key: cord-0956688-48o3m733 authors: Meena, Jagdish Prasad; Kumar Gupta, Aditya; Tanwar, Pranay; Ram Jat, Kana; Mohan Pandey, Ravindra; Seth, Rachna title: Clinical presentations and outcomes of children with cancer and COVID‐19: A systematic review date: 2021-03-15 journal: Pediatr Blood Cancer DOI: 10.1002/pbc.29005 sha: 3f38488393277cc754017c8a57c103cf48d5810b doc_id: 956688 cord_uid: 48o3m733 Information regarding the novel coronavirus disease (COVID‐19) in pediatric oncology is limited. We conducted a systematic review of the available published literature on children with cancer affected by COVID‐19. The last date of the study search was October 20, 2020, and 33 studies comprising 226 children were included for the final analysis. Data were extracted in a predefined data collection form, and the variables were extracted and analyzed. Patients with hematological malignancies were more in number. Males and children on intensive treatment were more frequently affected. Fever was the commonest symptom. The disease was asymptomatic/mild in 48% and severe in 9.6%. Consolidation, peribronchial cuffing, and consolidation with ground glass opacities were the common imaging findings. Hydroxychloroquine was the most frequently used drug for COVID‐19. About 10% of children required intensive care, and about 32% had oxygen requirements. The percentage of children who died due to COVID‐19 was 4.9%. The severity, morbidity, and mortality of COVID‐19 in pediatric oncology were more compared to the general pediatric population. This information can help in risk stratification for the management of COVID‐19. tion of children who are affected by COVID-19 is less in comparison to adults. 2 Children with cancer and on treatment for it are a vulnerable population. Cancer and its treatment cause immune suppression and increase the likelihood of acquiring an infection and the severity of any infection is more. Frequent visits to the hospital for treatment make it difficult to adhere to social distancing and compromise the use of facemasks: the two most imperative measures advocated for the prevention of the novel coronavirus infection. In adults, COVID-19 in cancer patients has higher fatality compared to the normal population. 3 This has also been supported by the findings of a recent systematic review and pooled analysis by Saini et al. 4 The incidence of COVID-19 in children with cancer has been reported to be higher than in the general pediatric population. 5 Although children with cancer are considered a high-risk population, data specifically in relation to outcomes of COVID-19 in the pediatric oncology population are limited and are still emerging. In the available studies, the sample size is small, and the findings in these studies have diverse reporting. The data in relation to COVID- 19 and pediatric cancers are from different countries, which have diverse health infrastructures and policies, making the available data heterogeneous. We aimed to conduct a systematic review of the available published literature on pediatric cancer patients affected by COVID-19 and analyzed the clinical manifestations and outcomes. The title was prospectively registered in PROSPERO. 6 The studies that described the outcomes of pediatric oncology patients who were positive for SARS-CoV-2 were included. Eligibility criteria for inclusion of the studies for review were, the ones in which the sub- Statistical analysis was done using the STATA 14.0 software. We used descriptive statistics. Continuous variables were expressed as mean (SD) or median (range/interquartile range [IQR]) depending on the distribution. Categorical variables were expressed as the number of cases and percentages (%). The PRISMA checklist for systematic reviews for this review is given in Table S6 . A search of the above databases yielded 753 results, out of which 27 were removed due to duplication. The abstracts and titles of 726 articles were screened and 56 studies were considered for eligibility. After screening the full text of each of the studies, 23 studies were excluded, and 33 studies were included in the final analysis ( Figure 1 ). 5,8-39 were Spanish, 7.5% were Mexican, and the remaining were from other nations. There were 133 males out of the 210 subjects (31 studies) for which data on gender were available (M:F = 1.7:1) and the median age was 7 years (IQR 4, 9) (Table 1) . For our first analysis to find out the rate of positivity on screening, out of the 33 studies we selected studies in which COVID-19 in pediatric cancer patients was diagnosed after screening a larger number of patients regardless of symptoms. Seven studies mentioned data in relation to positivity after the screening ( Table 2) . [8] [9] [10] [11] [12] [13] [14] In these seven studies (n = 1219), a total of 77 children were detected to be positive for the SARS-CoV-2 out of 1219 screened (6.3%). In 29 studies (n = 177 patients), 8, [11] [12] [13] [14] there was a mention of the type of test used to detect SARS-CoV-2. Among the 177 patients in these studies, PCR-based tests were used to establish the diagnosis in 142 (one was also positive on CBNAAT) and antibody-based tests in 23 (the type of test used was not mentioned for 12 patients in the study by Montoya et al. 18 ; we have considered these patients in the analysis as the remaining patients in that study were diagnosed either by RTPCR or antibody-based tests) ( Table 3 ). In 196 patients (31 studies), 5,10-39 there was a mention about the type of malignancy, and 120 (53%) had hematological malignancies, and 76 (47%) had solid tumors. In studies that reported remission status (18 studies), 23 patients out of 47 were in remission from the underlying malignancy 10, 11, 14, [20] [21] [22] [23] [24] [25] [26] [29] [30] [31] [32] [33] [34] [35] [36] [37] (Table 1) . Among 24 studies including 102 patients 5, 10, [13] [14] [15] [16] [17] [20] [21] [22] [23] [24] [25] [27] [28] [29] [30] [31] [32] [33] [34] [35] 37 for whom information was available on the phase of chemother-apy/hematopoietic stem cell transplant (HSCT) status, 34 were on the intensive phase of chemotherapy, 13 were on low-dose chemotherapy, six had completed treatment, and 17 post HSCT (Table 1 ). The X-ray findings were mentioned in 11 studies (n = 59 patients). 5 patients, and the presence of ground glass opacity (GGO) and consolidation were the commonest findings (six each), followed by reticular opacities in three (Table 3 ). Thirty-one studies (n = 204 patients) reported data about patients who were admitted. 5, 8, 9, [11] [12] [13] [14] [15] [16] [17] [18] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] Oseltamivir was also used in seven patients and convalescent plasma in two (Table 4) . Of the 226 patients, the outcomes were reported for all. Two hundred eleven patients recovered, and 15 died. Of the deaths, four deaths were not related to COVID-19. 18 The mortality in the cohort was 11/226, that is, 4.9% (Table 4 ) ( Figure 2 ) . The details of all studies are provided in Table 5 . SARS-CoV-2 has spread throughout the world at an alarming rate. Little is known about the effects of COVID-19 on children with cancer. In this systematic review on COVID-19 in pediatric cancer patients, we found that males were affected more, the infection was more common in hematological malignancies and during the intensive phase of treatment. RTPCR was the commonest modality for the detection of SARS-CoV-2 infection. Fever was the commonest symptom, followed by cough. Hypoxia was present in 10.8% of patients, and overall, 48% were either asymptomatic or mild in symptomatology. Forty-seven percent of patients were admitted, and chemotherapy was changed or modified in majority of the cases. Mortality attributable to COVID-19 11 (4.9) Abbreviations: ARDS, acute respiratory distress syndrome; HCQ, hydroxychloroquine; ICU, intensive care unit; IQR, interquartile range; IVIG, intravenous immunoglobulin; PAH, pulmonary arterial hypertension. mortality, severe/critical disease, ICU admission, and mechanical ventilation in cancer patients with COVID-19 than noncancer patients. These patients had significantly lower platelet levels and higher Ddimer levels, C-reactive protein levels, and prothrombin times. The authors concluded that cancer patients are at a higher risk of COVID-19 infection-related complications. 41 Patients with hematological malignancies were more in number than those with solid tumors in this review. Patients with hematological malignancies are usually on chemotherapy regimens that are more intensive or require more frequent hospital visits. The severity of symptoms in children with cancer affected by COVID-19 is more than the general pediatric population, with more chance of developing severe symptoms and need for oxygen therapy. and only 4% had a severe or critical illness. 45 We too found fever to be the commonest symptom in the cancer patients, but the percentage of children having severe disease was more. The systematic scoping review published by Dorantes-Acosta et al. (June 2020) focused on survival in pediatric oncology patients during the COVID-19 pandemic and included five studies also collated in our review, a 100% survival was reported. 46 Most cases in this review were reported in patients with leukemia, and fever was the commonest symptom in children requiring admission. Contrary to the findings reported in the above studies on COVID-19 in pediatric patients, in this review, pediatric oncology patients were more likely to have severe disease due to COVID-19. Most of the patients also had a delay or modification in chemotherapy. Fifty-seven percent were admitted, and a higher death rate (4.9%) was observed than what has been reported in the pediatric population overall. 42, 43 A limitation of our study was that the majority of studies in our review were case reports and case series. A few studies did not mention the clinical characteristics, and some did not describe secondary outcomes. We could not do risk-of-bias assessment and meta-analysis of the data as most of the data were extracted from case reports and descriptive case series. Another limitation of our study is the heterogeneous nature of the collected data due to the studies from many countries. The impact of differences in socioeconomic factors and resource availability for health care in different countries cannot be ignored. Most of the deaths in this review were reported from a single study from a middle-income country. 18 In the same study, there is mention of intensive care beds not being available for two patients. In this review, we described the clinical characteristics and outcome of pediatric cancer patients having COVID-19. The disease was more common in children with hematological malignancies and ones getting intensive treatment. Fever followed by cough were the commonest symptoms. This review found more mortality and complications in pediatric oncology patients with COVID-19 in contrast to other published studies describing pediatric outcomes. This information can be helpful in risk stratification for management of COVID-19. There is a need for more prospective studies with a large sample size to formulate policies and guidelines in this specific population for this relatively novel disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review Clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study Mortality in patients with cancer and coronavirus disease 2019: a systematic review and pooled analysis of 52 studies COVID-19 infection in children and adolescents with cancer in Madrid Clinical Presentation and Outcomes of Children with COVID-19 and Cancer: a Systematic Review Epidemiology of COVID-19 among children in China COVID-19 in children with cancer in New York City Screening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy Children with cancer in the time of COVID-19: an 8-week report from the six pediatric onco-hematology centers in Lombardia COVID-19 infection in febrile neutropenic pediatric hematology oncology patients Children with cancer during COVID-19 pandemic: early experience in Mexico Favourable outcome of coronavirus disease 2019 in a 1-year-old girl with acute myeloid leukaemia and severe treatment-induced immunosuppression Screening of SARS-CoV-2 in 299 hospitalized children with hemato-oncological diseases: a multicenter survey in Hubei, China COVID-19 in pediatric oncology from French pediatric oncology and hematology centers: high risk of severe forms? Pediatr Blood Cancer Clinical characteristics and outcome of SARS-CoV-2 infection in Italian pediatric oncology patients: a study from the Infectious Diseases Working Group of the AIEOP Clinical outcome of SARS-CoV-2 infection in immunosuppressed children in Spain COVID-19 in pediatric cancer patients in a resource-limited setting: national data from Peru managing newly diagnosed metastatic testicular germ cell tumor in a COVID-19 positive patient SARS-CoV-2 infection in a 7-year-old girl with pancytopenia during acute lymphocytic leukemia maintenance therapy SARS-CoV-2 infection during induction chemotherapy in a child with high-risk T-cell acute lymphoblastic leukemia (T-ALL) SARS-CoV-2 infection in children with febrile neutropenia SARS-CoV-2 viral clearance during bone marrow aplasia after allogeneic hematopoietic stem cell transplantation-a case report Acute lymphoblastic leukemia onset in a 3-year-old child with 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 oncohematologic patients in Spain 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 patient with leukemia: addressing the need for universal guidelines for treatment of SARS-CoV-2-positive, immunocompromised patients Convalescent plasma to aid in recovery of COVID-19 pneumonia in a child with acute lymphoblastic leukemia 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 Spanish Group of Transplant (GETMON/GETH). Pediatr Blood Cancer COVID-19 after hematopoietic stem cell transplantation: report of two children First case of coronavirus disease 2019 in childhood leukemia in China Clinical characteristics of hematological patients concomitant with COVID-19 Clinical features of severe pediatric 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. Pediatr Blood Cancer Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults The risk and prognosis of COVID-19 infection in cancer patients: a systematic review and metaanalysis COVID-19 in 7780 pediatric patients: a systematic review COVID-19 disease severity risk factors for pediatric patients in Italy COVID-19 in children: an epidemiology study from China Clinical features and outcome of SARS-CoV-2 infection in children: a systematic review and meta-analysis Survival in pediatric patients with cancer during the COVID-19 pandemic: scoping systematic review The authors declare that there is no conflict of interest. All datasets generated for this study are included in the article and will be provided upon reasonable request.