing the spread.

Patients that meet hospitalisation criteria will often require oxygen, high flow or rarely mechanical ventilation. Dexamethasone is often used in moderate to severe cases and the antiviral drug remdesivir is available for emergency authorisation.

Neither of these drugs has been well studied in the paediatric population. The author has used both of these drugs in two severe cases and both brought about  full recovery.

MIS-C is a rear, but increasingly recognised disease related to COVID- 19. It is similar to another illness termed Kawasaki’s Disease (KD), which presents with some characteristic features, including persistent fever, conjunctivitis, lesions in the mouth, swollen glands, skin rash and dilatation of the blood vessels of the heart.

There are, however, some significant differences to MIS-C. The symptoms generally begin three-four weeks after exposure or infection with COVID-19 (see Figure 1). The most common comorbidities are obesity and asthma and are seen in a disproportionate percentage of Black and Hispanic children.

Figure 1: Time course of MIS-C in PCR-positive COVID-19 cases

This lag of three to four weeks suggests that the illness is likely a pos- infectious complication, since it coincides with the timing of the body acquiring immunity. Many patients have a negative PCR test but have circulating antibodies to COVID-19, confirming that this is not an acute infection.

The mechanism by which this disease causes multisystem damage is under investigation (see Figure 2). This illness results in significant inflammation in many organs in the body, resulting in the release of certain proteins into the blood called inflammatory markers.

Figure 2: Possible mechanisms of inflammatory processes for MIS-C

There are a number of such markers, but the most common ones measured are C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and procalcitonin. These tend to be extremely high, especially in the first subtype and are measured serially to gauge recovery.

There appear to be three subtypes:

1. MIS-C without overlap with KD, or acute COVID-19 (35%) — patents in this group have significant heart dysfunction and often present in shock.
2. MIS-C overlapping with acute COVID-19 (30%) — these patients have a pneumonia similar to that seen in adults. Most of these children have a positive PCR for COVID-19 and the mortality is much higher than the other two groups.
3. MIS-C overlapping with KD (35 %) — many of these patients have a number of symptoms consistent with KD, without heart and lung involvement.

The author has provided care for seven such in the paediatric ICU in the US. All of them had varying involvement of the heart and most of them fell into subtype 1. None of them was PCR positive for COVID-19, but five had circulating antibodies suggesting recent infection.

All seven had an elevation in troponin levels (proteins released into the blood when the heart is damaged) and varying degrees of heart failure as seen on echocardiogram. Five of them required medications (inotropes) to improve the function of the heart. All required oxygen and one required mechanical ventilation for severe shock and respiratory failure.

For the successful treatment of these patients, it is crucial to recognise that the condition exists and be vigilant. The treatment consists of supportive care including close monitoring in an Intensive Care setting (providing oxygen to support the lungs and inotropes to support the function of the heart).

Since this condition is thought to be an immune-mediated reaction to COVID-19, therapy is directed towards suppressing the exaggerated immune response using intravenous immune globulin (IVIG). This has been found to be very successful and full recovery of the heart function is seen in most cases.

Dexamethasone is often utilised as part of the treatment protocol, especially in children with significant lung involvement. Clotting of the coronary arteries and other vessels has been described with KD and MIS-C and therefore low-dose aspirin is used prophylactically.

Cases of MIS-C have been reported in low and middle-income countries (LMIC). Because of the lack of recourses, including IVIG, steroids are a cheaper and more readily available option. Their potential to induce broad immunosuppression might be hazardous in countries in which tuberculosis and HIV infection are highly prevalent and where diagnostic facilities (to exclude other types of infection) are scarce.

Therefore, steroid use needs to be restricted to short-term courses in children who have been hospitalised with MIS-C and who are severely ill.

We are very fortunate that the most vulnerable in our population, our children, have been relatively spared from COVID-19. Let us not forget that they can be potential carriers and, therefore, wearing masks, hand-washing and social distancing are crucial to preventing the spread of the virus.

Parents and clinicians alike need to be aware that there is a group of high-risk children who are more susceptible to severe disease.

In addition, MIS-C is a new entity and with the opening of schools and the potential increase in cases, we need to be vigilant for an increase in such cases in the next few months.

Only incude PCR-positive cases in London, UK. Data taken from Public Health England. Figure courtesy of Alasdair Bamford and MyrsiniKaforou. MIS-C = multisystem inflammatory syndrome in children. SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Contributed by:

Dr. Narendra C. Singh

BSc, MB.BS, FRCPC, FAAP, FCCM, MSM, MBA, Hon LLD.

Humber River Hospital

Associate Clinical Professor

McMaster University

Canada

This article is part of the Ministry of Health’s  COVID-19 public information and education programme