key: cord-0912127-uduq6q6o
authors: Mercolini, Federico; Cesaro, Simone
title: COVID-19 in Children and Adolescents: Characteristics and Specificities in Immunocompetent and Oncohematological Patients
date: 2022-01-01
journal: Mediterr J Hematol Infect Dis
DOI: 10.4084/mjhid.2022.009
sha: 60e2b67062761dda6e751e9821d7f1f6437562fd
doc_id: 912127
cord_uid: uduq6q6o

SARS-CoV-2 pandemic affected fewer children and adolescents with lower morbidity and mortality rates than those reported for adults. This review focused on the clinical course, risk factors for severe COVID 19, mortality, treatment options, and prevention measures in the pediatric and adolescent setting with special attention to pediatric oncohematological patients. SARS-CoV-2 infection was often asymptomatic in these subgroups of patients, but 47 to 68% of them required hospitalization, and 9–10% of those hospitalized needed intensive care with a COVID 19 attributable mortality of about 4%. The multisystem inflammatory syndrome associated with COVID 19 was less frequent than that reported in the non-oncohematological pediatric population. Noteworthy, the course of COVID 19 was more severe in low-middle income countries. The key measures to prevent SARS-CoV-2 infection are reducing patient exposure to the SARS-CoV-2 and vaccination, now available for parents and caregivers and patients and siblings above 12 years of age. The treatment of COVID 19 in pediatric patients is mainly based on supportive care with dexamethasone and heparin prophylaxis for severely ill patients. Other measures, such as convalescent plasma, remdesivir, and monoclonal antibodies, have been used in limited cases or within experimental protocols. Further studies are needed regarding the risks factors and outcomes of SARS-CoV-2 infection in pediatric immunocompromised patients.

decreased exercise capacity and hypoxia, reduced diffusion capacity, restrictive pulmonary physiology, and ground-glass opacities and fibrotic changes on imaging), cardiovascular (palpitations, chest pain, myocardial fibrosis or scarring, arrhythmias, tachycardia), hematological (thromboembolism), renal (reduced eGFR), endocrine (new or worsening control of existing diabetes mellitus, subacute thyroiditis and bone demineralization) and neuropsychiatric (fatigue, myalgia, cephalea, dysautonomia, and cognitive impairment, anxiety, depression, sleep disturbances) involvement. 14 In the largest series 15, 16 at least one of these symptoms was reported in 30-87% of patients.

The most frequently reported symptoms were: fatigue (35-64%), dyspnoea (11-44%) , sleep disturbances (24-26%), anxiety / depression (20-25%) and chest pain (5-21%).

Adolescents. Due to their developing immune system, children, compared to adults, are more susceptible to infectious diseases. However, the susceptibility to SARS-CoV-2 infection in children seems to be lower, with a low incidence of severe COVID-19 17 and only rare fatality cases, estimated between 2 and 5 cases per million for subjects below 18 years of age. 18 About 80-90% of infected children and adolescents (80%) 19, 20 present with symptoms, usually mild or moderate. Since the first months after the start of the pandemic, children presented clinically milder cases and a better prognosis than adults. 18 This resulted in a lower hospitalization rate, 19 ranging from 2.5 to 4.1%. Among hospitalized patients, 15% were admitted to the ICU. 21 COVID-19 symptoms in children are similar to those in adults. The most frequent are fever (46%), cough (37%), headache (15%), diarrhea (14%), sore throat (13%), nausea/vomiting (10%), myalgia (10%), abdominal pain (7%), rhinorrhea (7%) and shortness of breath (7%). 22, 23 Several organ-specific involvements have been reported: heart failure, myocarditis, pericarditis, arrhythmias, pulmonary embolism in the cardiovascular system; [24] [25] [26] encephalopathy, stroke, Guillain-Barrè syndrome, cerebral edema, status epilepticus, transient ischemic attack in the nervous system; 27, 28 urticarial, maculopapular, vesicular skin rash, livedo reticularis, chilblain-like lesions as skin manifestations. 29 The most fearful complication of COVID-19 infection in pediatric age is the multisystem inflammatory syndrome in children (MIS-C), described as early as April 2020. MIS-C is characterized by fever, multisystem organ involvement, laboratory evidence of inflammation, and severe course ( Table 2) . Other features may include acute myocardial dysfunction, respiratory failure, Kawasaki-like disease, and toxic shock syndrome. 30, 31 MIS-C appears to be relatively rare, occurring in <1% of confirmed COVID-19 cases in children, corresponding to about 5-7 cases per million people per month. 32, 33 Among the hospitalized patients, the MIS-C rate varies between 10 to 25%. 34 Currently, no long-term follow-up studies that define with certainty the prognosis of patients with MIS-C are reported. In a systematic review including 16 studies and a total of 655 MIS-C patients, 10% of patients (68) required critical care, and the mortality rate was 1.7% (11 deaths ). 35 Treatment of MIS-C is mainly based on organ support, immunoglobulins, and steroids. [36] [37] [38] Regarding COVID-19 sequelae, these appear to be much less frequent than in adults: in a cohort of 25 children, Denina et al. 39 no COVID-19-related sequelae up to 4 months after the infection were reported.

In a larger collection of cases, 40 out of 151 children with COVID-19, whom 36% with asymptomatic course and 64% with mild, moderate, or severe disease, 12 patients (8%) had post-acute COVID-19 symptoms. The most frequent documented symptoms were mild postviral cough (6 patients), fatigue (3 patients), or both postviral cough and fatigue (1 patient). Resolution of symptoms was seen in all cases in up to 8 weeks.

Risk Factors for Severe Disease and Mortality. Most pediatric patients affected by COVID-19 have a symptomless or paucisymptomatic course that allows home management. In a review including more than 7400 COVID-19 positive children, only 2% of cases presented severe symptoms with dyspnea and hypoxemia, and critical conditions in 0.7%. The reported fatality rate was 0.08% (6 patients). 24 Similarly low (0.28%) is the mortality rate reported by Wang et al. 41 in a meta-analysis that collects data from more than 11,000 COVID-19 positive children. However, some pediatric patients may require hospitalization, particularly those with one or more comorbidities. Kim et al. 42 reported the different clinical characteristics on a total of 576 hospitalized patients, with a median age of 8 years and equal male/female distribution: 222 patients (38.5%) had one or more comorbidities, such as obesity (38%), chronic lung disease (18%), prematurity defined as gestational age <37 weeks (15.4%), neurologic disorder (14%), immunocompromised condition (5.4%). In a similar European study, 43 out of 582 patients with a median age of 5 years, 25% of hospitalized patients had one or more comorbidities. The latter group of patients had a 3.7 greater relative risk of admission to ICU. About one-third of hospitalized patients required intensive care and about 5% mechanical ventilation. 42, 44 Regarding mortality, children and young people have a lower risk than adults. 45 However, several authors reported case series of deceased pediatric patients. McCormick et al. 46 reported 112 deaths, with a median age of 17 years (range 0-21 years): 63% were male, and 86% of patients presented with at least one of the following conditions: obesity (42%), asthma (29%), and developmental disorders (22%). Similarly, Bixler et al. 47 reported 121 deaths in patients under 21 years old: only 30 (25%) were patients otherwise healthy, whereas 91 (75%) patients had at least one comorbidity, and 54 (45%) had two or more comorbidities: asthma (28%), obesity (27%), neurologic and developmental conditions (22%), cardiovascular diseases (18%), cancer or immune system disorder (14%) and diabetes mellitus (9.1%). In a systematic review that analyzed 9335 children with COVID-19, 27% of patients had underlying comorbidity, and among them, the most frequent was immunosuppression. 48 Conversely, other authors reported a similarly favorable course, compared to healthy children, in patients undergoing immunosuppressive treatment for inflammatory bowel diseases, rheumatic diseases, and kidney diseases. [49] [50] [51] Table 1 summarizes the major risk factors for severe COVID-19 in pediatric patients.

While cancer is an established risk factor for severe COVID-19 in adults, it has thus far not been considered so in children. In fact, the main risk factors for severe COVID-19 course in children are medical complexity, genetic, neurologic or metabolic conditions, congenital heart disease, obesity, diabetes, asthma or other chronic lung diseases, sickle cell disease, and immunosuppression. 52, 53 Unlike the adult oncohematological population, data regarding COVID-19 infection in pediatric oncohematological patients are relatively scarce. The incidence of COVID-19 is higher in patients with cancer than in the general population, both in adults 54 and children/adolescents. 55 This incidence could be explained by the increased susceptibility of immunosuppressed patients towards viral respiratory community infections and by the need for frequent hospital visits with higher exposure to contagion. From the beginning of the pandemic, recommendations for the prevention of infection have been released by the scientific community of pediatric oncology 56 that are still valid today: physical and social distancing of children on active treatment for cancer, patient screening before chemotherapy, limitation of hospital access for parents/caregivers, creation of dedicated COVID-19 free wards, implementation of telemedicine and the use of adequate personal protective equipment for health personnel, patients and parents or caregivers. However, the adherence to these measures has been variable during the pandemic, depending on country or region socio-economic level and readiness to implement the plans to prevent the diffusion of SARS-CoV-2 infection.

Cases of COVID-19 in children and adolescents with cancer have been reported worldwide. In the systematic review by Meena et al., 57 collecting data from 33 studies (18 case reports and 15 case series), 55,58-89 clinical and outcome of 226 children with cancer and COVID-19 were described: 53% of the patients were affected by hematological malignancies and 47% by solid tumors. The median age was seven years with a male to female ratio of 1.7:1; 34 patients were in intensive chemotherapy and 17 post-HSCT. Sixty-three patients were symptomless, 47 had mild-moderate and 20 severe infections. Interestingly, out of 169 patients with data regarding chemotherapy, 123 (72.8%) had a treatment delay, and 10 had a regimen modification. In this review, morbidity and mortality related to SARS-CoV2 infection and the risk of severe COVID-19 was higher compared with the general pediatric population. Indeed, 96 of 226 patients (47%) required hospitalization, and 21 needed ICU admission. Fifteen patients (11.5% of hospitalized patients) died due to COVID-19. A meta-analysis of 15 studies, including pediatric patients with hematological malignancies and solid tumors, showed that the overall survival rate was 99.4%, with no statistically significant differences in the risk of hospitalization, ICU admission, and need for ventilation between patients with hematological conditions malignancies and solid tumors. 90 Nicastro et al., 91 in a review on COVID-19 in immunosuppressed children, observed that pediatric cancer patients have overall good COVID-19 outcomes, though still slightly worse than the general population.

In a European cohort of 582 hospitalized pediatric patients, 43 27% were affected by malignancy and presented a relative risk of ICU admission 2.7 times higher than the entire group; on the contrary, 29 patients on immunosuppressive treatment and 3 affected by immunodeficiency did not show an increased risk of ICU admission.

The largest collection of COVID-19 infection in the pediatric oncology field has been recently published: 92 this study included data of 1319 patients under the age of 19 from 131 institutions of 45 countries who completed the 30-day follow-up. Deaths attributable to COVID 19 infection were 3.8% (50 out of 1319), more than ten times higher than the general pediatric population.

An important risk factor associated with severe or critical illness was low-income or lower-middle-income country status, with a relative risk 5.8 times greater than high-income country status. Other risk factors were an age between 15 and 18 years, lymphocytes <300/mmc, neutrophils <500/mmc, comorbidities, and being on intensive chemotherapy. Oncological treatment was modified globally in 55.8% of patients, and, among them, chemotherapy was suspended in 80% and reduced in 13.1%. In addition, radiation therapy was delayed in 6.6%, whereas surgery was postponed in 6.7% of patients.

Currently, given the small number of fatal cases in pediatric oncology, the risk factors for mortality are not known. On the contrary, in the adult hematological oncology field, worse overall survival was associated with advanced age, an uncontrolled or progressive disease status, the diagnosis of acute myeloid leukemia, aggressive non-Hodgkin's lymphoma, indolent non-Hodgkin lymphoma or plasma cell neoplasm, and the presence of COVID-19 in severe or critical form. 13 According to the European Society for Blood and Marrow Transplantation (EBMT) data, the mortality in 382 patients with COVID-19 after stem cell transplant was 25% with a 6-week overall survival rate of 77.9% 72.1% for allogeneic and autologous recipients, respectively. 88 In this series, only 3 of 32 pediatric patients (29 allogeneic transplants and 3 autologous transplants) died, all after allogeneic stem cell transplant, the 6-week overall survival being 93.4%. In multivariate analysis, the risk factors for lower survival were older age, ICU admission, and the moderate/high immunodeficiency index, whereas a better performance status was protective.

The comparison between the clinical course in the general pediatric/adolescent population and the pediatric/adolescent cancer patients is shown in Table 3 .

Treatment. The treatment of pediatric cancer patients with COVID-19 is similar to that of immunocompetent populations affected by COVID-19. Several pediatric guidelines 48, [90] [91] [92] stated that the cornerstone of treatment is the supportive measures, such as the administration of fluids and electrolytes, nutritional support, support of the respiratory function with the administration of oxygen, or the use of non-invasive or invasive ventilation systems, support of cardiac function with inotropes, support of renal function, and antibiotic treatment in case of bacterial superinfection. 96, 97 The underlying immunosuppression of pediatric cancer patients can prolong the viral phase of COVID-19 and reduce, delay or even nullify the inflammatory phase of the disease.

Since the onset of the pandemic, several drugs have been used in the treatment of pediatric cancer patients with COVID-19: 55, 61, 63, [66] [67] [68] 73, 74, 76, [81] [82] [83] 85, 87, 88 the most used drug was hydroxychloroquine, followed by steroids and oseltamivir. In addition, the use of lopinavir/ritonavir, azithromycin, remdesivir, tocilizumab, convalescent plasma, chloroquine, and IVIG has also been reported in the literature.

The use of these drugs was based on the protocols adopted for adults, but no treatment specific for the pediatric age has been developed. Currently, some drugs initially used, such as hydroxychloroquine/chloroquine (both in outpatients 98 and in hospitalized patients), 99,100 lopinavir/ritonavir, [101] [102] [103] and azithromycin) [104] [105] [106] [107] are no longer recommended due to their demonstrated ineffectiveness.

Instead, the following are the currently used drugs for the treatment of COVID-19, concerning the adult and pediatric literature.

Steroid therapy has shown conflicting results in adults hospitalized due to SARS-CoV-2 infection. 108 In a systematic review and meta-analysis, the use of systemic glucocorticoids was evaluated on a total of 15.754 patients: 109 neither a reduction in mortality nor in the duration of hospitalization and period of viral shedding was demonstrated. Steroid therapy has not shown efficacy even in adult oncology: Rivera et al. 110 reported a numerical (but not statistically significant) increase in 30-day all-cause mortality in 109 patients treated with high-dose steroids compared to negative controls.

However, the efficacy of dexamethasone has been demonstrated in hospitalized patients receiving oxygen, noninvasive or invasive mechanical ventilation, determining lower 28-day mortality. 111 Unfortunately, the same benefit was not found in patients not receiving respiratory support.

A Multidisciplinary Guidance on the Use of Immunomodulatory Therapies for COVID-19 in Pediatrics 112 published in December 2020 concluded that steroid therapy is not recommended for mild/moderate disease course, while it may be beneficial for severe or critical illnesses. Therefore the risk and benefits should be evaluated on a case-by-case basis.

Currently, there are no randomized trials that demonstrate the efficacy of steroid therapy in patients with cancer or immunodeficiency, neither in the adult nor in the pediatric population.

Remdesivir. Remdesivir showed mixed results in the adult population: while in the WHO solidarity trial 103 on 11,330 patients, of which 2750 treated with Remdesivir, no improvements of mortality, of the need for invasive ventilation and duration of hospitalization was found in patients treated with remdesivir, Beigel et al. 113 reported a significant reduction in mortality and days to recovery in a population of 1062 patients (of which 80 with cancer)treated versus placebo; in the analysis of subgroups based on respiratory support, efficacy was demonstrated in patients not receiving oxygen or receiving oxygen, but not in patients receiving high-flow oxygen, non-invasive ventilation, or invasive ventilation. In a study conducted on 2186 adults with cancer, including 470 with hematological malignancy, 110 124 were treated with remdesivir alone: its use was associated with a reduction in 30-day all-cause mortality in comparison with positive controls (Odds Ratio 0.41), however without statistical significance.

In the multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus, 114 experts suggested as a first choice the use of remdesivir for children with severe illness, defined as a supplemental oxygen requirement without the need for non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The evidence of good tolerance 113, 114 and the efficacy data deriving from the adult population suggest using remdesivir instead of other antivirals. and. However, no efficacy and safety data are currently available in pediatric cancer patients. Pag. 6 / 14 monoclonal antibodies to prevent severe COVID-19 has shown promising results in the adult population: several studies [115] [116] [117] demonstrated a reduction of hospitalizations and deaths among patients treated with banlanivimab + etesevimab and casirivimab + imdevivab.

The best results were obtained with an early administration of antibodies, and, therefore, their indication is mainly in the early stages of the disease. 118, 119 In 38 adult patients with active cancer, 120 the use of neutralizing monoclonal antibodies led to a lower hospitalization and mortality rate than those previously described among active cancer patients.

Based on the evidence available in December 2020, a panel of experts 121 expressed an opinion against the routine use of monoclonal antibody therapy in pediatric patients, including those at high risk of severe evolution.

Several randomized trials demonstrated that convalescent plasma has no significant impact on the main outcome indicators of COVID-19 in adult patients. 122, 123 However, the efficacy could be linked to the anti-SARS-CoV-2 antibody titer: Joyner et al. 124 demonstrated a reduction in the risk of death in hospitalized patients who were not receiving mechanical ventilation by administration of convalescent plasma with higher anti-SARS-CoV-2 IgG antibody levels, compared to those treated with plasma with lower antibody levels.

Other factors that could influence the effectiveness of this treatment are the timing of administration and the severity of the infection: Libster et al. 125 showed that early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced disease progression.

Convalescent plasma with high neutralizing antibody titers could find an indication in B-cell depleted patients, 126 although there are currently no randomized studies that can confirm benefits in this cohort.

In the adult cancer population, convalescent plasma has shown efficacy in treating COVID-19. In a retrospective study 127 conducted on 966 adult patients with hematologic malignancy, hospitalized for COVID-19 infection, the outcome of patients treated with plasma (n = 143) compared to those who did not receive it (n = 823) was evaluated. In patients treated with plasma, a favorable Hazard Ratio of 0.6 in 30-day all-cause mortality, 0.4 for ICU admission, and 0.32 for mechanical ventilation was found.

However, the efficacy of plasma in the adult cancer population remains unclear in the absence of randomized trials. 128 Convalescent plasma was generally well tolerated in the adult population, 129 and no specific adverse reactions were reported.

In a literature review, 130 in pediatrics, 8 case report studies with a total of 14 children treated with plasma (age range 9 weeks-18 years) were described: no adverse events related to plasma administration were documented. All patients had a positive outcome, and 7 of the 8 studies concluded that convalescent plasma could be a useful therapeutic option. However, given the small number and heterogeneity of the sample, more studies are needed.

Although tocilizumab (anti-IL-6R monoclonal antibody) has been emergently authorized in the USA in hospitalized patients over 2 years of age on steroid therapy and in need of oxygen, mechanical ventilation, or ECMO, there are currently no data on efficacy and safety in the pediatric population.

Tocilizumab showed variable efficacy in various retrospective and case-control studies in the adult population. 131, 132 Furthermore, being associated with an increase in the rate of superinfection, 133 the risk/benefit ratio of its use is to assess carefully in oncology 134 patients.

Several case reports and case series 66, 67, 73, 83 have shown that treatment with Tocilizumab is feasible and well-tolerated in pediatric cancer patients, but large studies are lacking.

is not yet well defined, and thromboprophylaxis in these patients is limited to cases at higher risk of thrombosis.

There are two main pediatric consensus-based recommendations 135, 136 suggesting the administration of low-dose low molecular heparin subcutaneously twice daily, targeting a 4-hour post-dose anti-Xa activity level of 0.2 to < 0.5 U/ml, as prophylaxis in children hospitalized for COVID 19. The indication to prophylaxis with heparin is the presence of an elevated D-dimer value (> 5 times above the upper limit) or of risk factors for hospital-related deep vein thrombosis (i.e., presence of a central venous catheter, mechanical ventilation, prolonged length of stay, complete immobility, obesity, active malignancy, cystic fibrosis exacerbation, sickle cell disease vaso-occlusive crisis, congenital or acquired cardiac disease with venous stasis or impaired venous return, previous history of venous thromboembolism (VTE), first-degree family history of VTE before 40 years of age, known thrombophilia, postpubertal age, estrogen-containing oral contraceptive pill therapy, status-post splenectomy for underlying hemoglobinopathy).

Vaccination. COVID-19 infection in the pediatric setting has other consequences than health, such as social isolation and interruption of education. Furthermore, the pediatric patient could act as a vector of the disease within society and then pose risks for the adult population and certain subsets of pediatric patients at risk of developing severe COVID 19. 137 Therefore, vaccination against COVID 19 should be considered in the entire pediatric population.

To date, safety, immunogenicity, and efficacy studies have only been conducted in the population over 12 years of age. Frenck et al. 138 reported the experience of administering the BNT162b2 Covid-19 vaccine in the population aged 12 to 15 years in a multinational, placebo-controlled, observer-blinded trial: 2600 adolescents were enrolled, of whom half received the vaccine and half received placebo. The vaccine showed a favorable safety and side-effect profile, presenting mostly mild to moderate reactogenicity in the absence of serious vaccine-related adverse events. The vaccine efficacy was 100%.

Similarly, the mRNA-1273 vaccine showed a good safety profile and a serological response in the population between 12 and 17 years, comparable to that of young adults, with efficacy in preventing COVID 19. 139 Walter et al. reported recently the results of phase 2-3 study where 2268 children of 5-11 years of age were randomized (ratio 2:1) to receive 2 doses of 10 mg of BNT162b2 vaccine, 21 days apart, versus placebo. After a median follow-up of 2.3 months from the second dose, the vaccine efficacy against documented COVID-19 was 90.7%; moreover, no vaccine-related serious adverse events were noted, and the serum antibody level of neutralizing antibodies against SARS-CoV-2 was comparable to that observed in a control group of subjects of 16-25 years vaccinated with the adult dose of 30 mg BNT162b2 vaccine. 140 Although mRNA vaccines' safety and tolerability profile is favorable, myocarditis has been reported as a rare complication, especially in adolescent or young adult males. A recent Israeli study 141 showed that the incidence of myocarditis, albeit low, was increased in 16-19-year-old males who received the BNT162b2 mRNA vaccine (8.62 events / 100,000). The relative risk of developing myocarditis was 5.34 for the entire population and up to 13.6 in males between 16 and 19 years. It should be noted that after SARS-CoV-2 infection, the myocarditis complication is greater (11.54 events/100,000). The clinical presentation of myocarditis after vaccination was generally mild with response to conservative or symptomatic treatment.

Data on COVID 19 vaccines in patients with malignancy are limited since these patients were largely excluded from the phase III vaccine trials. However, the experience on 151 adult patients with cancer, of which 95 with solid tumors and 56 with hematological cancer, has recently been reported. 142 The vaccine was welltolerated, and no vaccine-related deaths were reported. The serological response (IgG positivity) was found after the first dose in 38% of patients with solid tumors, 18% of hematological malignancies, 94% of healthy controls, while after the second dose in 95%, 60%, and 100%, respectively.

Several reports have been published in reference to specific cancers in the adult population: after the second vaccine dose the antibody response was 45-65% for chronic lymphocytic leukemias, 143 147, 148 Several observations showed that, in the patients who have received anti-CD20 monoclonal antibody therapy, B-cell directed immunotherapy or patients with profound hypogammaglobulinemia or marked lymphopenia, the response to vaccination is very poor. 149, 150 Revon-Liviere et al. 151 reported the single-center vaccination experience of 10 patients between 16 and 21 years under treatment for solid tumors or within 6 months after treatment conclusion. Vaccination was well tolerated in all patients who presented exclusively mild local reactivity symptoms; 7 out of 10 patients showed positive serology after the first vaccine and 9 one month after the second. No patient developed COVID 19 disease.

Vaccination has been shown to be safe in adolescents and young adults (12-29 years) with a previous PEGasparaginase allergy, showing no vaccine reaction. 152 In Europe, the indication issued by National Authorities is to recommend the full vaccination with a vaccine approved by the European Medical Agency (EMA) in all people above 12 years of age, including frail patients due to the presence of comorbidities, immunosuppression, cancer treatment, chronic disease, and organ or stem cell transplant. 151 Considering that vaccination is not yet available for patients under the age of 12, full vaccination of all eligible family members of cancer patients is of paramount importance because it reduces the viral transmission to these patients at high risk of severe COVID 19 course. 153 Conclusions. Pediatric patients have a reduced incidence of severe COVID 19 compared to the adult population. However, a subset of pediatric patients is at greater risk for a severe course. This subset includes pediatric and adolescent patients with active cancer and immunosuppression.

In pediatric cancer patients, severity, morbidity, and mortality are higher than the general pediatric population, particularly in low-middle income countries.

The clinical course may be asymptomatic; however, 47-68% of patients require hospitalization and 9-10% admission to intensive care. Mortality attributable to COVID 19 infection is about 4%.

A key measure for these patients is the prevention of COVID 19 infection by reducing the risk of exposure and vaccinating contacts.

Data regarding the efficacy and safety of vaccination in adolescent cancer patients are still very limited; however, based on data collected on studies in adults, the safety profile and tolerability are reassuring.

In the case of COVID 19 infection, the cornerstone of treatment is supportive care. However, transferring the evidence gained from adults, some medical treatments, such as the use of dexamethasone for severely ill patients, the early adoption of convalescent plasma, the use of remdesivir to reduce the viral shedding, and the anticoagulant prophylaxis are reasonable in hospitalized patients. The use of monoclonal antibodies must be assessed on the basis of the patient clinical situation or within experimental protocols. Further studies are needed to elucidate better the risk factors, treatment, and outcomes of COVID 19 in pediatric cancer patients.

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Us-sowicz M. SARS-CoV-2 viral clearance during bone marrow aplasia after allogeneic hematopoietic stem cell transplantation-A case report

Acute lym-phoblastic leukemia onset in a 3-year-old child with COVID-19

Respiratory Failure in a Child With Pulmonary Metastatic Osteosarcoma and COVID-19

Remdesivir during induction chemotherapy for newly diagnosed paediatric acute lymphoblastic leukaemia with concomitant SARS-CoV-2 infection

Two Cases of SARS-CoV-2 Infection in Pediatric Oncohemato-logic Patients in Spain

Soler Palacín P. Tocilizumab in a child with acute lymphoblastic leukaemia and COVID-19-related cytokine release syndrome

Repeat-positive SARS-CoV-2 in a child with cancer

SARS-CoV-2 infection in a neutropenic pediatric pa-tient with leukemia: Addressing the need for universal guidelines for treatment of SARS-CoV-2-positive, immunocompromised patients

Conva-lescent plasma to aid in recovery of COVID-19 pneumonia in a child with acute lymphoblastic leu-kemia

Severe COVID-19 infection in a child receiving immunotherapy for cancer

Severe COVID-19 disease in two pediatric oncology patients

COVID-19 in pediatric hematopoietic stem cell transplantation: The experience of Span-ish Group of Transplant (GETMON/GETH)

COVID-19 after hematopoietic stem cell transplantation: report of two children

First Case of Coronavirus Disease 2019 in Childhood Leukemia in China

Clin-ical characteristics of hematological patients concomitant with COVID-19

Clinical features of severe pediat-ric patients with coronavirus disease 2019 in Wuhan: a single center's observational study

Benign course of SARS-CoV-2 infection in a series of pediatric oncology patients

Survival and Complications in Pediatric Patients With Cancer and COVID-19: A Meta-Analysis

COVID-19 in Immunosuppressed Children

Global Registry of COVID-19 in Childhood Cancer. Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a co-hort study

COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey

COVID-19 resources

Society CP The acute management of COVID-19 in paediatrics (spring 2021 update) Canadian Paediatric Society

A Case Series of Children With 2019 Novel Coronavirus Infection: Clinical and Epidemiological Fea-tures

Coronavirus Infections in Children Including COVID-19: An Overview of the Epidemiology, Clinical Features, Diagnosis, Treatment and Prevention Options in Children

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Se-vere Covid-19

Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results

Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

COALITION COVID-19 Brazil II Investigators. Azithromycin in addition to standard of care versus standard of care alone in the treatment of pa-tients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, openlabel, platform trial

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

A living WHO guideline on drugs for covid-19

Are the steroids a blanket solution for COVID-19? A system-atic review and meta-analysis

Utili-zation of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

Dexamethasone in Hospitalized Patients with Covid-19 -PubMed

Multidisciplinary Guidance Regarding the Use of Immunomodulatory Therapies for Acute Coronavirus Disease 2019 in Pediatric Patients

ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 -Final Report

Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2

Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

BLAZE-1 Investigators. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19

Trial Inves-tigators. REGN-COV2, a Neutralizing Antibody Cocktail

EMA reviewing data on monoclonal antibody use for COVID-19

COVID-19) Update: FDA Authorizes Monoclonal Antibody for Treatment of COVID-19

Outcomes of active cancer patients with COVID-19 infection treated with COVID-19 neu-tralizing monoclonal antibodies

Initial Guidance on Use of Monoclonal Antibody Therapy for Treat-ment of Coronavirus Disease 2019 in Children and Adolescents

PlasmAr Study Group. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19

INFANT-COVID-19 Group. Early High-Titer Plasma Therapy to Prevent Se-vere Covid-19 in Older Adults

Effects of treatment of COVID-19 with convalescent plasma in 25 B-cell depleted patients

COVID-19 and Cancer Consortium. Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19

Opportunities and Challenges of Observa-tional Studies and Randomized Controlled Trials for Evaluating the Therapeutic Efficacy of COVID-19 Convalescent Plasma

Safety Update: COVID-19 Convalescent Plasma

The use of convalescent plasma for pe-diatric patients with SARS-CoV-2: A systematic literature review

Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study

Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study

Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19

Evidence-based management of COVID-19 in cancer patients: Guideline by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO)

Pediat-ric/Neonatal Hemostasis and Thrombosis Subcommittee of the ISTH SSC. Consensusbased clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospital-ized for COVID-19-related illness

COVID-19 anticoagulation recommendations in children

COVID-19 vaccine development: a pediatric per-spective

C4591001 Clinical Trial Group. Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents

Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents

Gruber WC; C4591007 Clinical Trial Group. Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age

Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospec-tive observational study

Safety and efficacy of BNT162b mRNA Covid19 Vaccine in patients with chronic lym-phocytic leukemia

An-tibody response to SARS-CoV-2 vaccines in patients with hematologic malignancies

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma

BNT162b2 COVID-19 vaccine is significant-ly less effective in patients with hematologic malignancies

Antibody response after second BNT162b2 dose in allogeneic HSCT recipients

Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study

Association (EHA) TEH Expert opinions for COVID-19 vaccination in patients with hema-tologic cancer

COVID-19 Vaccine

The BNT162b2 mRNA COVID-19 vaccine in adolescents and young adults with cancer: A monocentric experience

Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vac-cine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase

Impact of the COVID-19 Vaccine on Asymptomatic Infection Among Patients Under-going Pre-Procedural COVID-19 Molecular Screening