Management

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Table 2. Features of Kawasaki Disease and pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2 artery disease when administered within 10 days of onset of fever. In addition, acetylsalicylic acid, glucocorticoids and anti-TNF monoclonal antibodies have been used treatment is common (Verdoni 2020,) Management on the pediatric intensive care unit is often necessary: progression to vasoplegic shock is common Hemodynamic support, treatment with noradrenaline and milrinone, mechanical ventilation is often required (Riphagen 2020)

Prognosis Self-limited vasculitis lasting for an average of 12 days without therapy. Without timely treatment, CAAs, and in particular aneurysms, can occur in up to 25% of children Overall prognosis not yet clear More severe course than KD Potentially fatal in individual cases

National guidelines and guidance documents have been published from different medical societies in China, North America, Italy, UK and Germany (https://rcpch.ac.uk; Venturini 2020, Chiotos 2020, Liu 2020; https://www.rcpch.ac.uk/key-topics/covid-19; https://dgpi.de/stellungnahme-medikamentoese-behandlung-von-kindernmit-covid-19/)

Infection control in the medical setting

Early identification of COVID-19 and quarantine of contacts is imperative. In the in- and out-patient setting it is advised to separate children who have infectious diseases from healthy non-infectious children. Nosocomial outbreaks have played a role in the clustering of COVID-19. It is advised to admit children with COVID-19 to the hospital only if an experienced pediatrician feels it is medically necessary (e.g. tachypnea, dyspnea, oxygen levels below 92%). In the hospital the child with COVID-19 or suspicion of COVID-19 needs to be isolated in a single room or admitted to a COVID-19-only ward in which COVID-19-exposed medical personnel is protected by non-pharmacological interventions (wearing FFP-2 masks, gowns, etc.) and maintains distance and is cohorted themselves (e.g. no shifts on other wards). The presence of one parent is not negotiable in the care of the sick child both for emotional reasons as well as for help in the nursing of the child. At present it is not recommended to separate healthy newborns from mothers with suspicion of COVID-19 (CDC-2 2020). Clearly, a preterm or newborn

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that has been exposed to CoV-2 needs to be closely monitored by the hospital and/or the primary care pediatrician. If there are signs of COVID (e.g. poor feeding, unstable temperature, tachy/dyspnea) it needs to be hospitalized and tested and lab examinations and chest x-ray to be done. Testing for CoV-2 is not useful before day 5 because of the incubation period. There needs to be strict hygiene as much as possible in this mother-child setting. During peak phases of the COVID-19 pandemic, precautions in the outpatient and hospital setting include entrance control, strict hand and respiratory hygiene, daily cleaning and disinfection of the environment, and provision of protection (gloves, mask, goggles) for all medical staff when taking care of a COVID-19 or a suspected COVID-19 case (Wang 2020). In neonatal intensive care units (NICU), negative pressure rooms and filtering of exhaust would be ideal (Lu Q 2020). Respirators with closed circuit and filter systems should be used. Aerosol generating procedures, e.g. intubation, bronchoscopy, humidified inhalations/nebulization should be avoided as much as possible.

Infection control outside the medical setting

Some of the interventions to control the COVID pandemic have caused significant damage to children and adolescents. The description of their impact is beyond the scope of this artivcel and reviewed elsewhere.11

Supportive treatment (respiratory support, bronchodilatation therapy, fever, superinfection, psychosocial support)

Having the child sitting in an upright position will be helpful for breathing. It might be useful to have physiotherapy. Insufflation of oxygen via nasal cannula will be important to children as it will increase lung ventilation and perfusion. In neonates, high flow nasal cannula (HFNC) has been utilized widely due to its superiority over other non-invasive respiratory support techniques. The clinical use and safety of inhaling different substances is unclear in COVID-19. In other common obstructive and infectious childhood lung diseases, e.g. in bronchiolitis, the American Academy of Pediatrics is now recommending against the use of bronchodilators (Dunn 2020). Regarding the inhalation of steroids as part of maintenance therapy for asthma bronchiale there is no evidence to discontinue this treatment in children with COVID-19. There is a large controversy over the extent of antipyretics usage in children. Still, in a child with COVID-19 who is clinically affected by high-degree fever,

11 Recommendations regarding attendance to kindergartens and schools have been published (Cohen 2020).

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paracetamol or ibuprofen may be useful. There is no restriction despite initial WHO warnings of using ibuprofen, there is no evidence that the use of paracetamol or ibuprofen is harmful in COVID-19 in children (Day 2020). The differentiation between CoV-2-induced viral pneumonia and bacterial superinfection is difficult unless there is clear evidence from culture results or typical radiological findings. Bacterial superinfection will be treated according the international and national guidelines (Mathur 2018). The virus outbreak brings psychological stress to the parents and family as well as medical staff; therefore, social workers and psychologists should be involved when available.

Treatment of respiratory failure

The treatment of pediatric acute respiratory distress syndrome (pARDS) is reviewed elsewhere (Allareddy 2019). For neonates with pARDS high-dose pulmonary surfactant replacement, nitric oxide inhalation, and highfrequency oscillatory ventilation might be effective. In critically ill neonates, continuous renal replacement and extracorporeal membrane oxygenation need to be implemented if necessary.

COVID-19-specific drug treatment

As of yet there are no data from controlled clinical trials and thus there is currently no high-quality evidence available to support the use of any medication to treat COVID-19. The drugs listed below are repurposed drugs and there is limited or almost no pediatric experience. In the case of a severe or critically ill child with COVID the pediatrician has to make a decision whether to try a drug or not. If initiation of a drug treatment is decided, children should be included into clinical trials (https://www.clinicaltrialsregister.eu) if at all possible. However, there are very few, if any, studies open for recruitment in children.

When to treat with drugs

Under the lead of the German Society for Pediatric Infectiology (DGPI) an expert panel has proposed a consensus on when to start antiviral or immunomodulatory treatment in children (Table 3)). A panel of pediatric infectious diseases physicians and pharmacists from North American institutions published an initial guidance on the use of antivirals for children with SARS. It is advised to limit antiviral therapy to children in whom the possibility for benefit outweighs the risk of toxicity and remdesvir is the preferred agent (Chiotos 2020).

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Inhibitors of viral RNA synthesis

Remdesivir is available as 150 mg vials. Child dosing is • < 40 kg: 5 mg/kg iv loading dose, then 2,5 mg/kg iv QD for 9 days • ≥ 40 kg: 200 mg loading dose, then 100 mg QD for 9 days Remdesivir is an adenosine nucleotide analogue with broad-spectrum antiviral activity against various RNA viruses. The compound undergoes a metabolic mechanism, activating nucleoside triphosphate metabolites for inhibiting viral RNA polymerases. Remdesivir has demonstrated in vitro and in vivo activity in animal models against MERS and SARS-CoV. Remdesivir showed good tolerability and a potential positive effect in regard to decrease of the viral load and mortality in Ebola in Congo in 2018 (Mulangu 2019). In Europe this drug has rarely been used in children so one should be extremely careful. It can be obtained through compassionate use programs (https://rdvcu.gilead.com).

Table 3. Consensus on antiviral or immunomodulatory treatment in children

Disease severity in child Intervention

Mild or moderate disease pCAP, upper respiratory tract infection, no need for oxygen

More severe disease and risk groups* pCAP, need for oxygen

Critically ill, admitted to ICU

Secondary HLH (hemophagocytic lymphohistiocytosis) Treat symptomatically No need for antiviral or immunomodulatory treatment

Treat symptomatically Consider antiviral therapy

Treat symptomatically Consider antiviral therapy Consider immunomodulatory treatment

Treat with immunomodulatory or immunosuppressive drugs

* Congenital heart disease, immunosuppression, inborn/acquired immunodeficiencies, cystic fibrosis, chronic lung disease, chronic neurological/kidney/liver disease, diabetes/metabolic disease

Lopinavir/r (LPV/r, Kaletra®) is a co-formulation of lopinavir and ritonavir, in which ritonavir acts as a pharmacokinetic enhancer (booster). LPV/r is an HIV-1 protease inhibitor successfully used in HIV-infected children as part of highly active antiretroviral combination therapy (PENTA Group, 2015). In the SARS epidemics, LPV/r was recommended as a treatment. A recent study in adult COVID-19 patients did not show an effect regarding the primary end point in a controlled clinical trial. Despite the fact that there is long experience with LPV/r in HIV, it is not advised to use it in children with COVID-

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19 as it does not appear to be effective at all (see Treatment chapter, page 385

Inhibitors of viral entry

Hydroxychloroquine (HCQ, Quensyl®), Chloroquine (CQ, Resochin junior®, Resochin®) The experience among pediatricians with HCQ/CQ (except pediatriciancs working with malaria) is very limited. Authorities in the US are now warning about a widespread use of HCQ/CQ in COVID-19 (https://mailchi.mp/clintox/aact-acmt-aapcc-joint-statement). It is not ad-

vised to use HCQ or CQ in children with COVID as neither drug appears to be effective at all (see Treatment chapter, page 385).

Immunomodulatory drug treatment

The rational for immunomodulation in COVID-19 adult patients comes from a high expression of pro-inflammatory cytokines (Interleukin-1 (IL-1) and interleukin-6 (IL-6)), chemokines (“cytokine storm”) and the consumption of regulatory T cells resulting in damage of the lung tissue as reported in patients with a poor outcome. In children, the proinflammatory cytokines TNF and IL-6 do not appear to be central in CoV-2 induced hyperinflammation (Consiglio 2020). Blocking IL-1 or IL-6 can be successful in children with (auto) inflammatory disease (reviewed in Niehues 2019), but both interleukins are also key to the physiological immune response and severe side effects of immunomodulators have been reported. In adults with COVID-19, blocking interleukin-1/6 might be helpful (see the Treatment chapter). In the rare sit-

uation that the condition of the child deteriorates due to hyperinflammation and they are resistant to other therapies, anakinra may be an option as IL-1 seems to play a role in endothelial activation.

Steroids (e.g. prednisone, prednisolone) are available as oral solution, tablets or different vials for intravenous application. Dosage in children is 0,5 to 1 mg/kg iv or oral BID. Short term use of steroids has few adverse events. Administration of steroids will affect inflammation by inhibiting the transcription of some of the pro-inflammatory cytokines and various other effects. Initially, the use of corticosteroids in children and adults with CoVinduced ARDS was controversial (Lee 2004, Arabi 2018, Russell 2020). Only in severe and critically ill children the use of dexamethasone appears justified in children. In adults, the use of steroids in severe COVID-19 is clearly beneficial although the corticosteroid-induced decrease of antiviral immunity (e.g. to eliminate CoV-2 viruses) might be theoretically disadvantageous. Data supporting the use of steroids in children with CoV-induced ARDS are lacking.

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Only in severe and critically ill children might the use of dexamethasone appear justified. Most patients with pediatric inflammatory multisystem syndrome associated with SARS-CoV-2 (PIMS-TS) published so far were treated with high dose IVIG and methylprednisolone (Verdoni 2020, Riphagen 2020). In these patients, features of macrophage activation syndrome and IVIG resistance were common, requiring adjunctive steroid treatment (Verdoni 2020). Clearly, any child severly affected by CoV-2 will need steroids at some stage. Tocilizumab (Roactemra®) is available in 80/200/400 mg vials (20 mg/ml). Dosing is • < 30 kg: 12 mg/kg iv QD, sometimes repeated after 8 hrs • ≥ 30 kg: 8mg/kg iv QD iv (max. 800 mg) Adverse events (deriving largely from long term use in chronic inflammatory diseases and use in combination with other immunomodulatory drugs): severe bacterial or opportunistic infections, immune dysregulation (anaphylactic reaction, fatal macrophage activation), psoriasis, vasculitis, pneumothorax, fatal pulmonary hypertension, heart failure, gastrointestinal bleeding, diverticulitis, gastrointestinal perforation (reviewed in Niehues 2019). Anakinra (Kineret®) is available as 100 mg syringes (stored at 4-8° C). Dosing is 2-4 mg/kg sc QD daily as long as hyperinflammation persists. Thereafter, dose reduction by 10-30% per day. Higher dosage (> 4mg/kg-10mg/kg; max 400mg/d) may be necessary in patients with PIMS-TS. Adverse events (deriving largely from long-term use in chronic inflammatory diseases and use in combination with other immunomodulatory drugs): severe bacterial or opportunistic infections, fatal myocarditis, immune dysregulation, pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatitis, encephalitis, psoriasis, vitiligo, neutropenia (reviewed in Niehues 2019).

Immunotherapy

There are no systematic data on the use of convalescent plasma in children yet, but in a child with acute lymphoblastic leukemia and a young adult with a SCID (Severe Combined Immunodeficiency) phenotype and a high CoV-2 viral load, administration of convalescent plasma resulted in complete viral suppression (Shankar 2020, unpublished observation). Engineering monoclonal antibodies against the CoV spike proteins or against its receptor ACE2 or specific neutralizing antibodies against CoV-2 present in convalescent plasma may provide protection but are generally not available yet. Interferon α has been inhaled by children with COVID-19 in the original cohorts but there are no data on its effect (Qiu 2020). Type I/III interferons (e.g.