COVID-19: A review of drugs and therapies for children

Introduction The World Health Organisation (WHO) has declared the disease as Corona Virus Disease (COVID-19) due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Coronavirus infection was restricted to animals but gained importance in medicine as it acted as the aetiological factor responsible for the SARS epidemic in 2002 in the Guangdong province of China. WHO reported its spread to over 26 countries, causing infections in 8096 individuals and 774 deaths. This group of viruses caused another outbreak in 2012 as Middle Eastern Respiratory Syndrome (MERS). Since December 2019, a strain of novel coronavirus has wreaked havoc in the Hubei province of China and has caused severe pneumonia. On March 11, the WHO declared it a ‘pandemic’. More than 1.5 million cases of COVID 19 have been reported with a mortality of over 85,000 across 212 countries. The largest study on children with COVID 19 to date includes an analysis of 2143 children documented from 16 of January, 2020 to 8 of February, 2020. This study showed that only 1 child had died while 5.9% were critical or had severe pneumonia, the majority having mild to moderate illness. Although pneumonia remains the chief cause of death among the under 5 year age category, the features of COVID-19 pneumonia were relatively milder compared to pneumonia of other aetiologies and the prognosis was better with deaths being extremely rare.


Introduction
The World Health Organisation (WHO) has declared the disease as Corona Virus Disease (COVID-19) due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Coronavirus infection was restricted to animals but gained importance in medicine as it acted as the aetiological factor responsible for the SARS epidemic in 2002 in the Guangdong province of China 1 . WHO reported its spread to over 26 countries, causing infections in 8096 individuals and 774 deaths 2 . This group of viruses caused another outbreak in 2012 as Middle Eastern Respiratory Syndrome (MERS) 3 . Since December 2019, a strain of novel coronavirus has wreaked havoc in the Hubei province of China and has caused severe pneumonia 4 . On March 11, the WHO declared it a 'pandemic'. More than 1.5 million cases of COVID 19 have been reported with a mortality of over 85,000 across 212 countries 5 . The largest study on children with COVID 19 to date includes an analysis of 2143 children documented from 16 th of January, 2020 to 8 th of February, 2020. This study showed that only 1 child had died while 5.9% were critical or had severe pneumonia, the majority having mild to moderate illness 6 . Although pneumonia remains the chief cause of death among the under 5 year age category, the features of COVID-19 pneumonia were relatively milder compared to pneumonia of other aetiologies and the prognosis was better with deaths being extremely rare 6-8 .

Clinical presentation in infants and children
Since the outbreak of the pandemic, 9 infants were reported to be positive till 6 th February, 2020 in _________________________________________ It must be ensured that the child and accompanying parents/ relatives are using a 3-ply surgical mask 12 .

Respiratory support
Oxygen support is required in a child with oxygen saturation (SpO2) less than 90% and/or with signs of respiratory distress 13 . The British Paediatric Respiratory Society (BPRS) has advised that hypoxic children should initially receive low flow nasal cannula (LFNC) oxygen rather than high flow nasal cannula (HFNC) oxygen as HFNC is associated with an increased risk of aerosol spread 14 . HFNC may be the next step if the child continues to be hypoxic 14 . Improvement is indicated by reduced heart and respiratory rates by 10-20%, reduced fraction of inspired oxygen (FiO2) requirements to less than half and improved SpO2 13 .
Both the European Society of Intensive Care Medicine and the American Association for Respiratory Care have advised against usage of non-invasive ventilation (NIV) in acute respiratory failure in H1N1 influenza as it is a high risk procedure which should be cautiously used due to the high probability of spread of infection 13,15 .
Bubble continuous positive airway pressure (Bubble CPAP) is an alternative procedure which may be used for newborns and children with hypoxia when both NIV and mechanical ventilation are not available 13 . Lung protective mechanical ventilation is a recommended strategy for treatment of acute hypoxic respiratory failure 16 .

Nutritional supplementation
Riboflavin supplementation has been reported to effectively scale down the titres of MERS-CoV in the human plasma products 17 . Treatment with nicotinamide was able to significantly repress neutrophil infiltration into lungs during ventilator induced lung injury but had no effect on cytokine production or protein leakage and was also found to paradoxically lead to hypoxaemia 18 . Pyridoxine plays a vital role in antibody production and immune system regulation 19 . Thus, B complex vitamins are a valuable adjunct in COVID-19 therapy.
Five trials found preventive or therapeutic benefits of vitamin C against pneumonia with the overall quality of the studies being good 20 . Thus, Vitamin C supplementation is a potential therapy in the treatment of viral pneumonias. Because of this, a triple blinded randomised controlled trial (RCT) is being carried out by Peng et al 21  Intravenous immunoglobulins (IVIg) may be used in severe cases or critically ill patients but requires further validation. The recommended dose in children is 1g/kg/day for 2 days or 400mg/kg/day for 5 days 35 . In a single centre observational study by Dan Sun et al 36 , immunoglobulin therapy was administered to 4 patients with 2 children getting discharged while the other 2 were still in the intensive care unit at the time of publication of the study.

CoV specific therapy CoV protease inhibitors
Cinanserin is a drug well-known for its antagonistic action on serotonin receptor. In the study by Chen et al 37

Spike (S) protein ACE 2 blockers
Griffithsin, a lectin, binds to oligosaccharides present on the surface of some viral glycoproteins, including SARS-CoV spike glycoprotein and HIV glycoprotein 120 39 . ACE2 is a receptor for SARS-CoV virus and mediates its entry into the cell by binding with S protein 40 . Blocking the binding of S protein to ACE2 is an important therapeutic option which could be used for treatment in the form of mAb 41 . Sui et al 42 have developed an anti-S1 human monoclonal antibody 80R which neutralizes SARS-CoV infection with a strong nanomolar affinity and also efficiently inhibits formation of syncytia by receptor binding blockage. The data in this in vitro study also suggested that the monoclonal antibody may be further developed and tested in in vivo animal studies to determine its clinical utility as a potent inhibitor of viral entry for use in prophylaxis and treatment of SARS.
CoV specific treatment is yet to be evaluated in the paediatric population.

Anti-viral drugs
Ribavirin, Remdesivir, Galidesivir, Tenofovir and Sofosbuvir are potent drugs against SARS-CoV2 as they tightly bind to its RNA dependent RNA polymerase 45 . There is no consensus on the use of these drugs in children. Lopinavir (LPV) is a protease inhibitor of HIV-1 which is combined with Ritonavir (RTV) in order to increase its halflife. Combination of LPV/RTV has shown efficacy against the SARS-CoV in tissue cultures as well as in patients with estimated EC50 being 4 mcg/ml in foetal rhesus kidney-4 cells 46 . A randomized clinical trial in China, comparing the use of LPV/RTV to the prevailing care in 199 admitted COVID-19 patients, concluded that LPV/RTV did not significantly decrease the 28 day mortality or the time to clinical improvement and that this drug regimen was associated with more adverse events 47 .

Antibiotics
Teicoplanin, a glucopeptide antibiotic usually used for treatment of bacterial infection, was found to be active against SARS-CoV in vitro 48 . A recent nonrandomised clinical trial in France showed that hydroxychloroquine could reduce the viral load and also that addition of azithromycin had increased its efficiency significantly 49 . Azithromycin is thus a potential therapeutic agent which could be exploited further in paediatric clinical trials for COVID-19 pneumonia.

Anti-parasitic drugs
Ivermectin, FDA approved for parasitic infections, is an inhibitor of SARS-CoV2 in vitro and a single treatment can effect a 5000 fold reduction in virus at 48 hours in cell culture 50 . Thus, it merits further study for treating COVID-19 infection in children.
In conclusion, Anti-CoV drugs need to be further evaluated and studied for their mechanism of action, appropriate dosing regimen as per body surface area or body weight, and efficacy with special consideration being given for adverse reactions and possible drug interactions in children.
Although COVID-19 has been relatively less severe in children, there is a dire need to come up with a definitive treatment protocol for children.
Keeping this in mind, this article reviews all possible beneficial therapeutic agents in the paediatric population. Ascorbic acid and zinc supplementation may be useful as preventive measures as well as in asymptomatic patients.
Interferons, SARS-CoV-2 specific antivirals, HCQ/CQ, Azithromycin and Ivermectin present the best available therapeutic agents for symptomatic children. However, a series of clinical trials are required at the earliest to evaluate their efficacy and safety in the paediatric population.