Diagnosis and classification

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tomatic children resembled those in adults. Systematic measurements of SARS-CoV-2 viral load measurements in children are lacking. Therefore, transmission of SARS-CoV-2 from children is plausible (L’Huillier 2020). SARSCoV-2 in children is transmitted through family contacts and mainly through respiratory droplets (Garazzino 2020). In a study from France, child-to-child and child-to-adult transmission seems to be uncommon (Danis 2019). Prolonged exposure to high concentrations of aerosols may facilitate transmission (She 2020). SARS-CoV-2 may theoretically also be transmitted through the digestive tract. ACE2 is also found in upper esophageal and epithelial cells as well as intestinal epithelial cells in the ileum and colon (She 2020). SARS-CoV-2 RNA can be detected in the feces of patients (Holshue 2020). Cai revealed that viral RNA is detected from feces of children at a high rate (and can be excreted for as long as 2-4 weeks) (Cai 2020). However, direct evidence of a fecal-to-oral transmission has not yet been documented. Onward transmission from children to others is low (Viner 2020, Merckx 2020). In a study from Milan, Itlay, in 83 children and 131 adults hospitalized and symptomatic in regard to COVID-19, adults were retrospectively more likely to be CoV-2 positive, asymptomatic carriers as compared to children (9% vs 1%) (Milani 2020).

Testing for the virus is only necessary in clinically suspect children. If the result is initially negative, repeat nasopharyngeal or throat swab testing of upper respiratory tract samples or testing of lower respiratory tract samples should be done. Sampling of the lower respiratory tract (induced sputum or bronchoalveolar lavage) is more sensitive (Han 2020). This is not always possible in critically ill patients and in young children. Diagnosis is usually made by real-time polymerase chain reaction RT-PCR on respiratory secretions. For SARS-CoV, MERS-CoV and SARS-CoV-2, higher viral loads have been detected in samples from lower respiratory tract compared with upper respiratory tract. In some patients, SARS-CoV-2 RNA is negative in respiratory samples while stool samples are still positive indicating that a viral gastrointestinal infection can last even after viral clearance in the respiratory tract. (Xiao 2020). Fecal testing may thus be of value in diagnosing COVID-19 in these patients. As in other viral infections, a CoV-2 IgM and IgG seroconversion will appear in days (IgM) to 1-3 weeks (IgG) after infection and may or may not indicate protective immunity (still to be determined). Interestingly, asymptomatic

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seroconversion has been hypothesized in a very small series of health workers (mean age 40 years) exposed to a child with COVID-19 in a pediatric dialysis unit (Hains 2020). Serology may be useful in patients with clinical symptoms highly suggestive of SARS-CoV-2 who are RNA negative, i.e in children with pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2 (PIMSTS). If serology indicates protective immunity, this will be extremely important from a public health perspective, e.g. it will allow for strategic staffing in medical care and for the assessment of CoV-2 epidemiology (herd immunity).

Table 1. COVID classification in children (Shen 2020) 1 Asymptomatic without any clinical symptoms 2 Mild fever, fatigue, myalgia and symptoms of acute respiratory tract infections 3 Moderate pneumonia, fever and cough, productive cough, wheezing but no hypoxemia 4 Severe fever, cough, tachypnea, oxygen saturation less than 92%, somnolence 5 Critical quick progress to acute respiratory distress syndrome (ARDS) or respiratory failure

Laboratory and radiology findings

Laboratory and/or radiology studies in outpatient children who have mild disease are not indicated. Upon admission to the hospital the white blood cell count is usually normal. In a minority of children decreased lymphocyte counts have been documented. In contrast, adults (with hyperinflammation and cytokine release syndrome) often have an increase in neutrophils and lymphopenia. The inflammation parameters C reactive protein and procalcitonin can be slightly elevated or normal while there are elevated liver enzymes, creatine kinase CK-MB and D dimers in some patients. LDH appears to be elevated in severe cases and can be used to monitor severe disease. A chest X-ray should only be done in children with moderate or more severe disease as CT scans mean a very high radiation exposure for the child and should only be done in complicated or high-risk cases. In the beginning of the pandemic in China, children all received CT scans even when they were asymptomatic and oligosymptomatic; surprisingly, they displayed very severe changes. On chest radiography there are bilateral patchy airspace consolidations and so-called ground-glass opacities. CT scans were more impressive

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than chest x-ray examinations. In 20 children with CT, 16 (80%) had some abnormalities (Xia 2020).

Symptoms and signs: Acute infection

Children and adolescents

In a clinical trial of 171 children from Wuhan, fever was reported in 41% (71 of 171), cough in over 50% (83 of 171), tachypnea in 28% (49 of 171). In 27 of the patients there were no symptoms at all (15,8%). At initial presentation very few children required oxygen supplementation (4 of 171, 2,3%). Other symptoms like diarrhea, fatigue, runny nose and vomiting were observed in less than 10% of the children (Lu 2020). In the cohort from Zhejiang as many as 10 out of 36 patients (28%) had no symptoms at all. None of the children had an oxygen saturation below 92% (Qiu 2020). In a Korean case series of children with COVID-19, 20 children (22%) were asymptomatic during the entire observation period. Among 71 symptomatic cases, only 6 (9%) were diagnosed at the time of symptom onset while 47 children (66%) had unrecognized symptoms before diagnosis and 18 (25%) developed symptoms after diagnosis. Fifty-one percent had “mild” disease, 22% “moderate” disease and 2% “severe” disease. No patient required intensive care (Han 2020). A larger UK series reports on 651 children and young people aged less than 19 years. Median age was 4.6 years, 35% (225/651) were under 12 months old. 18% (116/632) of children were admitted to critical care. Six patients died in hospital, all of whom had profound comorbidity (Swann 2020). A recent comprehensive systematic review analysed 131 studies in 7780 pediatric COVID-19 patients across 26 different countries (Hoang 2020). In this review 19,3% of the patients were asymptomatic, the most common symptoms were fever (59%), cough (55,9%), rhinorrhea (20%) and myalgia/fatigue (18,7%). The need for intensive care treatment was low (3,3%). In 52 hospitalized children from London, UK, renal dysfunction was frequent especially in those with pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2. 24 (46%) had elevated serum creatinine, and 15 (29%) met the diagnostic criteria for acute kidney injury (Stewart 2020). In a case series of 4 children with PIMS-TS (see below) from London, UK, neurological symptoms were described (encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, reduced reflexes) with signal changes in the splenium of the corpus callosum on neuroimaging and required intensive care admission for the treatment of COVID-19 pediatric multisystem inflammatory syndrome (Abdel-Mannan 2020).

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Neonates and infants

Zeng reports 33 newborns born to mothers with COVID-19 in Wuhan. Three of the 33 infants (9%) presented with early-onset SARS-CoV-2 infection. In 2 of the 3 neonates there were radiological signs of pneumonia. In one child disseminated intravascular coagulation was described but eventually all children had stable vital signs three weeks after the infection (Zeng L 2020). In a second cohort, 9 infants aged 1 month to 9 months were described without any severe complications (Wei 2020). Whether there are long-term complications of COVID-19 in these newborns and infants is unclear at this stage of the pandemic.

Pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2 (PIMS-TS) (or synonym Multisystem Inflammatory Syndrome in Children (MIS-C) or Kawasaki-like Disease

While most children with COVID-19 have a very mild disease, in April 2020 clinicians from the UK, France, Italy, Spain and the US reported on children with a severe inflammatory syndrome with Kawasaki-like features, some of whom had tested positive for CoV-2, while others not. Prior to this, Jones had described the case of a six-month-old baby girl with fever, rash and swelling characteristic of a rare pediatric inflammatory condition, Kawasaki disease (Jones 2020). Eight patients from the UK and 10 patients from Bergamo in Italy with features of Kawasaki disease were published including one death in a 14-year-old boy in the UK during the SARS-CoV-2 epidemic (Riphagen 2020, Verdoni 2020). Some children presented with vasculitic skin rash (Schneider 2020). In Bergamo, the region with the highest infection rate in Italy, a 30-fold increased incidence of Kawasaki disease has been reported following the SARSCoV-2 epidemic (Verdoni 2020). Of 21 children and adolescents from London, UK (19 with recent SARS-CoV-2 infection), 12 (57%) presented with Kawasaki disease shock syndrome, 16 (76%) with myocarditis, 17 (81%) required intensive care support. All had noticeable gastrointestinal symptoms and high levels of inflammatory markers, received intravenous immunoglobulin and 10 (48%) corticosteroids; the outcome was favourable in all (Toubiana 2020). In the UK, 78 of the PIMS-TS cases reported 36 (46%) were invasively ventilated, 28 (36%) had evidence of coronary artery abnormalities, three children needed ECMO and two children died (Davies 2020). In another study from the UK, 50% of the 58 “PIMS-TS” cases developed shock and required inotropic support or fluid resuscitation; 22% met diagnostic cri-

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teria for Kawasaki disease; and 14% had coronary artery dilatation or aneurysms (Whittaker 2020). In a US MIS-C study on 186 patients 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing. Detailed analysis of clinical manifestation revealed the gastrointestinal system (92%), cardiovascular (80%), hematologic (76%), mucocutaneous (74%), and respiratory involvement (70%). In total, 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, and 4 (2%) died. Coronary-artery aneurysms were documented in 15 patients (8%), and Kawasaki disease–like features were documented in 74 (40%) (Feldstein 2020). In the largest cohort to date, 570 US MIS-C patients were reported as of July 29. A total of 203 (35.6%) of the patients had a typical MIS-C clinical course (shock, cardiac dysfunction, abdominal pain, and markedly elevated inflammatory markers) and almost all had positive SARS-CoV-2 test results (Class 1). The remaining 367 (64.4%) of MIS-C patients (Class 2 and 3) had manifestations that appeared to overlap with acute COVID-19 or had features of Kawasaki disease. 364/570 patients (63.9%) required care in an intensive care unit. Ten patients (1.8%) died. Approximately two thirds of the children had no pre-existing underlying medical conditions (Godfred-Cato 2020). In summary, the pathophysiological overlap between COVID-19-associated inflammation and Kawasaki disease is not yet clear, their features are summarized in Table 2. The main pathophysiological differences appear to be an IL17A-driven inflammation in Kawasaki disease (KD) and a stronger endothel activation in coronary artery involvement in MIS-C. In both, MIS-C and KD autoantibodies may play an important role and MIS-C patients show distinct CD4 subset abnormalities. (Consiglio 2020).

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Table 2. Features of Kawasaki Disease and pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2

Kawasaki (Hedrich 2017, ECDC 2020) (previously called mucocutaneous lymph -node syndrome) PIMS-TS (pediatric inflammatory multisystem syndrome temporarily associated with SARSCoV-2 or MIS-C (multisystem inflammatory syndrome in children) (Verdoni 2020; Riphagen 2020, https://covid19-surveillancereport.ecdc.europa.eu/)

“Kawasaki-like disease”

Epidemiology Incidence 5–19/100,000 annually < 5 years of age (EU, US), in north-east Asia higher; seasonal increase in winter/spring, geographic wave-like spread of illness during epidemics (Rowley 2018) Incidence unknown 230 suspected cases temporally associated with COVID-19 reported to ECDC by May 15th (EU/EEA, UK). More common in afro-caribbean descent, obesity? (Riphagen 2020)

Age, sex >90% < 5 years of age, more males 5-15 years of age, sex distribution unclear

Etiology Unknown, hypothesis: infection with common pathogens, e.g. bacteria, fungi and viruses which cause immune-mediated damage (Dietz 2017) (Jordan-Villegas 2010, Kim 2012, Turnier 2015). Genetic factors (increased frequency in Asia and among family members of an index case) Unknown, no working hypothesis yet. Hyperinflammation/shock associates with immune response to SARS-CoV-2. In CoV1 antibody-dependent enhancement (ADE): presence of antibodies can be detrimental, enable the virus to spread (demonstrated in SARS-CoV)

Case definition fever ≥5 days, combined with at least 4 of the 5 following items 1.Bilateral bulbar conjunctival injection 2. Oral mucous membrane changes, including injected or fissured lips, injected pharynx, or strawberry tongue 3. Peripheral extremity changes, including erythema of palms or soles, edema of hands or feet (acute phase) or periungual desquamation (convalescent phase) 4. Polymorphous rash 1. Persistent fever, inflammation (neutrophilia, elevated CRP and lymphopenia) and single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal or neurological disorder) with other additional clinical, laboratory or imagining and ECG features. Children fulfilling full or partial criteria for Kawasaki Disease may be included 2. Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus 3. SARS-CoV-2 PCR testing positive or negative (Royal College of Paediatrics and Child Health)

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Table 2. Features of Kawasaki Disease and pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2 5. Cervical lymphadenopathy (McCrindle 2017)

Children suspected of having KD who do not fulfill diagnostic criteria may have incomplete or atypical KD (Cimaz 2009)

CoV-2 status in most cases CoV-2 Ag (PCR); Abs (Elisa) negative CoV-2 Ag (PCR) negative and Abs (Elisa) positive

Typical Lab Marked Elevation of acutephase reactants (eg, Creactive protein [CRP] or erythrocyte sedimentation rate [ESR])

Thrombocytosis (generally after day 7 of illness Leukocytosis, left-shift (increased immature neutrophils) Marked elevation of acute phase reactants CRP, ESR Thrombocytopenia Leucopenia Lymphopenia Hyperferritinemia

Elevated myocarditis markers Troponin, proBNP

Acute Complications Kawasaki disease shock syndrome (KSSS) (rare), features of macrophage activation syndrom, MAS (rare), coronary artery abnormalities, mitral regurgitation, prolonged myocardial dysfunction, disseminated intravascular coagulation (Kanegaye 2009) Gastrointestinal complications (Ileitis, vomiting, abdominal pain) rare Shock (common), features of macrophage activation syndrome (common), myocardial involvement evidenced by markedly elevated cardiac enzymes (common), myocardial infarction, aneurysms, disseminated intravascular coagulation Gastrointestinal complications (Ileitis, vomiting, abdominal pain) are very common

Long term Complications Artery abnormalities (aneurysms of mid-sized arteries, giant coronary artery aneurysms CAAs) Aneurysms

Management High-dose intravenous immunoglobulin (IVIG) (2g/kg) first-line treatment; effective in reducing the risk of coronary So far, most patients published were treated with high dose IVIG, glucocorticoids, ASS (Verdoni 2020, Riphagen 2020, Ahmed 2020) IVIG resistance requiring adjunctive steroid