Acute SARS-COV-2 Treatment Overview For Pediatrics

Abstract

Purpose of review:

The novel SARS-CoV-2 virus has caused a world-wide pandemic with devastating effects. Fortunately, most children display only mild to moderate symptoms, but there are a subset that will have severe symptoms warranting treatment. This review evaluates the current evidence for anti-viral and anti-inflammatory treatment of acute SARS-COV-2 infections, including COVID-19 in pediatrics.

Recent findings:

Treatment recommendations continue to evolve with emerging results from clinical trials. Initial therapies were tailored to repurposed medications, and have now transitioned towards more specific anti-viral therapy. In addition to specific anti-viral therapy, there is also support to modulate the immune system and reduce inflammatory damage seen in COVID-19. Much of the data result from adult studies with subsequent extrapolation to pediatrics.

Summary:

Recommended therapy will continue to adapt as results return from clinical trials. A continued commitment from the NIH and research community to assist in determining optimal therapies for pediatric patients is essential. Until then, most recommendations will likely be informed from the results seen in adult populations.

Introduction:

COVID-19, the acute infection with the novel coronavirus severe respiratory syndrome coronavirus-2 (SARS-CoV-2), has continued to persist with over 30,000,000 infections and 1,000,000 deaths world-wide to date.(1) Initially, acute treatment had a plethora of directed and “repurposed” potential therapeutic options that were used empirically while awaiting clinical trial data.(2) Multiple clinical trials have since been published that have brought clarity to optimal therapies and to discourage use of many of the repurposed medications. While most of the data is arising from adult observational and clinical trials, pediatric treatment recommendations have been developed to assist based upon these adult studies. (3**, 4)

In children, SARS-COV-2 has been described as predominately mild to moderate with only a small fraction requiring hospitalization or ICU care.(5–7) Many of the therapeutic options that have been used thus far have been reserved for the more critically ill and empirically used with similar rationale for the adult indications. The purpose of the article is to provide pediatricians with review of therapeutic options for children infected with SARS-COV-2, and upcoming studies that may affect future care for pediatric patients with acute Coronavirus Disease 2019 (COVID-19)

Remdesivir

Remdesivir is a nucleotide analogue broad-spectrum RNA antiviral activity (8) that binds viral RNA-dependent RNA polymerase leading to chain termination and suppression of viral replication.(9) Due to inhibitory activity against MERS-CoV(10), remdesivir was identified as an early potential therapeutic candidate for COVID-19. The Adaptive COVID-19 Treatment Trial (ACTT-1) was one of the first international randomized controlled trials (RCT) of remdesivir in 1059 adults hospitalized with COVID-19.(11**) ACTT-1 reported a 4 day faster median recovery time and a decrease in estimated mortality, with 7.1% mortality at 14 days with remdesivir versus 11.9% with placebo (HR for death, 0.7; CI, 0.47–1.04).(11**) Following these results, on May 1^st, 2020, the U.S. FDA issued an emergency use authorization (EUA) for remdesivir to treat suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. Following studies showing no difference in outcome in less severe cases with 5 versus 10-days of therapy (12, 13), the FDA updated recommendations with a duration up to 10 days for those requiring mechanical ventilation and/or ECMO and 5 days for those that do not. On August 28, the EUA was expanded to include all hospitalized adult and pediatric patients with confirmed or suspected COVID-19, regardless of severity of disease.(14)

With respect to safety, attributable serious adverse events were not reported with remdesivir in 43 children <18 years-old with Ebola.(15) In children with COVID-19 treated with remdesivir, neither a European cohort including 17 children nor a US cohort of 9 children reported safety or clinical impact data.(6, 16) While remdesivir is generally well tolerated, elevations of hepatic transaminases have been reported in 5–12% of recipients and range from mild to less frequent serious elevations.(17) Acute kidney injury is another side effect of unclear impact, potentially due to accumulation of sulfobutylether-beta-cyclodextran sodium salt (SBECD) in remdesivir formulations. Intravenous voriconazole uses the same carrier and while elevated levels of SBECD can be found in patients with pre-existing renal failure, short courses are generally well tolerated without significant events.(18) SBECD content in the lyophilized powder (3gm per 100mg of remdesivir) is half of that compared to the solution (6gm per 100mg)(18) and is the currently recommended formulation for pediatric patients weighing 3.5kg to < 40kg.

Three additional cases employing remdesivir in children appear in the literature. A 23 day-old neonate recovered after receiving 7 days of remdesivir started on day 4 of symptoms due to concern for myocardial involvement and oxygen requirement.(19) A 5 year-old boy simultaneously diagnosed with precursor B-cell ALL and COVID-19 received remdesivir for 5 days.(20) Remdesivir was discontinued due to elevations of alanine aminotransferase (ALT), although chemotherapy was the suspected cause. Finally, a 12 year-old previously healthy girl with severe COVID-19, initially treated with IVIG and steroids followed by azithromycin and hydroxychloroquine, experienced improvement in symptoms when 2-doses of tocilizumab and 5 days of remdesivir were started on hospital day 7.(21)

The decision to initiate antiviral therapy for a pediatric patient with suspected or confirmed COVID-19 remains a complicated one for providers, primarily because most children with COVID-19 have mild to moderate symptoms and recover with supportive care. To assist in this process an expert panel of the Pediatric Infectious Diseases Society (PIDS) has released two documents to provide guidance for pediatric care providers which generally suggest remdesivir for children with severe COVID-19 (defined as a new oxygen need or increased need from baseline) and consideration for all children with critical COVID-19 with Table 1 showing recommended dosing.(3**, 4) In addition, there are guidelines published by the Infectious Diseases Society of America (IDSA) and the NIH with limited pediatric-specific data.(14, 22)

Table 1.

Treatment Options for Hospitalized Pediatric Patients with Acute Covid-19

Targeted Therapy	Drug/Active Agent	Dosing
Anti-Viral	Remdesivir	Children < 40 kg: 5 mg/kg/dose IV x 1 dose then 2.5 mg/kg/dose IV Q24 hours Children 12 years of age and older and weighing >40 kg: a single loading dose of 200mg on Day 1 followed by once-daily maintenance doses of 100mg from Day 2
Adjunctive Viral Targeted Therapy	Convalescent Plasma	Adult: 1–2 units (approx. 200 ml/unit) Pediatric: Under study – 10mL/kg/dose (up to 2 units per dose) times two doses per patient for a total dose of 20mL/kg (NCT04458363 )
Immunotherapy	Dexamethasone Can consider immunomodulator therapy if severe or no improvement	0.3 mg/kg/dose (max 6 mg per dose) once daily.

Convalescent Plasma

Based on the concept that passive antibody transfer can bind directly to the pathogen and neutralize its activity, convalescent plasma (CP) has been used as a preventive measure prior to or after pathogen exposure and as treatment of a variety of viral infections, including SARS-CoV-1 in the early 2000s (23). On August 23 2020, the U.S. FDA issued an EUA for CP to treat hospitalized patients with COVID-19. This decision was based on historical and preclinical evidence, results from small clinical trials and data from the National Convalescent Plasma Expanded Access Protocol (EAP).(24)

Early publications of 5 adult mechanically ventilated patients and 10 patients with severe COVID treated with CP in addition to steroids and/or antivirals showed promise. Unfortunately, neither of these early studies contained a control arm and lacked adjustments for confounders.(22, 25, 26) In a pre-print publication, over 35,000 transfused patients as part of the National Convalescent Plasma EAP found that 7-day mortality was significantly reduced in patients transfused within 3 days of COVID-19 diagnosis compared to those at 4 or more days after diagnosis (8.7% versus 21%), p<0.001) as well as a reduction in mortality for those given higher COVID-19 antibody titer CP.(27) While the available data do not contain blinded, placebo-controlled randomized results, there is modest evidence supporting early use of CP in adult patients with severe and/or life-threatening COVID-19. The first report of CP use in children included 4 pediatric patients, ages 14–18 years, on mechanical ventilation with life-threatening COVID-19.(28) All were given 2–4mL/kg of plasma with the infusion occurring between approximately 8–14 days after the onset of symptoms. One patient died, two remained hospitalized on ventilatory support and one patient was discharged home following recovery from their critical illness including ECMO. The authors note that the CP for that recipient contained the highest level of SARS-CoV-2 antibody titers (>1:6000) compared to the other donors.

While plasma transfusion is associated with the same risks as any other blood product, there are two specific concerns often raised regarding COVID-19. Transmission of SARS-CoV-2 is a theoretical risk, but is typically felt to be of low likelihood considering that the collection occurs after the donor has recovered from infection and that rate of detectable SARS-CoV-2 in blood during active infection is only ~1%.(29) The other theoretical concern is antibody-dependent enhancement (ADE) of clinical severity due to antibodies from one type of coronavirus enhancing infection to a different SARS-CoV-2 viral strain. Reassuringly, a report of 20,000 adults given CP for severe or life-threatening COVID-19 as part of the EAP referenced above, found that CP was generally well tolerated with 141 serious adverse events related to transfusion (<1%); although this did include 10 related deaths.(30)

Currently, there are no clear consensus guidelines for the use of convalescent plasma for pediatric patients with COVID-19. The IDSA guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial and the FDA notes that there are insufficient data for their panel to recommend either for or against CP therefore decisions should be based on individual assessment.(22, 24) While the majority of the published data are in adults with (or at high-risk of progression to) severe or life-threatening COVID-19, the use of COVID-19 convalescent plasma may be a reasonable option for pediatric patients (Table 1) with severe or life-threatening infection.

Repurposed Drugs

During the early stages of the pandemic, there was an emphasis to investigate existing known small molecules that could have anti-viral properties towards SARS-COV-2, leading to the identification of many potential therapeutic options requiring clinical trial evaluation. As the results of these clinical trials are published many of the repurposed agents with potential activity have been found not to provide meaningful clinical impact.

Hydroxychloroquine has been used both as an anti-inflammatory and malaria drug that also has a history of possible antiviral activity. It has previously, and unsuccessfully, been investigated for treatment of HIV, hepatitis C and dengue.(31) With early but methodologically flawed studies suggesting antiviral and antinflammatory prospects, the FDA granted emergency access use on April 28, 2020 leading to further RCT and widespread empiric use.(32, 33) Subsequent randomized control trials have since been published showing no benefit, leading to the formal recommendation to not use hydroxychloroquine by the NIH and IDSA and removal of EUA by the FDA on June 15, 2020. (34–39)

In pediatrics, off-label use was restricted at many centers to children with worsening respiratory status and oxygen requirement.(40, 41) Zachariah and colleagues reported 30% of pediatric patients (n=15) admitted to a single center hospital had received hydroxychloroquine with 3 patients experiencing adverse effects leading to discontinuation.(41) Despite its empiric use, and given the overwhelming lack of supportive data in adult studies, it is currently not a recommended therapy per updated expert guidance.(3**)

Azithromycin, a commonly used macrolide antibiotic, has been investigated in combination with hydroxychloroquine. Unfortunately, the combination of two known cardio-toxic medications has led to many adult case series and one RCT suggesting risk for prolonged QT.(42, 43) Due to risk seen with combination therapy and lack of efficacy data, azithromycin is not a recommended therapeutic option for COVID-19 in IDSA and PIDS guidelines.(3**, 22)

Additionally, other agents have been investigated including famotidine, ivermectin, and nitazoxanide. All have been limited to in vitro or small study observational studies suggesting possible benefit, and have not been shown beneficial in any RCT studies.(2, 44–46) Other specific antivirals, lopinavir/ritonavir and favipiravir, have also failed to show benefit in open label trials or RCTs.(47–49) There are still ongoing RCTs of favipiravir in Russia and the United States that should clarify its potential benefit. At the time of this writing, none of these agents are being currently investigated in pediatrics.

Adjunctive Therapies for Acute COVID-19 Infection

There is increasing evidence that adults with severe COVID infection have features of systemic hyperinflammation resembling a cytokine storm(50), and that markers of hyperinflammation are associated with poor clinical outcomes.(51, 52) Although children generally have mild COVID-19 symptoms, some children similarly display hyperinflammatory features and may benefit from steroids and other specific immunomodulatory therapies. However pediatric-specific data are sparse, and mostly consists of case series or extrapolation from adult evidence.

The American College of Rheumatology (ACR) and PIDS have published guidance for pediatric patients with COVID-19 hyperinflammation.(50**, 53*) The PIDS approach states that as there were no immunomodulators with proven efficacy in pediatric patients at the time of publication and no recommendations were made to support the use of one over the other. The WHO has provided guidelines based on best available evidence for treatment of children with severe COVID,(54) while the NIH has provided only limited guidelines about adjunct therapies for children.(55)

Glucocorticoids:

Glucocorticoid treatment is commonly used in hyperinflammatory states such as cytokine storm or ARDS. There is increasing evidence in adults that COVID-19 mortality is lower with glucocorticoid treatment in critically ill adults, although individual studies have had mixed results.(54, 56, 57) The RECOVERY RCT preliminary report showed significantly lower mortality in patients requiring respiratory support treated with dexamethasone.(58**) However, this trial did not include a significant number of pediatric patients. Despite this, the WHO guidelines strongly recommend treatment with glucocorticoids for critically ill children.(54) The ACR guidelines note that glucocorticoids may be considered, but were reached prior to the RECOVERY results publication.

IL-1 Blockade

IL-1 is a central cytokine in hyperinflammation, and its blockade with anakinra, a recombinant IL-1 receptor antagonist, is routinely used in macrophage activation syndrome, sepsis, and other cytokine storm scenarios.(59) In the case of COVID-19 infection, a retrospective cohort study of 36 adult patients treated with low dose or high dose anakinra found that high dose anakinra (10 mg/kg per day) was associated with higher survival rate at 21 days compared to those receiving standard treatment of hydroxychloroquine, lopinavir, and ritonavir (200 mg hydroxychloroquine twice a day and 400 mg lopinavir with 100 mg ritonavir twice a day).(60) Multiple case reports and small case series have also shown decreased mortality with anakinra therapy as compared to institutional standard therapy.(61–65) While these studies are only in adults, the results are promising and the ACR guidance recommends anakinra as first line biologic treatment for acute COVID-19.(50**)

IL-6 Blockade

IL-6 is a central cytokine for activation of systemic and local inflammatory pathways. Blockade of IL-6 with the IL-6 receptor blocking monoclonal antibody, tocilizumab is approved for multiple rheumatic diseases as well as cytokine release syndrome from CAR-T cell therapy.(66) Given high levels of IL-6 in the blood, and association with poor outcomes, IL-6 was an early potential treatment target.(67) While early studies showed largely, but not exclusively positive results,(68–71) results of RCTs have been mixed and overall unimpressive. Results of the phase III ARCHITECTS RCT on the safety and efficacy of tocilizumab in severe infection are still pending. (72) Results of the CORIMUNO-19 open label RCT for tocilizumab in patients with moderate to severe COVID-19 pneumonia showed a potential decrease in need for non-invasive ventilation, intubation, or death at 14 days, although the results did not show a difference in mortality at 28 days.(73) Results of the BACC Bay Tocilizumab trial, a randomized, double blind, placebo controlled trial of early administration of tocilizumab did not show reduction in need for intubation or death in moderately ill patients.(74) Additionally, results of the COVACTA phase III trial of tocilizumab did not meet its primary endpoint(75) and an RCT of another IL-6 inhibitor, sarilumab, was also suspended for futility,(76) casting some doubt on the efficacy of IL-6 blockade for hyperinflammatory COVID-19. These studies are also largely limited to adults, although there are a few pediatric case studies.(77, 78) The ACR guidelines state that there is insufficient evidence to recommend tocilizumab treatment in children with hyperinflammatory COVID-19, but that it may be considered for severe disease.(50**) The PIDS guidelines state that IL-6 blockade may be considered, but priority given to clinical trial enrollment (the same recommendation as for IL-1 blockade).(53*) Both of these guidelines were published prior to the CORIMUNO-19 and BACC Bay Tocilizumab trials.

JAK/STAT Inhibitors

JAK/STAT pathways are crucial in signaling for a broad array of cell functions including immune pathways, and JAK inhibitors are used to treat autoimmune disease.(79, 80) Ruxolitinib (a JAK1/JAK2 inhibitor) was studied in a small phase II RCT for severe COVID-19, but did not show significant changes in mortality or improvement.(81) Baricitinib (a JAK1/JAK2 inhibitor) has been suggested for treatment of severe COVID-19 infection, but data is limited to a small open label study with promising results (82) Accounting for infection and other complications, (83) JAK/STAT inhibitors are not recommended by the ACR guidelines unless the above therapies are ineffective or contraindicated.(50**) The PIDS guidelines recommended against use of JAK inhibitors outside of clinical trials, given lack of evidence in adults, safety profile, and no FDA approved pediatric indications at the time of publication.(53*)

Conclusion:

As we continue to investigate therapeutic regimens for COVID-19 treatment in both adults and pediatrics, there are over 1500 on-going interventional clinical trials that will hopefully provide insight. While therapeutic agents for acute COVID-19 in children remain limited, remdesivir and convalescent plasma, either alone or in combination, and dexamethasone are reasonable options for those with severe or life-threatening disease. As we gain a better understanding of the disease in pediatrics it is also imperative to include children in prospective trial design.

Keywords:

• The majority of children infected with SARS-COV-2 will not require any treatment with anti-viral or ant-inflammatory medications

• There is significant lack of data in pediatrics to promote therapy in treatment of SARS-COV-2 with most recommendations driven by adults studies

• In children who are admitted to the hospital with severe disease, it is reasonable to consider anti-viral and ant-inflammatory medications

• There needs to be continued emphasis on pediatric clinical trials for treatment of acute SARS-COV-2 infections