Pharmacotherapy of Acute COVID-19 Infection and Multisystem Inflammatory Syndrome in Children: Current State of Knowledge

Abstract

Background:

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic is a health care emergency across the world. Although mitigation measures, such as social distancing and face masks, have attempted to slow the spread of the infection, cases continue to rise. Children who are otherwise healthy tend to develop a milder acute Coronavirus disease 2019 (COVID-19) infection and have lower mortality rates compared with adults.

Methods:

Guidelines and current primary and secondary literature on the treatment of COVID-19 and the multisystem inflammatory syndrome in children were searched and reviewed. There are 6 published pediatric series that included 252 children with acute COVID-19 infection and describe various treatments and outcomes.

Results:

Guidelines recommend treating pediatric patients similarly to adult patients. Currently, no prophylactic drug therapy has been shown to reduce the spread of infection. Treatment options for acute COVID-19 are limited to remdesivir and glucocorticoids for patients who require oxygen and/or mechanical ventilation. The efficacy of hydroxychloroquine, chloroquine, and azithromycin has not been proven and their safety has been a concern. Other therapies that are being explored include interleukin (IL)-1 and IL-6 inhibitors. In children, an atypical Kawasaki-like disease emerged after recent exposure to SARS-CoV-2 and has been named Multisystem Inflammatory Syndrome in Children (MIS-C). Nine case series, including 418 pediatric patients, described pharmacotherapies used and patient outcomes. These pharmacotherapies included intravenous immune globulin and glucocorticoids and in some patients, IL-1 and IL-6 inhibitors.

Conclusion:

Given the paucity of data in children, this article presents currently recommended pharmacotherapies for the treatment of acute COVID-19 infection in adult patients and whenever available, in pediatric patients. Pharmacotherapies used in the treatment of MIS-C in children are also reviewed.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by the World Health Organization on March 12, 2020 after the outbreak in Wuhan, Hubei Province, China in December 2019.¹ At the time of this publication, SARS-CoV-2 has infected more than 12,500,000 people worldwide and has caused more than 566,000 deaths.² Children make up a smaller proportion of patients with acute coronavirus disease 2019 (COVID-19) infection and tend to develop a milder disease than adults. However, beginning in April 2020, a new disease entity was reported from the United Kingdom of a Kawasaki-like presentation in pediatric patients that was associated with a recent infection with SARS-CoV-2. This syndrome was soon reported worldwide and was designated as Multisystem Inflammatory Syndrome in Children (MIS-C). This article will describe the pharmacotherapies used to treat both entities.

Acute COVID-19 Infection

Background

The incidence of COVID-19 infection is currently reported in 2% of children in the United States, as compared with cases internationally ranging from 0.8% (Spain) to 2.2% (China).³ Clinical presentation in children commonly involves the upper respiratory and gastrointestinal tracts and includes fever, cough, shortness of breath, abdominal pain, diarrhea, nausea, and vomiting.³ Rates of morbidity and mortality in children are low compared with adults, except children less than 1 year of age and children with comorbidities tend to require more hospitalizations.¹ Morbidity has been reported in 0.6% to 2% of children, according to reports from Chinese and American children, respectively. Complications include respiratory distress or failure, encephalopathy, cardiac injury or failure, acute kidney injury, septic shock, and/or coagulation abnormalities.⁴ Reported incidence of death from COVID-19 in children is lower than in adults.⁴ Testing in children is similar to adults. For acute infection, detection of SARS-CoV-2 RNA is made by reverse transcription polymerase chain reaction (RT-PCR) and for recent infection, serologic tests can detect antibodies to the virus.

SARS-CoV-2: the virus

SARS-CoV-2 is a single-stranded RNA-enveloped virus. It has a spike protein (S) that targets host cells and binds to the angiotensin-converting enzyme (ACE)2 receptor for cell entry. After binding to the receptor, host cell protease, such as transmembrane serine protease 2, cleaves the S protein of the SARS-CoV-2 to allow it to enter the cell. On entry, viral proteins synthesize RNA through RNA-dependent RNA polymerase. Structural proteins are then formed and allow gathering and release of viral particles.^5,6 There are 3 proposed reasons why children have a reduced incidence and a milder course of COVID-19 to date: (1) ACE2 may not be fully developed, reducing binding of SARS-CoV-2 to human host cells; (2) priming of the child's immune response due to a greater exposure to other viruses may provide a greater number of antibodies against SARS-CoV-2; and (3) a child's underdeveloped immune system may not respond as strongly to pathogens as compared with adults.⁷

Acute COVID-19 reports in pediatric patients

To date, there have been 6 published or pre-published case series and retrospective studies that included 252 pediatric patients with acute COVID-19 infections (Table 1).^8–13 The patients' ages ranged from 26 days to 21 years. Comorbidities were noted in many reports, and laboratory abnormalities were similar to those reported in adult patients. The most common pharmacotherapies used were interferons (IFNs) alfa aerosolized (48, 19%), hydroxychloroquine (HCQ) (48, 19%), glucocorticoids (40, 15.8%), and remdesivir (11%). The remaining medications that were commonly used included lopinavir/ritonavir, tocilizumab, and oseltamivir. By the time of their publication, authors reported that most children were discharged from the hospital; however, 5 (2%) children died. There are no prospective, controlled trials in pediatric patients in the treatment of COVID-19 to objectively delineate the impact of these therapies. Also, the combinations used to date, some proven to be effective in the adult population, such as remdesivir and glucocorticoids, make it difficult to single out one pharmacotherapy's impact on the treatment and outcome in pediatric patients (Table 1).

Table 1.

Acute Coronavirus Disease 2019 Infections Reported in Pediatric Patients

Authors (location)	Liu et al.⁸ (China)	Shekerdemian et al.⁹ (USA, Canada)	Qiu et.¹⁰ (China)	Zheng et al.¹¹ (China)	Chao et al.¹² (USA)	Derespina et al.¹³ (USA)
Study design, N	Case series, n = 6	Retrospective multicenter, n = 48	Retrospective, n = 36	Retrospective, n = 25	Retrospective, n = 67	Retrospective, n = 70
Age range (years)	1 to 7 years	26 days to 21 years (median 13 years)	1 to 16 years (mean 8.3 ± 3.5 years)	3 months to 14 years, (median 3 years)	1 months to 21 years, (median 13.1 years)	1 months to 21 years, (median 15 years)
Comorbidities	None	40 (83%)	None	CHD (2)	Obesity, asthma	Obesity, respiratory, heart disease, hematologic system, diabetes, neurologic, 74.3%
Presentation	Fever, cough	Fever, dyspnea	Fever, cough	Fever, cough	Fever, cough SOB	Fever, cough, SOB
Disease severity	Moderate to severe RD	Critically ill admitted to PICU (48)	Pneumonia (53%), mild-to-moderate illness. None critically ill	Critically ill (2), remaining patients had mild URI/pneumonia	46 children hospitalized, 13 admitted to PICU	All children admitted to PICU; ARDS 21, Respiratory support 70%; IMV 20 (29%)
Laboratory abnormalities			Leukopenia, lymphopenia, increased creatinine kinase MB levels	Increased CRP	Increased CRP, procalcitonin, BNP, platelets in severely ill patients	Increased CRP, procalcitonin, lactate, pro-B type, IL-6 BNP, and platelets in patients with ARDS
Pharmacotherapy	Oseltamivir (6), glucocorticoids (4), ribavirin (2) IVIG (1)	HCQ (11) 44%, HCQ/azithromycin (7, 37.5%); remdesivir 2 (4%), in combination (6, 12.5%); tocilizumab (1), in combinations (4)	IFN alfa aerosolized (36, 100%), lopinavir/ritonavir (14, 39%)	IFN, arbidol, oseltamivir, lopinavir/ritonavir, IFN (12, 48%): Corticosteroids (2), IVIG (2)	HCQ (10), remdesivir (8), methylprednisolone (11)	HCQ (27), remdesivir 13, corticosteroids 23, tocilizumab 3, anakinra 1, iNO 2
Complications	O₂ and ICU (1)	Mechanical ventilation (38%), ECMO (1)	O₂ requirements (6)	ARDS, mechanical ventilation, CRRT (2)	Severe sepsis/septic shock (7), ARDS (10), AKI, CRRT	Severe sepsis 17%, ARDS 30%, AKI 12.9%, cardiac arrest 2.8%, vasopressor support (20%), ECMO 1, LV dysfunction (6), RV dysfunction (3)
Outcome(s)	All patients survived	2 patients died	All patients survived	All patients survived	1 patient died (history of metastatic cancer)	2 patients died (history of metastatic cancer (1), hemoglobinopathy (1)). Discharged home 55 (78.6%), remaining patients remain hospitalized

AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; BNP, brain natriuretic peptide; CHD, congenital heart disease; CRP, c-reactive protein; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; HCQ, hydroxychloroquine; ICU, intensive care unit; IL, interleukin; IFN, interferon; iNO, inhaled nitric oxide; IMV, intermittent mechanical ventilation; IVIG, intravenous immune globulin; LV, left ventricle; PICU, pediatric intensive care unit; RD, respiratory depression; RV, right ventricle; SOB, shortness of breath; URI, upper respiratory infection.

Pharmacotherapies for the treatment of acute COVID-19 infection

At this time, no pharmacological agents are FDA-approved for treatment or prophylaxis against SARS-CoV-2. Infectious Disease Society of America (IDSA) guidelines published April 21, 2020 for the treatment of patients with COVID-19 were geared toward adult patients.¹⁴ The National Institute of Health (NIH) guidelines of August 27, 2020 provide guidance for adults and some guidance for pediatric patients.¹⁵ Due to limited data in children, a panel of pediatric infectious disease specialists published a guidance document on April 22, 2020, on the use of antiviral pharmacotherapies.¹ Given the occurrence of a milder disease in children, the paucity of data, and the potential for toxicity from antiviral agents, the panel determined that the risks of antiviral therapies may outweigh the benefits. Children should, therefore, receive antiviral agents if severe or critically ill and then only as part of a clinical trial. If an antiviral agent is indicated, the panel and NIH recommended remdesivir first.^1,15 If remdersivir is contraindicated or could not be obtained, the pediatric panel recommended HCQ to be considered as an alternative agent.¹ However, the NIH guidelines disclosed that the data are not sufficient to recommend for or against alternative agents and this should be decided on a case-by-case basis.

This article presents the recommended and commonly used drugs in the treatment of COVID-19, according to guidelines published by the NIH, IDSA, and a pediatric Infectious disease specialist panel. Because of the acuity and evolving situation with COVID-19, traditional literature searches using Pubmed and Embase searches were not applicable. Periodic searches in medical and pharmacy journals were performed weekly as well as cross-referencing published guidelines and review articles. Primary literature was selected based on published, pre-published data or pre-proof in adult and pediatric patients. The pediatric literature on acute SARS-CoV-2 infection and MIS-C is limited at this time. Pediatric data will be reviewed and in cases where there are no pediatric data, adult data will be used. Dosing and administration of all drugs will be presented from a pediatric perspective.

Pharmacotherapies for the Treatment of Acute COVID-19 Infection

Current treatments

Remdesivir

Remdesivir is an adenosine nucleotide analogue that has a wide spectrum of antiviral activity against paramyxoviruses, pneumoviruses, Middle East Respiratory Syndrome (MERS), and SARS-CoV-1. It is a pro-drug that undergoes phosphorylation to its active triphosphate analogue. Once phosphorylated, it binds to RNA-dependent RNA polymerase and terminates the RNA chain prematurely before viral translation and assembly.^5,6 Remdesivir is selective for viral RNA polymerase. As compared with ribavirin, remedesivir is resistant to the effects of a unique 3′- to 5′ exoribonuclease proofreader on the coronavirus.⁵

Pharmacokinetics/pharmacodynamics

Remdesivir has shown in vitro activity against SARS-CoV-2 [half-maximal effective concentration (EC₅₀) (EC₅₀ and EC₉₀ 0.77 and 1.76 μM, respectively) in animal models where it reduced viral load in the lungs and reduced pulmonary damage.⁶ Studies on drug disposition of remdesevir in children are ongoing. Adult data show that the drug displays linear pharmacokinetics and is rapidly converted in the plasma to an intermediate metabolite and nucleoside analogue. This nucleoside analogue is then converted by intracellular esterases in respiratory epithelial cells to the active triphosphate form. Plasma t½ is short for the drug and its nucleoside analogue metabolite, whereas intracellular half-lives of the drug and metabolite are long, 24 and 40 h, respectively.¹⁶ Simulations of remdesivir pharmacokinetics in pediatric patients predicted similar exposure to adult patients with a cutoff for adult dosing at 60 kg of weight.¹⁷

Clinical trials

Human trials have been carried out mainly in adult patients. In a randomized, double-blind, placebo-controlled trial, remdesivir reduced the time to recovery in adult hospitalized patients.¹⁸ The treatment group had 8 patients and there were 521 patients in the control group (no remdesivir). The dose was 200 mg i.v. on the first day of therapy, then 100 mg i.v. daily for 5 or 10 days. Shorter time to recovery occurred in patients in the treatment group as compared with the control group, a difference of 4 days, rate ratio for recovery 1.32 [95% confidence interval (CI) 1.12–1.55], P < 0.001. Benefits were most observed in patients who required oxygen therapy at study enrollment. There was no significant difference in mortality between the treatment and control groups (8% versus 11.6%, respectively, P = 0.059). The sample size may have been too small to detect a significant difference. There was no difference in the occurrence of serious adverse effects.

A randomized, open-label trial of remdesivir was conducted in 397 hospitalized adolescent (≥12 years of age) and adult patients to compare clinical improvement between treatment durations of 5 or 10 days.¹⁹ Patients had pneumonia at study entry and received remdesivir 200 mg i.v. on the first day of therapy, then 100 mg i.v. daily for 5 or 10 days. In the 10-day group, some patients had worse clinical status before starting therapy (P = 0.02). After adjustment for baseline status, there was no significant difference in clinical improvement or time to clinical improvement between the 5- and 10-day groups (P = 0.14). This open-label study compared 2 groups of patients without a comparison with an active control group. The authors did not report or analyze data in children 12 to 18 years of age separately.

A multicenter, randomized, placebo-controlled study of remdesivir was conducted in adult patients in China.²⁰ The primary goal of the study was time to clinical improvement. The treatment group had 158 and placebo group 79 adult patients. Remdesivir dose was 200 mg i.v. on the first day of therapy, then 100 mg i.v. daily for 10 days. For study entry, patients had to have low O₂ saturation, ≤94% on room air or low PaO₂/FiO₂, <300 mmHg, and pneumonia. Comorbidities were more common in the placebo group. Patients received IFNs, L/R, and corticosteroids equally between groups. The authors stopped the study before achieving goal sample size because of low enrollment. Time to clinical improvement was not different between groups (−2 days hazard ratio (HR) 1.23; 95% CI 0.87–1.75), and there was no difference in mortality. Adverse effects led to early discontinuation of remdesivir (12% versus 5% placebo group). The study was underpowered, which may have limited the findings.

Role in pediatric COVID-19 patients

Remdesivir is the antiviral of choice when an antiviral is indicated in the treatment of COVID-19 in pediatric patients.¹ In addition to supportive care, antiviral therapy was recommended only in critically ill children who have a positive virologic test or who are highly suspected of having SARS-CoV-2; in patients with underlying cardiopulmonary and immunocompromised conditions, who have new or increased requirements for noninvasive or invasive mechanical ventilation; and in patients who are septic, have multiorgan failure, or rapid decline in clinical status.¹ Remdesivir has been used in case series in pediatric patients with acute COVID-19 infection; however, there are no data that have been sub-analyzed, specifically for pediatric patients.

Dosing

Recommended doses for children are^1,21: 3.5 to <40 kg: 5 mg/kg i.v. day 1; then 2.5 mg/kg i.v. every 24 h (use lyophilized powder preparation only); children ≥40 kg: 200 mg i.v. day 1; then 100 mg i.v. every 24 h (use either powder or liquid preparation). The drug is infused over 30 to 120 min. Remdesivir should not be administered to patients with an estimated glomerular filtration rate of <30 mL/min (adults or full-term neonates >28 days of age) or in full-term neonates (7 to ≤28 days of age) who have a Scr ≥1 mg/dL, or in patients whose baseline alanine aminotransferase is more than 5 times normal or baseline levels.

Administration

Remdesivir can be obtained through the FDA and the U.S. government by an “emergency use authorization” (EUA). Aseptic technique is essential in the preparation of remdesivir since the pharmaceutical preparation does not contain any preservatives or bacteriostatic agents. Once diluted, remdesivir should be used within 4 h at room temperature or 24 h if refrigerated. After this period, any remaining drug must be discarded. Remdesivir is available as a lyophilized powder and concentrated liquid vial, 5 mg/mL. Both formulations are then further diluted in 0.9% sodium chloride for administration. Once the administration is completed, the intravenous line (IV) line should be flushed with 0.9% normal saline. Although either preparation can be used in children ≥40 kg and adult patients, liquid preparations should not be used in children <40 kg because they contain a higher amount of the excipient sulfobutylether-β-cyclodextrin sodium salt (SBECD). SBECD is used to improve the drug's solubility but it can increase the tonicity of the final product and cause severe renal damage.^15,21 The lyophilized product is used only for these pediatric patients.²¹ Caution must be observed for patients who are also receiving amiodarone or voriconazole, because their preparations also contain SBECD and this may result in accumulation of this excipient.

Adverse effects

Nausea and constipation have been reported.¹⁹ Infusion-related reactions and hypersensitivity reactions can be managed by extending the administration infusion rate to 120 min. Increases in liver transaminases may occur. Rising or worsening liver function tests necessitate discontinuation of the drug.

Drug interactions

Strong inducers of P-glycoprotein, such as rifampin, should be avoided with remdesivir because they can decrease remdesivir levels.¹⁶ The FDA issued a warning not to use remdesevir together with HCQ or chloroquine (CQ), because these agents may interfere with the conversion of remdesivir to its active form and its antiviral activity.²²

Summary

Based on well-designed trials showing efficacy and safety, current guidelines recommend remdesivir as the antiviral of choice in the treatment of all pediatric and adult patients hospitalized with COVID-19 infection regardless of disease severity.^14,23 The duration of therapy is 5 days for patients who are not intubated but it may be extended to 10 days for patients who are mechanically ventilated on extracorporeal membrane oxygenation (ECMO), or who fail to improve by 5 days of therapy.^1,14,15 It is hoped that future trials will provide more data in pediatric patients.

Corticosteroids

Systemic corticosteroids are generally used in non-viral lung injury and ARDS to reduce inflammatory response to the invading pathogen in the lungs. Earlier guidance from NIH recommended against use of corticosteroids in mechanically ventilated patients, except those with ARDS. Concern regarding their routine use stemmed from data in patients with influenza and MERS that included increased mortality, hospital-acquired pneumonia, and delayed viral clearance.^6,24

Clinical trials

A large multicenter, open-label, randomized trial from the U.K. (RECOVERY) trial reported that adult patients who were randomized to receive dexamethasone had reduced 28-day mortality.¹⁵ The dexamethasone group had 2,104 adult hospitalized patients with COVID-19 infection as compared with 4,321 patients who received usual care. At study enrollment, the majority of patients (60%) required oxygen at enrollment and 16% required mechanical ventilation. Some patients received HCQ, lopinavir/ritonavir, remdesivir, or tocilizumab. The results are preliminary since the trial has not been peer-reviewed or published in its final form. Dexamethasone was given at 6 mg/day, i.v. or p.o. for 10 days or until discharge from the hospital. The dexamethasone group had reduced mortality by 17% in an age-adjusted analysis (relative risk [RR] 0.83; 95% CI 0.74–0.92, P < 0.001), by 35% in patients receiving mechanical ventilation at enrollment (29% versus 40.7% in the dexamethasone and control groups, respectively; RR 0.65; 95% CI 0.51–0.82, P < 0.001), and by 20% in patients who required oxygen therapy alone (21.5% versus 25% for dexamethasone and control groups, respectively; RR 0.8; 95% CI 0.70–0.92, P = 0.002). Patients who did not require oxygen at enrollment did not have reduced mortality (RR 1.22; 95% CI 0.93–1.61, P = 0.14). Some pediatric patients were enrolled in the trial, but there are no data available on this subgroup.

Though data from the RECOVERY trial only included dexamethasone, equivalent doses of other glucocorticoids proposed are methylprednisolone 32 mg, prednisone 38 mg, and hydrocortisone 160 mg.¹⁵

Adverse reactions

Aside from well-known short- and long-term adverse effects of corticosteroids, their use in the management of viral infections raises concerns of reactivating latent infections and causing delayed viral clearance.

Drug interactions

As an inducer of 3A4, dexamethasone may decrease the efficacy of other CYP3A4 substrates. Clinicians need to check for drug interactions when other medications that use the same metabolic pathways are used.

Summary

Based on the results of the RECOVERY trial, dexamethasone 6 mg a day for up to 10 days is recommended in the treatment of COVID-19 only in adult patients who are on mechanical ventilation or requiring oxygen therapy, but not on mechanical ventilation.¹⁵ Due to the limited number of pediatric patients in the RECOVERY trial, the use of corticosteroids in children <18 years of age is not established. Corticosteroids may be considered in pediatric patients who are on mechanical ventilation.¹⁵ The efficacy of glucocorticoids may stem from their reduction of the hyper-inflammatory state that tends to occur with COVID-19.

Proposed drugs without demonstrable benefit

Chloroquine/hydroxychloroquine

Proposed mechanisms of CQ and HCQ include interference with viral entry, as well as anti-inflammatory and immunomodulatory effects through reducing the production of cytokines.^1,6 These drugs may interfere with the fusion of SARS-CoV-2 with the host cell surface by raising endosomal pH, a condition for cell entry. They may also block entry of the virus into host cells by interfering with N-glycosylation of the ACE2 receptor, the cell surface viral receptor.^1,15 As compared with CQ, HCQ is more potent and has fewer adverse effects, or drug–drug interactions, and it has been studied more frequently in COVID-19. It is unclear whether one drug is more clinically effective than the other in SARS-CoV-2.²⁵

Pharmacokinetics/pharmacodynamics

The maximal effective concentration EC₅₀ of HCQ is 6.14 μM whereas EC₅₀ of CQ is 23.90 μM.⁶

Adverse effects

Gastrointestinal, hematological, ophthalmic, and neuromuscular adverse effects have been reported, as well as headache and hypoglycemia.²² Cardiovascular adverse effects, including corrected QT interval (QTc) prolongation, have increased the risk-to-benefit ratio in the setting of COVID-19. In patients with underlying heart disease or patients who are also receiving medications that prolong QTc interval, including fluoroquinolones and azithromycin (AZM), this risk is higher and monitoring for QTc prolongation is essential.¹⁵

Drug interactions

HCQ and CQ are metabolized by CYP 450 2C8, 2D6, and 3A4; therefore, drug interactions with other drugs metabolized through these enzyme systems must be monitored. Inducers or inhibitors of these isoenzymes are expected to affect the metabolism and clearance of HCQ or CQ. Patients with G6PD deficiencies may experience hemolysis with HCQ.^1,14 The FDA issued a warning not to use remdesevir together with HCQ or CQ, because these agents may interfere with the conversion of remdesivir to its active form and its antiviral activity.²²

CQ phosphate, clinical trials

There are very limited data on CQ for the treatment of COVID-19. A randomized, double-blind, parallel, clinical trial enrolled 81 adult patients who were hospitalized with COVID-19 and severe ARDS.²⁶ The CQ high doses (n = 41; 600 mg twice a day for 10 days) and low doses (n = 40; 450 mg twice a day for 4 days) were compared with the expectation that high doses would reduce mortality. Patients who received the high dose were older and had an increased incidence of heart disease, and all patients received AZM and oseltamivir. The trial was stopped early due to increased mortality in the high-dose group (39% and 15%, respectively). The increased mortality rate, however, was not significant when the age of the patients was included in the analysis. QTc prolongation occurred more frequently in the high-dose group.

Dosing

The NIH lists the dose of CQ in adolescent patients ≥50 kg and adult patients as 1 g p.o. on day 1, then 500 mg once a day for 4 to 7 days.²² Doses ≥600 mg twice a day or higher are not recommended due to concern for adverse effects.¹⁵ There are no dosage recommendations for the treatment of COVID-19 in pediatric patients who weigh <50 kg.

Administration

The FDA revoked an earlier EUA for HCQ due to lack of efficacy and reports of adverse effects.²² To obtain the drug for use in the treatment of COVID-19 outside of a clinical trial, U.S. providers can contact local health departments. CQ phosphate is only available in oral dosage forms as 250 and 500 mg tablets. Tablets are bitter but can be crushed and mixed with cherry or chocolate syrup to mask their taste, with a resulting concentration of 16.67 mg/mL CQ phosphate suspension. This preparation is stable for 4 weeks at room temperature or under refrigeration.²⁷ CQ phosphate 16.6 mg is equivalent to 10 mg CQ base; however, dosing recommendations are listed as the phosphate salt.

HCQ, clinical trials

A multicenter, open-label, randomized, controlled trial enrolled 150 adult patients with mild-to-moderate COVID-19 infection.²⁸ The primary endpoint was resolution of viral infection within 28 days. Secondary outcomes were improvements in symptoms and markers of inflammation. The authors administered HCQ to 75 patients at high doses and for a long duration (1,200 mg daily orally for 3 days, then 800 mg once daily orally for 2–3 weeks). The control group consisted of 75 patients who did not receive the drug (control). Treatment with HCQ did not result in virologic clearance (85.4% HCQ versus 81.3% control groups, respectively) or reduced time to clearance (median 8 days versus 7 days, respectively). Similarly, symptom improvement was not different between groups. Adverse effects were reported in 30% of patients in the HCQ group and included gastrointestinal and blurred vision as compared with 9% in the control arm. The use of higher doses of HCQ in this study did not support the concept of improved efficacy with higher doses or longer duration of treatment. In an observational retrospective study, 181 adult patients with severe COVID-19 infection from 4 tertiary French centers were enrolled.²⁹ All patients required oxygen therapy and received HCQ (n = 84) and were compared with patients who received the standard of care (n = 89). HCQ 600 mg by mouth per day was administered within 48 h of admission in most patients, whereas 8 patients received the drug after 48 h. Survival without admission to intensive care at day 21, the primary outcome, was not different between groups (76% versus 75% for the HCQ and control groups, respectively). Also, the incidence of death was not different between groups. Eight patients (9.5%) in the HCQ group had ECG changes that necessitated discontinuation of the drug, and 1 patient developed a new first-degree atrioventricular block.

Pharmacokinetics

In pediatric and adult patients, HCQ has a slow onset of action, variable absorption rates, low plasma protein binding, and a large volume of distribution. In adult patients, the half-life was ∼40 days. The drug's onset of action and time to achieve steady state are measured in weeks. This justifies higher initial doses to attain higher serum levels. Smaller doses are meant to minimize gastrointestinal adverse effects. Recent pharmacokinetic simulations predicted that pediatric patients are expected to achieve lower free drug concentrations in lung interstitial fluid that would optimize antiviral activity; however, confirmation is needed in a prospective trial.¹⁷

Dosing

Current recommendations for adult patients or patients ≥50 kg for HCQ are 800 mg day 1, then 400 mg PO once a day for 4 to 7 days in total.²² Given the lack of specific data on the treatment of COVID-19 in children, dosing used in malaria or based on pharmacokinetic modeling was recommended in the pediatric panel.¹ One option is to use HCQ 13 mg/kg (maximum: 800 mg) orally; then 6.5 mg/kg (maximum: 400 mg), 6, 24, and 48 h after the first dose for up to 5 days. Alternative dosing is 6.5 mg/kg/dose (maximum: 400 mg/dose) orally twice a day on day 1, then 3.25 mg/kg/dose (maximum: 200 mg/dose) twice a day for up to 5 days. Longer treatment durations have been reported.¹ There are no data on dosing in neonatal patients.

Drug administration

HCQ sulfate is only available in a 200 mg oral dosage form tablet. Tablets are film-coated and can only be crushed after using a moist alcohol pad to remove the film coating. Extemporaneous compounding of the tablets may be prepared with Ora-Plus into a 25 mg/mL oral suspension.²⁷

Summary

Data on the efficacy and safety of CQ and HCQ in the treatment of COVID-19 have been disappointing. Trials that enrolled a large sample size did not show resolution of the infection, symptom improvement, or improved survival in patients who received these medications. On June 15, 2020, the FDA revoked the EUA of HCQ and CQ due to ineffectiveness and potential for adverse effects.¹⁵ Guidelines do not recommend using these agents in the treatment of COVID-19.^14,15 In pediatric patients, HCQ was considered as second-line therapy in children, in case remdesivir cannot be used.¹ These recommendations were published before these newer data were available. It is likely that the management of children will also involve the use of these agents only as part of a clinical trial at this point.

AZM, added to HCQ

The role of AZM in the treatment of COVID-19 stems from its in vitro activity against Ebola and Zika viruses, as well as anti-inflammatory and immunomodulatory effects. The exact mechanism of action in SARS-CoV-2 is unknown. AZM has been proposed to bind the spike protein to the ACE2 protein, thereby interfering with viral entry.³⁰

Clinical trials of the combination of HCQ and AZM

In a retrospective uncontrolled study, Gautret et al. enrolled 80 adult patients who had a mild course of disease.³¹ Patients received HCQ 200 mg 3 times a day for 10 days and AZM 500 mg day 1, then 250 mg once a day for 4 days. Nasopharyngeal RT-PCR was negative in 93% of patients by day 8 of therapy; however, there was no control group in the study. In a large, retrospective, uncontrolled trial, Million et al.³² enrolled 1,061 adult patients with mild illness and included children older than 14 years of age (exact number not provided). The combination resulted in a good clinical outcome, defined as survival, not requiring intensive care, or hospitalization for 10 days, in 91.7% of patients. Interestingly, the group that included children 14 years of age and older had a good clinical outcome, raising the possibility that this age group skewed the results for a better outcome since children tend to have a milder disease course. In a large open-label observational study of 1,376 adult patients in NY, Geleris et al. compared HCQ, HCQ with AZM and no treatment on the rate of intubation or death.³³ HCQ 600 mg orally on day 1 was followed by 400 mg/day for 4 additional days and was administered to 811 patients within 48 h in the majority of patients. AZM was added to HCQ in 60% of the patients, with a dose of 500 mg day 1, followed by 250 mg daily for 4 days. Patients who received HCQ tended to be sicker at baseline than those who did not. The authors did not find a reduction in the composite outcomes of death or intubation with HCQ (propensity-score analyses hazard ratios 1.04, 95% CI 0.82–1.32) or with the addition of AZM (HR 1.03; 95% CI 0.81–1.31). A limitation to this trial is the retrospective study design.

Adverse effects

AZM is associated with gastrointestinal adverse effects and prolonged QT intervals, torsade de pointes, and ventricular tachycardia. QTc prolongation occurred at a mean time of 3.6 ± 1.6 days after starting the drug.³⁴ The combination of HCQ and AZM is expected to increase the likelihood of cardiac conduction disturbances. If the combination is used as part of a clinical trial, the IDSA recommends monitoring for potential drug interactions and obtaining a baseline and follow-up electrocardiogram.

Summary

Although initial data on the combination of HCQ and AZM were promising for viral clearance, larger studies did not show improvements in mechanical ventilation or death in patients treated with these agents. Current guidelines do not recommend the combination of HCQ/CQ and AZM outside of a context of a clinical trial.^14,15 The pediatric panel discouraged the addition of AZM to HCQ for the sole purpose of treating COVID-19, outside of treating a bacterial supper infection, due to lack of demonstrated efficacy and the possibility of adverse effects.¹

Lopinavir/ritonavir

Used as protease inhibitors in the treatment of HIV infection, this combination showed some in vitro antiviral activity against SARS-CoV-1 and MERS-CoV. The proposed mechanism of action in SARS-CoV-2 is interference with the splitting of polyproteins into RNA-dependent RNA polymerase, which depend on 2 protease enzymes for viral processing.⁶ Ritonavir's role in this combination is to inhibit the metabolism of lopinavir by CYP3A4 and increase its serum levels.

Clinical trials

A randomized, open-label, controlled trial enrolled 199 adults with COVID-19 infection and oxygen saturations of less than 94% to receive lopinavir/ritonavir or the standard of care.³⁵ Lopinavir/Ritonavir 400/100 mg twice daily for 14 days was administered to 99 patients, whereas the remaining 100 patients received the standard of care (control group). The primary outcome of time to clinical improvement was not different between groups (HR 1.31; 95% CI 0.95–1.80). There were no significant differences in reduction of viral loads or mortality between groups. Gastrointestinal adverse effects were commonly reported in the lopinavir/ritonavir group. It is not known whether starting the combination of drugs earlier than the 13-day median used in this study may have improved patient outcome.

Dosing

Guidelines list the following recommendations for lopinavir/ritonavir dosing in pediatric patients: For neonates ≥14 days with a post-menstrual age of ≥42 weeks and children <18 years of age, lopinavir 300 mg/m²/ritonavir 75 mg/m² (maximum: lopinavir/ritonavir 400 mg/100 mg/dose) was administered orally twice a day for 7 days.^1,15

Drug administration

Lopinavir/ritonavir is available in oral dosage forms only, as 100 mg/25 mg and 200 mg/50 mg tablets and a commercially available liquid preparation 80 mg/20 mg/mL. Inactive ingredients in the liquid preparation include ethanol, 42.4% and propylene glycol, 15.3%. An oral syringe is important to ensure dosing accuracy. The preparation has a very bitter taste and may be mixed with flavoring agents to improve palatability. Administration of the liquid preparation with food increases bioavailability. Crushing LPV/r tablets is not recommended, because it may decrease the formulation's area under the curve by ∼50%.²⁷

Adverse effects

Nausea, vomiting, altered taste, diarrhea, skin reactions, elevations in transaminase levels, and QTc interval prolongation may occur.^1,3 Gastrointestinal adverse effects led to a 14% discontinuation rate.³⁵

Drug interactions

Lopinavir is a CYP3A4 inhibitor and substrate. Ritonavir is a CYP3A4 inhibitor and an inducer of CYP1A2, 2C8, 2C9, 2C19, and UGT1A1. Clinicians need to check for drug interactions when other medications that use the same metabolic pathways are used.

Summary

The role of lopinavir and ritonavir in the treatment of COVID-19 infection in adult patients is not established due to lack of demonstrable efficacy and possibility of adverse effects. Current guidelines do not recommend their use unless in the context of a clinical trial.^1,14,15 The pediatric infectious disease panel did not provide a definitive guidance on the use of lopinavir/ritonavir in pediatric patients.

Interferon alfa, beta

IFNs are cytokines that have immunomodulatory, antiproliferative, and antiviral properties in vitro and in vivo; however, their activity against SARS-CoV and MERS-CoV was modest. IFN-α-1b by inhalation has been used in a series of children with SARS-CoV-2 in China, with good overall outcome. However, in other countries where IFNs were not used in the treatment of COVID-19 in children, the outcome remained good.

Administration

IFN-α-1b by injection is approved for multiple sclerosis, but the inhalation form is not available in the United States. There are no randomized controlled trials to assess the efficacy and safety of IFN therapy for the treatment of COVID-19 in children.

Adverse effects

Adverse effects reported with IFNs include flu-like symptoms, nausea, fatigue, weight loss, cytopenias, elevated transaminases, depression, and suicidal ideation.¹⁵

Drug interactions

IFN-α is a CYP1A2 inhibitor that may affect the metabolism of other 1A2 isoenzymes. IFN toxicity may increase if used with chemotherapeutic agents and immune modulators.

Summary

Current guidelines for adult and pediatric patients do not recommend the use of IFNs in the treatment of COVID-19 unless as part of a clinical trial due to a lack of demonstrable efficacy and the association with adverse effects.¹⁵

Investigational drugs

Interleukin-6 inhibitors: anti-interleukin-6 receptor monoclonal antibody: tocilizumab

The body's response to a serious infection may involve the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-12, and IL-6. IL-6 is a pro-inflammatory cytokine that is produced by lymphocytes, monocytes, and fibroblasts and binds the IL-6 receptor on target cells, which can lead to a cytokine storm or inflammation in bronchial epithelial cells and other organs.^15,36 This complex binds to the gp130 on the cell membrane to promote signal transduction and exert a pro-inflammatory effect.³⁶ Patients with COVID-19 frequently have elevated IL-6 levels and may develop a cytokine storm. Tocilizumab is a recombinant humanized IL-6 receptor monoclonal antibody that is approved for use for rheumatoid arthritis. It works by binding to the soluble IL-6 receptor with high affinity, forming a complex, and preventing the binding of IL-6 to its receptor, with the expectation of reducing immune damage to the cells and reducing the inflammatory response. Tocilizumab's role is likely in the setting of the cytokine storm that may develop as a complication of SARS-CoV-2.

Pharmacokinetics/pharmacodynamics

The absorption of tocilizumab by the subcutaneous route is slower than the IV route by several days, because it goes through the lymphatic system to get to the systemic circulation. Bioavailability of tocilizumab by the subcutaneous (SC) route in adults with acute COVID-19 infection is ∼50%.³⁷ There are no pharmacokinetic studies in pediatric patients. IL-6 levels do not drop during therapy, because tocilizumab blocks IL-6 receptors, allowing a greater amount of free tocilizumab in the plasma. Tocilizumab is not metabolized by CYP450; however, other drugs that are metabolized by CYP3A4 may be affected by IL-6 levels. Although IL-6 levels are elevated in inflammatory states and inhibit metabolism through this pathway, an IL-6 inhibitor, in turn, may increase the metabolism of these drugs and reduce their levels.

Clinical trials

A study in China included 21 adult patients who received tocilizumab 4 to 8 mg/kg i.v., with usual doses of 400 up to 800 mg.³⁶ Three patients received a second dose of tocilizumab due to persistent fevers 12 h after the dose. Standard-of-care therapies included lopinavir/ritonavir, IFN-α, ribavirin, and glucocorticoids. The authors used a historical control group to estimate mortality and compared it to outcome with tocilizumab. Clinical findings, such as fever and oxygen requirements, improved and patients showed improved lung opacity, and decreased lymphocyte counts and CRP levels, as compared with baseline. All patients survived. The lack of a concomitant control group limited the application of these data. In an open-label, prospective trial, tocilizumab was administered to 63 adult patients with SARS-CoV-2.³⁸ The primary endpoint was safety, whereas clinical and improved laboratory values were secondary objectives. Criteria for tocilizumab use were ARDS and evidence of inflammation, such as elevations in CRP, ferritin, d-dimer, and/or lactate dehydrogenase. All patients received a protease inhibitor. Tocilizumab 8 mg/kg i.v. or 324 mg SC were administered to all patients, and a second dose was given in 52 of the 63 (83%) patients. After drug administration, there was a reduction in fever, CRP, ferritin, and d-dimer levels. PaO₂/FiO₂ ratios improved in patients who received tocilizumab on the seventh day of hospitalization as compared with baseline (152 ± 53 and 284 ± 116 mmHg, respectively, P < 0.05). Seven patients died. Without a control group, the impact of tocilizumab was not clear.

In a retrospective case-controlled study in Italy, Guaraldi et al. evaluated the role of tocilizumab in adult patients with COVID-19 and severe pneumonia.³⁷ Tocilizumab was administered to 179 patients, whereas 365 patients received the standard of care only. The primary endpoint was a composite of invasive mechanical ventilation or death. Patients also received HCQ, AZM, and protease inhibitors. Due to shortages, some patients received tocilizumab by either the IV or SC routes of administration (i.v. 8 mg/kg, up to 800 mg for 2 doses 12 h apart), SC [324 mg (162 mg 2 × injections)]. Doses through the SC route were divided to simulate exposure to the drug through the IV route due to variations in absorption and distribution through the SC site.³⁷ Patients who received tocilizumab tended to be sicker at baseline and more of them received glucocorticoids after starting tocilizumab. The incidence of death in patients who received tocilizumab was lower than patients who did not receive the drug (7% versus 20%, P < 0.0001). Invasive mechanical ventilation was not different between groups. As a composite endpoint of the 2 outcomes and after adjustments for symptoms and other factors, tocilizumab was associated with a reduced incidence of mechanical ventilation or death (adjusted HR 0.61 95% CI 0.4–0.92, P = 0.02). There was an increased risk for infections in patients who received tocilizumab of 13% versus 4% for tocilizumab and standard of care, respectively, P < 0.0001. Preliminary results of the randomized, double-blind, placebo-controlled, Phase 3 study (COVACTA) were recently provided.³⁹ Four hundred fifty adult patients hospitalized with severe COVID-19 pneumonia received either tocilizumab 8 mg/kg (maximum dose 800 mg) or placebo. The primary outcome was improvement in clinical outcome, such as incidence of mechanical ventilation, ventilator-free days, intensive care unit admission, oxygen requirements, and time to clinical failure and the secondary outcome was mortality. There was no difference in the primary endpoint of clinical improvement between tocilizumab and placebo (OR 1.19; 95% CI 0.81–1.76, P = 0.36) and no difference in mortality (−0.3%; 95% CI −7.6% to 8.2%, P = 0.94). This was the first large prospective, controlled trial that did not show tocilizumab to be an effective therapy in improving clinical outcomes or mortality in adult patients with acute COVID-19 infection.

Dosing

In adult patients, tocilizumab doses are 400 mg i.v. or 8 mg/kg and can be repeated 8 to 12 h after the first dose.⁶ In children, a dose of 8 mg/kg/dose i.v. once can be used with an additional dose 12 h after the first if clinical symptoms worsen or show no improvement; maximum dose: 800 mg/dose.

Administration

Tocilizumab is available as 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL in single-dose vials. It is diluted further before administration. The drug is infused over 60 min and cannot be co-infused with other drugs.

Adverse effects

In general, tocilizumab may cause infusion-site reactions, neutropenia, thrombocytopenia, elevated liver enzymes, hematologic effects, increased risk for infections, and hepatitis B reactivation.²²

Summary

Due to conflicting results from clinical trials of tocilizumab in acute COVID-19 infection, NIH and IDSA guidelines do not recommend its use in adult or pediatric patients with acute COVID-19 infections, unless part of a clinical trial.^14,15

IL-1 inhibitors: anakinra

In acute COVID-19 infection, mortality is higher in patients who developed respiratory failure from ARDS. Mortality has been linked to an inflammatory state, a cytokine storm or macrophage activation syndrome (MAS) whereby inflammatory mediators are released, including IL-1, IL-6, IL-18, and IFN γ. Anakinra is an IL-1 antagonist that blocks proinflammatory cytokines such as IL-1α and IL-1β from binding to the IL-1 receptor. In a small retrospective case series of 29 adults with severe ARDS and evidence of inflammation, Cavalli et al. compared the use of anakinra with a control group of 16 patients who received the standard of care only.⁴⁰ Anakinra 5 mg/kg/dose i.v. twice a day improved survival at 21 days (90% versus 56%, anakinra and control group, respectively, P = 0.009). All patients also received HCQ 200 mg PO BID and lopinavir/ritonavir 400 mg/100 mg PO BID, which may have confounded the results. In a letter to the editor, Aouba et al. presented a case series of 9 hospitalized adult patients with COVID-19. Patients had COVID-19 pneumonia, had elevated CRP, and were receiving oxygen.⁴¹ Anakinra was administered SC at a dose of 100 mg every 12 h for 3 days, then 100 mg/day for up to 7 additional days. After drug therapy, all but 1 patient had reduced fever and oxygen requirements and stabilization of pulmonary infiltrates; however, there was no control group to assess the efficacy of anakinra.

Pharmacokinetics/pharmacodynamics

Anakinra pharmacokinetics/pharmacodynamics (PK/PD) have not been studied extensively in pediatric patients. In infants and children with juvenile idiopathic arthritis and autoinflammatory syndrome, doses of 2 to 10 mg/kg were used to develop PK/PD modeling.⁴² The authors described linear absorption and elimination. Body weight correlated with volume of distribution and clearance of the drug.

Dosing

There are no studies that describe the use of anakinra in pediatric acute SARS-CoV-2 infection. Usual doses used for other indications in neonates, infants, and children are 1 to 6, up to 10 mg/kg/day administered subcutaneously.

Summary

In the treatment of COVID-19, data on anakinra in pediatric and adult patients are very limited, and the NIH guidelines do not provide a recommendation for or against this IL-1 inhibitor.¹⁵

Intravenous immune globulin

For the treatment of acute COVID-19 infection, the NIH guidelines do not support or refute the use of non-SARS-CoV-2 specific intravenous immune globulin (IVIG). At present, there are no peer-reviewed published data to support its use in acute COVID-19 infection.¹⁵

Additional information on IVIG is provided under MIS-C in pediatric patients.

Famotidine

Famotidine is a histamine-2 receptor antagonist used for gastrointestinal acid suppression, which has been also shown to inhibit replication of HIV. By molecular modeling, famotidine was also expected to bind and inhibit proteins that are necessary for viral replication, such as the 3-chymotrypsin-like protease in SARS-CoV-2. Earlier observations of improved outcome in patients with COVID-19 who were receiving famotidine prompted a retrospective review. In a single center in the United States, famotidine use was reviewed in 84 adult hospitalized patients within 24 h of admission to the hospital.⁴³ Any route of administration was included and famotidine was used for a median of 5.8 days during hospitalization. Famotidine was associated with lower composite endpoints of mechanical ventilation or death (adjusted hazard ratio 0.42, 95% CI 0.21–0.85). Interestingly, these results were not reproduced with proton pump inhibitors or in non-COVID-19 patients. Famotidine use was correlated to lower ferritin levels, which suggests a role in reducing cytokine release in SARS-CoV-2 infected patients.⁴³ The results have not been peer-reviewed and are preliminary.

In summary, famotidine is not recommended for use in the treatment of COVID-19 unless part of a clinical trial.¹⁴ There is a lack of data regarding the role of famotidine in the treatment of COVID-19 in pediatric patients.

Other comedications associated with controversy in the management of COVID-19

Nonsteroidal anti-inflammatory agents

Early reports linking the use of nonsteroidal anti-inflammatory agents (NSAIDS) with worsened clinical outcomes in patients with COVID-19 have not been substantiated.¹⁴ The proposed mechanism is the upregulation of ACE2 by NSAIDS. ACE2 is the binding site for SARS-CoV-2 to enter the host cell so in theory there would be a greater likelihood of virus entry. There has been no evidence that NSAIDS worsen COVID-19 infections and the NIH recommends either acetaminophen or NSAIDS in patients with COVID-19.¹⁵ Other reasons to be cautious when using NSAIDS in general include gastrointestinal, cardiovascular, and renal complications.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

ACE1 inhibitors and angiotensin receptor blockers (ARBs) may increase the tissue expression of ACE2, the same receptor that SARS-CoV-2 uses for cell entry, thereby potentially increasing the entry of the virus into the cell. On the other hand, ACE2 may increase the conversion of AgII to Ag (1–7), which are associated with anti-inflammatory effects. Researchers attempted to discern whether there was a greater risk of a COVID-19 infection in patients who were receiving these medications. Mancia et al. did not find an increased risk for COVID-19 or a severe clinical course in adult patients who were receiving angiotensin-converting enzyme inhibitor (ACEI) or ARBs at the time of a COVID-19 infection.⁴⁴ Reynolds et al. did not find an association between 5 classes of antihypertensive medications (ACEI, ARBs, beta-blockers, calcium-channel blockers, or thiazide diuretics) and risk for testing positive or a severe COVID-19 infection.⁴⁵ At this time, the American Heart Association and the American College of Cardiology recommend continuing these medications if started before COVID-19 infection.¹⁴

There is currently no information on the role of NSAIDS, ACEI, or ARBs in children in the treatment of acute COVID-19 infection.

Pediatric-Specific COVID-19 Manifestation: MIS-C

In April 2020, reports from the United Kingdom described a toxic shock syndrome or atypical Kawasaki-like syndrome in children, with a temporal association with a recent infection with COVID-19.⁴⁶ The centers of disease control provided a case definition that consists of persistent fever and serious illness requiring hospitalization in children ≤21 years old, multisystem (≥2) organ involvement, laboratory evidence of inflammation and evidence of SARS-CoV-2 infection by RT-PCR or serology, or exposure to COVID-19 in the preceding 4 weeks before illness.⁴⁷ The syndrome seems to lag behind an acute covid-19 infection by 1 to 4 weeks, suggesting a possible immunological injury from SARS-CoV-2.⁴⁸ The MIS-C may involve multiple organs, including cardiac, dermatologic, mucocutaneous, gastrointestinal, hematologic, cardiovascular, respiratory, renal, and/or neurologic systems.^48,49 Hence, MIS-C is believed to be related to a trigger by SARS-CoV-2 that stimulates the immune system.⁴⁸ As compared with Kawasaki disease, this atypical presentation occurs in older children from all ethnic groups, and it presents with greater and more severe incidence of cardiovascular involvement and MAS. In addition, children who developed MIS-C had a lower incidence of coronary artery abnormalities (CAA) (9% versus 25%, respectively) but were much more likely to present with cardiovascular shock than children with typical kawasaki disease (KD) (50% versus 5%, respectively).

Reports on MIS-C in pediatric patients

Currently, there are 9 published case series of MIS-C that include 418 children with a confirmed or highly suspected diagnosis of MIS-C (Table 2).^48–56 Patients had a wide age distribution, and comorbidities were found in 10%–48% of cases. Common laboratory abnormalities included lymphopenia and thrombocytopenia, elevations in serum CRP, d-dimers, brain natriuretic peptide (BNP) and Pro-BNP, ferritin, procalcitonin, troponin, fibrinogen, ferritin, and IL-6 and IL-8 levels.⁴⁸ Cardiac complications were common and included cardiomegaly, reduced left ventricular ejection fraction, myocarditis, shock, coronary artery dilation/aneurysm, pericarditis, pericardial effusions, and dysrhythmias. Gastrointestinal involvement included effusions and inflammation around various organs. Other complications included coagulopathies and acute kidney injury. The majority of children were treated with IVIG, whereas in IVIG-resistant cases, additional IVIG doses were given. Corticosteroids and IL inhibitors were also used. Earlier case series reported treatment with IVIG, corticosteroids, IL-1 and IL-6 inhibitors, as well as aspirin therapy. As the condition was recognized to be atypical KD, later reports did not include aspirin therapy. Overall, outcomes from MIS-C have been encouraging, with the majority of children (78%) surviving and discharged home. Only in one series, the authors described full recovery of the patient's left ventricular dysfunction.⁵⁴ At this time, the NIH does not provide any formal recommendations for the treatment of MIS-C in children.¹⁵

Table 2.

Multisystem Inflammatory Syndrome in Children

Authors (location)	Riphagen et al.⁵⁰ (U.K.)	Verdoni et al.⁵¹ (Italy)	Belhadjer et al.⁵² (France, Switzerland)	Chiotos et al.⁵³ (USA)	Grimaud et al.⁵⁴ (France)	Toubiana et al.⁵⁵ (France)	Kaushik et al.⁵⁶ (NY)	Feldstein et al.⁴⁸ (USA)	Dufort EM, et al. (NY)⁴⁹
Published/preliminary results	Published	Published online	Preliminary results—not peer reviewed	Published online	Published	Published	Preliminary results—not peer reviewed	Published	Published
Case series, sample size, N, total 133	8	10	35	6	20	21	33	186	99^a
Age range (years)	4–14	Mean: 7.5 ± 3.5	2–16	5–14	2.9–15	3.7–16.6	Median 10 years	Median 8.3 years (IQR 3.3–12.5)	0–5 years, n = 316–12 years, n = 4213–20 years, n = 26
Comorbidities	2/8 (25%)Autism, ADHD (1)Alopecia areata/allergic rhinitis (1)BMI ≥30 (2)	1/10 (10%)Congenital adrenal hyperplasia (1)	10/33 (30%)Asthma (3)SLE (1)BMI ≥25 (6, (17%)	None	None	None described	16/33 (48%)Asthma (5), allergic rhinitis (3), obesity (2), cardiac (2), hematologic (2), others (3)	51/186 (27%)Respiratory 33 (18%),Cardiac 5 (3%),Immune system 10 (5%)Obesity 18 (10%)	36/99 (36%)Chronic lung disease 14 (14%)Obesity 29 (29%)
Laboratory abnormalities	⇑CRP, ⇑d-dimers, ⇑BNP, ⇑ferritin ⇑Procalcitonin, ⇑troponin	⇑CRP, ⇑ferritin, ⇑d-dimers, ⇑BNP, ⇑Procalcitonin, ⇑troponin	⇑CRP, ⇑d-dimers, ⇑BNP, ⇑Procalcitonin, ⇑IL-6	⇑CRP, ⇑ferritin, ⇑d-dimers, ⇑BNP, ⇑Procalcitonin	⇑CRP, ⇑Procalcitonin	⇑CRP, ⇑d-dimers, ⇑BNP, ⇑Procalcitonin, ⇑troponin, ⇑IL-6	⇑CRP, ⇑d-dimers, ⇑pro-BNP, ⇑ferritin, ⇑troponin ⇑Procalcitonin, ⇑fibrinogen, ⇑IL-6, ⇑IL-8	⇑CRP, ⇑d-dimers, lymphopenia, ⇑BNP, ⇑ferritin, ⇑fibrinogen, prolonged INR ⇑troponin	Lymphopenia, ⇑CRP, ⇑d-dimers, ⇑pro-BNP, ⇑Procalcitonin, ⇑fibrinogen, ⇑ferritin, ⇑IL-6, ⇑troponin
Pharmacotherapy
Inotropes/Vasoactive Support	DopamineNoradrenalineAdrenalineArgipressinMilrinone	Inotropes	Used but no specification of which agents	EpinephrineNorepinephrineMilrinoneDopamineDobutamineVasopressin	EpinephrineNorepinephrineMilrinoneDobutamine	15 (71%)AdrenalineDobutamineMilrinoneNoradrenaline	NorepinephrineDopamineEpinephrineDobutamineVasopressin Milrinone	90/186 (48%)— no further information	61 (62%)—no further information
Anti-inflammatory agents^b	IVIG (2 g/kg)Hydrocortisone (1)Methylprednisolone (4)Infliximab (1)	IVIG (2 g/kg) (all) + [ASA (50–80 mg/kg/day) × 5 days] or [ASA (30 mg/kg/day) + methylprednisolone (8) (2 mg/kg/day) × 5 days] then tapered, based on risk stratification	IVIG (25)Corticosteroids (12)IL-1 receptor antagonist, anakinra (3)	IVIG (2 g/kg × 1) (all) [second dose, n = 2)]Methylprednisolone 2 mg/kg/day) (n = 5)Methylprednisolone (10 mg/kg) (n = 1)Pulse methylprednisolone (30 mg/kg/day × 3 days) + Anakinra (4 mg/kg QD) (n = 1)	IVIG (2 g/kg) (all)Corticosteroids (2)IL-1 receptor antagonist (anakinra) (1)IL-6 receptor antagonist (1)	IVIG (2 g/kg) (all) + “Corticosteroids” (2–10 mg/kg/day) (7)[IVIG repeat dose (5) + corticosteroids) (4)]	IVIG (18, 54%), corticosteroids (17, 51%), tocilizumab (12.36%), remdesivir (7, 21%), anakinra (4, 12%), convalescent plasma 1 (3%)	IVIG (144, 77%), [second dose 39 (21%)]corticosteroids (91, 49%), tocilizumab/siltuximab (14, 8%), anakinra (24, 13%)	IVIG (69, 70%)corticosteroids (63, 64%)
Aspirin	ASA (50 mg/kg) (6)	Aspirin 30–80 mg/kg/day then 3–5 mg/kg/day. Once patient was afebrile for 48 h, aspirin dose was reduced to 3–5 mg/kg/day for 8 weeks	—	Low dose ASA	—	ASA (3–5 mg/kg/day)	8 (24%)	None	None
Anticoagulants	Heparin (1)	—	Heparin (23)	—	—		33	87 (47%)	None
ECMO			10/35 (28.6%)				1/33 (3%)	8/186 (4%)	4/99 (4%)
Outcome(s)
Survival	7 (87.5%)	10 (100%) “responded to treatment”	Data not final	Data not final	20 (100%)	21 (100)	32 (97%)	Data not final	Data not final
Continued hospitalization	—	—	7 (20%)^c	1 (16.7%)^c	—	—	—	52 (28%)^c	21 (21%)^c
Discharge	7 (87.5%)	10 (100%)	28 (80%)	5 (83.3%)	20 (100%)	21 (100%)	32 (97%)	130/186 (70%)	76/99 (76%)
Clinical outcome							Recovered LVEF 20 (95%)	No details
Death	1	—	0	0	0	0	1 (stroke)	4 (2%) (2 underlying conditions)	2 (2%)

Ninety-five confirmed, 4 suspected multisystem inflammatory syndrome in children.

Doses are listed if disclosed by authors.

At time of publication.

ADHD, attention deficit hyperactivity disorder; BMI, body mass index; SLE, systemic lupus erythematosis; INR, international normalized ratio; ASA, acetylsalicylic acid; LVEF, left ventricular ejection fraction.

Pharmacotherapy options for treatment of MIS-C

Intravenous immune globulin

A product derived from pooled blood of thousands of donors that is purified, IVIG is the mainstay of therapy in KD. This explains its use early on in pediatric patients with MIS-C who presented with a Kawasaki-like picture. The mechanism of action of IVIG has not been fully understood in KD. Proposed mechanisms include competitive binding to Fc receptors which clears autoantibodies, working on macrophages to activate Fc receptor inhibition, providing antibodies that can neutralize cytokines, regulation of T cells to control inflammation and vascular damage, and blocking adhesion molecules that play an important role in the migration of inflammatory cells to the vascular endothelium.⁵⁷ The mechanism of action of IVIG in MIS-C is unknown but may be similar to KD. To reduce the incidence of CAA in KD, guidelines recommend a single IVIG dose of 2 g/kg within 7 and up to 10 days of illness. Although this regimen reduced the incidence of CAA in KD from 25% to 4%, some children are resistant to IVIG.⁵⁸ Children with KD who present with shock tend to be IVIG-resistant, possibly due to polymorphism in the Fc gamma receptors.^58,59 Options to treat these cases include a second dose of IVIG, IVIG combined with corticosteroids, or infliximab, cyclosporine, anakinra, and cyclophosphamide.⁵⁸ Children with MIS-C tended to develop cardiogenic shock far more frequently than in KD, which explains why second doses of IVIG and combinations of IVIG with corticosteroids were frequently used.

Dose

All reported dosing of IVIG in children with MIS-C was 2 g/kg.

Administration

There has been no difference between IVIG brands and outcomes.⁵⁸ Infusions for Kawasaki disease are typically done over 10 to 12 h, starting with lower infusion rates to monitor for infusion-site reactions.⁵⁸

Adverse effects

In children with KD, infusion-site reactions, headache, myalgia, nephrotoxicity, and thromboembolic events have been reported.⁵⁷ Hemolysis from repeated and cumulative doses of IVIG has been reported, especially in the context of pre-existing inflammation. A proposed mechanism for hemolysis associated with inflammation is upregulation of Fc receptors on monocytes and macrophages. In case series of children with MIS-C, IVIG seemed to be well tolerated.

Corticosteroids

Inflammatory and immune responses of glucocorticoids in MIS-C may be related to inhibition of cytokines, including IL-1, IL-6, and TNF-α, by these agents. The addition of IL-1 and IL-6 inhibitors was made in 16% of cases to date, and this may have helped further reduce the inflammatory response.

Administration

In the series of children with MIS-C, 52% of children were treated with corticosteroids (CS) using varied dosages and regimens, which ranged from low to very high doses. Many authors did not describe doses used and in some instances the exact CS used was not provided. It is, therefore, difficult to assess any dose-dependent effects on MIS-C outcomes.

Adverse effects

Acute adverse effects of CS include gastritis, hyperglycemia, elevations in blood glucose and blood pressure, and psychoses. None of these were reported in the case series to date, though retrospective analyses present a challenge in assessing adverse effects to medications.

IL-1 and IL-6 inhibitors in MIS-C

IL-1 inhibitor: anakinra

Activation of IL-1β has been implicated in IgA vasculitis and cardiac inflammation.⁶⁰ Anakinra is a recombinant IL-1β antagonist that has been used in some children with MIS-C. The drug inhibits binding of IL-1α and IL-1β to the IL-1-type receptor and has been used as an anti-inflammatory agent in pediatric patients. It is used in complicated and IVIG-resistant KD.⁶⁰ Anakinra was used in 33 of reported cases of MIS-C in children. Doses were not provided in the case series but usual doses in KD are 2 to 6 mg/kg/day subcutaneously.⁵⁸ It was likely chosen in cases of MIS-C as an alternative in the treatment of IVIG-resistant KD. Due to limited data, it is difficult to assess its role in the treatment of MIS-C.

IL-6 inhibitors: tocilizumab

Tocilizumab or siltuximab were used in 27 of reported case series of MIS-C in children. The role of tocilizumab in these series is to manage the cytokine storm that may occur in MIS-C.

Conclusion and Future Direction

The SARS-CoV-2 pandemic has upended health systems and normal daily life around the world. The extensive spread of the virus and the lack of antibodies in humans continue to cause numerous hospitalizations and deaths, especially in patients who are older, and/or who have pre-existing conditions. Data are very scarce in children so adult data have been applied to the care of pediatric patients, using pediatric dosing established for other conditions. At this point, the only pharmacotherapies recommended in the treatment of COVID-19 include remdesivir and glucocorticoids in adult and by extension in pediatric patients. These drugs have been shown to improve outcomes in adult patients who are severely ill and requiring oxygen support and/or mechanical ventilation or on ECMO. Clinicians' initial excitement over the possible benefits of CQ and HCQ and AZM waned when data did not show benefit but possible harm. The role of IL inhibitors remains unclear but they may be beneficial in the setting of a cytokine storm with COVID-19.

This is an evolving situation and new data may shed better light on new and old effective and safe pharmacotherapies. There are numerous ongoing trials of medications for the treatment of COVID-19 with the hope of improving outcome further. The occurrence of MIS-C is an unexpected complication of COVID-19. It appears to mimic Kawasaki disease in some ways but differs in its presentation and its multiorgan involvement. It has responded to pharmacotherapies that included IVIG and corticosteroids, with some cases including IL inhibitors, and patient outcome has generally been good. Many vaccines against SARS-CoV-2 are in development. It is hoped that effective and safe vaccines will reduce the burden of disease and death from COVID-19 and prevent the occurrence of MIS-C in children.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received.

References

Chiotos

, Hayes

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