key: cord-1022916-e38sqq6q authors: Hammad, Mahmoud; Shalaby, Lobna; Sidhom, Iman; Sherief, Nancy; Abdo, Ibrahim; Soliman, Sonia; Madeny, Youssef; Hassan, Reem; Elmeniawy, Shaimaa; Khamis, Nagwa; Zaki, Iman; Mansour, Tarek; El-Ansary, Mohamed Gamal; El-Halfawy, Ahmed; Abouelnaga, Sherif; Elhaddad, Alaa title: Management and Outcome of Coronavirus Disease 2019 (COVID-19) in Pediatric Cancer Patients: A Single Centre Experience from a Developing Country date: 2021-07-26 journal: Clin Lymphoma Myeloma Leuk DOI: 10.1016/j.clml.2021.07.025 sha: 8d3a63d5602d684755cf958949f5f865b75fd6b7 doc_id: 1022916 cord_uid: e38sqq6q INTRODUCTION: : Sufficient data pertaining to the impact of the Coronavirus disease-2019 (COVID-19) on pediatric cancer patients is still lacking. The aim of this prospective study was to describe clinical management and outcomes of COVID-19 in pediatric oncology patients. PATIENTS AND METHODS: : Conducted between May 1(st) and November 30, 2020, this study included 76 pediatric oncology patients with confirmed COVID-19. Remdesivir (RDV) was the antiviral therapy used. RESULTS: : The median age of patients was 9 years. Sixty patients were on first line treatment. Hematological malignancies constituted 86.8% of patients. Severe to critical infections were 35.4% of patients. The commonest symptom was fever (93.4%). Chemotherapy was delayed in 59.2% of patients and doses were modified in 30.2%. The sixty-day overall survival (OS) stood at 86.8%, with mortalities occurring only among critical patients. Of sixteen acute leukaemia patients in the first induction therapy, 13 survived and 10 achieved complete remission. A negative RT-PCR within 2 weeks and improvement of radiological findings were statistically related to disease severity (p=0.008 and 0.002, respectively). Better OS was associated with regression of radiological findings after 30 days from infection (p=0.002). Forty-five patients received RDV, 42.1% had severe and critical forms of infection compared to 25.7% in the No-RDV group and yet OS was comparable in both groups. CONCLUSION: : Most paediatric cancer patients with COVID-19 should have good clinical outcomes except for patients with critical infections. Cancer patients can tolerate chemotherapy including induction phase, alongside COVID-19 treatment. In severe and critical COVID-19, RDV might have a potential benefit. The Coronavirus disease-2019 (COVID-19) outbreak was declared a pandemic at the start of 2020. Cancer patients are amongst the most vulnerable groups to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Most healthy children present with asymptomatic or mild form of the disease. 1 Data pertaining to children with cancer are still limited. The general fear is that the course of infection might be more severe compared with healthy children. 2 Of the few published studies so far, most have concluded that pediatric oncology patients experience mild to moderate courses of infection. 3, 4 Still mortality rates higher that 3% have been reported. 5, 6 The difficulty in determining the true impact of SARS-CoV-2 infection in cancer patients is that cancer encompasses different tumor subtypes and the lack of a unified approach to patient screening and management across different cancer centers. 3 Risks of administering chemotherapy to children infected with SARS-CoV-2 is still unclear. A higher risk of severe events was observed among adult patients who had received chemotherapy during the month prior to a COVID-19 diagnosis compared with those who had not . 7 The current situation mandates that chemotherapy be tailored according to the clinical scenario of each patient. 8 Studies are still ongoing in order to determine the best antiviral therapy for COVID-19. 9 Preliminary studies have touted the potential benefits of remdesivir (RDV) in patients with severe COVID-19. 10, 11 This study aimed to describe the clinical course and management of SARS-CoV-2 infections in 76 pediatric oncology patients, detailing disease severity, duration to achieve a negative RT-PCR test, modifications made to protocols, and survival outcomes in patients who had been treated with RDV and those treated without it. This prospective study recruited 76 pediatric oncology patients ≤18 years of age with confirmed COVID-19 infection. Patients were treated at the Children's Cancer Hospital of Egypt, from May to November 2020 and followed up for a minimum of two months. Patients were eligible for COVID-19 screening, if they had respiratory symptoms and at least two of the following: 1) unexplained fever or gastrointestinal symptoms 2) abnormal chest imaging 3) laboratory test with lymphopenia or elevated C-reactive protein (CRP) or D-dimer 4) contact with SARS-CoV-2 confirmed patients Data included demographics, cancer diagnosis and treatment, COVID-19 severity and management, computed tomography (CT) and laboratory findings, and survival outcomes. Approval of the hospital ethical committee and family consents were obtained. llplex 2019-nCoV Assay (Seegene, Seoul, South Korea) was used for Multiplex real-time PCR detection of SARS-CoV-2 according to manufacturer instructions. According to the guidelines for scoring pediatric patients with COVID-19, disease severity was classified as mild, moderate, severe or critical forms (Table S1 ). 4 Management according to our institutional policy was as follows: 1. Positive reverse transcription polymerase chain reaction (RT-PCR) tests were repeated weekly. 2. Investigations included a daily complete blood picture, liver and kidney functions, besides weekly ferritin, LDH, CRP and D-dimer tests. 3. All patients underwent baseline chest CTs and repeated every two weeks. 4. SARS-CoV-2 treatment approach included: a. All patients received methylprednisolone 1 mg/kg for 7 days and tapered over another week. c. Patients with solid tumours received their chemotherapy without dose adjustment or interruptions alongside with steroids and antiviral therapy. Infection with SARS-CoV-2 is considered cleared -viral clearance‖ after obtaining two consecutive negative RT-PCR tests. Radiological improvement was defined as any regression in CT chest findings up to total resolution within 1 month of the baseline CT. The tabulated information was presented using standard descriptive statistics. Chi-square and Fisher's exact tests were used for categorical variables. Sixty-day overall survival (OS) was estimated using the Kaplan-Meier method with survival duration calculated in days from the date of diagnostic RT-PCR. Log-Rank test was used to compare survival probabilities between subgroups. A two-sided p<0·05 was considered significant. IBM-SPSS Statistics Version-20·0 was used in conducting data analyses. Of 420 suspected patients screened, 76 (18%) were laboratory-confirmed as SRAS-COV-2 infection. All except 5 patients were hospitalised, with a median length of hospital stay (LOS) of 14 days (range, 4-55 days). COVID-19 severity. The median age of patients was 9 years (range, 1-18 years) and more than 50% were ≤ 10 years of age. Sixty-day overall survival (OS) was not significantly influenced by age or gender ( Figure S1A and S1B). Sixty patients were on first line treatment, while 7 and 9 patients were on relapsing protocols and under follow up, respectively. The commonest malignancy was acute lymphoblastic leukemia/lymphoma (ALL/LL) (50%). More than 50% of patients had moderate clinical forms of infection. The median time from onset of symptoms to SARS-COV-2 diagnosis was 4 days (range, 1-14 days), with no statistical difference with respect to survival outcome ( Figure S1C ). The commonest clinical symptom was fever (93.4%). Eighteen patients (23.6%) had oxygen saturation <95% at time of admission. Importantly, 34 (44.7%) patients of the whole cohort were on non-intensive chemotherapy or off therapy and, therefore, most cytopenias were related to a prior intensive chemotherapy before COVID-19 diagnosis. All patients underwent baseline chest CTs. Six (7.89%) had no radiological findings all through the course of COVID-19. Follow up CT data were not available for 10/70 patients. The commonest CT chest finding was ground glass opacities (74.2%). Regression in CT chest findings was noticed in 60% of patients after one month of follow up. Each of the following 4 radiological findings; ground glass opacities, consolidation, nodular lesions and effusion were noted as sole findings or in combinations in some patients ( Figure S2 ). The initial number of CT findings had statistically significant relation with the increased need for supplementary oxygen (p=0.01) and invasive ventilation (p=0.04), but no significant impact on OS, ( Figure S1D ). Regression in CT findings occurred more significantly in patients with moderate and severe illness than in critical patients (p=0.002) and was associated with better OS (p=0.001) (Figure 2A ). SARS-CoV-2 PCRs remained positive for a median of 14 days (range, 7-68 days). Sixty-five patients had their PCR tests followed up until a negative result was achieved ( Figure S3 ). Thirty-six patients (55.3%) reached a negative PCR within 2 weeks of the initial positive test. All patients who reached negative PCR survived except for 2 patients. Statistically significant difference in LOS (P= 0.0001) and disease severity (p=0.008), but not OS, were found between patients who had achieved negative PCRs ≤14 versus >14 days post-initial positive test ( Figure 2B and Table S2 ). To be noticed, that only few patients with severe and critical forms of infection (19/65) were followed up until they had reached a negative PCR result, with 8/12 critically ill patients died before confirming a negative PCR result. Neutropenia and lymphopenia did not statistically impact the time needed to reach a negative PCR (P =0.08 and 0.6, respectively). It is worth noting that there were no mortalities among patients with persistently positive PCRs for >30 days. Repeated positive PCRs may thus not be true indicator of continued infectivity, but rather of inactive virus shedding ( Figure S1E ). Patients with acute leukaemia encompassed 76.3% of our cohort (Table S3 ). Most ALL/LL (88%) were on maintenance therapy, while 55% of AML patients were in the induction phase. Despite not being statistically significant, AML patients were more likely than ALL patients to present with severe or critical form of disease (40% vs 27%); to require invasive ventilation; and to have increased need for tocilizumab. Furthermore, only 25% of AML reached a negative PCR within 2 weeks compared to 52.6% of ALL. Improvement of CT chest findings was statistically higher in the ALL group; P=0.003. Interestingly, all acute leukaemia patients ≤ 2 years of age (n=5) have survived, and only one patient presented with severe clinical course that required oxygen support and tocilizumab. Twenty newly diagnosed acute leukaemia patients were confirmed as SARS-COV-2 infected during or at the start of their first induction cycle. There were seven new ALL patients with no dose adjustment needed except for one patient who completed induction without 6-mercaptopurine. More than half (n=40) of our patients were on intensive chemotherapy and 44.7% (n=34) had received chemotherapy within 2 weeks prior to their COVID-19 diagnosis ( Figure S1F ). There were no reported remdesivir-related adverse events except for a 16-year-old patient who developed a 2 folds elevation in serum creatinine above the baseline. Based on remdesivir administration, the time needed to reach a negative PCR between both groups (≤14 and >14 days) did show statistical difference. Similarly, there were no statistically significant difference in the duration of delay of chemotherapy, the need for tocilizumab, improvement of CT findings and LOS between both groups. At the end of the study 10 patients had died with 60-day OS of 86.8% ( Figure 2C ). All deceased patients had hematological malignancies except for one with a CNS tumour. The direct cause of death was difficult to be linked solely to COVID-19, but 5, 2 and 3 patients died from ARDS, malignant disease progression and gram-negative septicemia, respectively. Few cancer centers from Egypt have described the management and course of SARS-CoV-2 infection in pediatric cancer patients. 14, 15 The percentage of patients that were included in this study stood at 18% of all suspected patients; higher than other single and multicentre studies. 16 The slightly higher percentage of male patients in this study was comparable to another study on healthy children that reported a 56.6% of males. 19 The median age for our patients was lower than the New York-New Jersey report, where most of their patients were older than 10 years with a median age of 12 years. 18 In this study, most severe to critical patients belonged to >2 -≤ 10 age group. Madhusoodhan et al. reported, that severe disease forms were more common in age >10 years. 18 21 Nevertheless, a study on solid malignancies did not find a significant increase in mortality associated with recent chemotherapy. 22 Avoiding interruptions in chemotherapy is a challenge during a pandemic. A multicenter survey reported that chemotherapy administration was adversely affected in 29%-54% of participating centers. 25 Another study reported that 67% of patients needed delays of 2-78 days in their cycles, compared to 59% in our patients. 18 Notably, 42.5% of delays in this study lasted ≤ 15 days. Others reported that 40%-54% experienced delays in their treatment. 8, 16 It should be noted that 84% of our ALL patients were on weekly maintenance therapy and skipping one week was labelled as -a delay‖. Although no definitive recommendations can be given based on this study, our whole cohort survival and remission rates in new patients suggest for that treatment should start without delay or dose adjustment, as also stipulated by Ding et al. 26 The use of remdesivir was based on preliminary recommendations of studies conducted on severe patients. 11, 27 Fifty-nine percent of patients received RDV with a median of 4 days (range, 1-14 days) from onset of symptoms. The lack of parent/guardian awareness to the importance of seeking early hospital care and the similarity of symptoms to those of chemotherapy related complications resulted in a delay of antiviral therapy in some patients. The insignificant difference in OS between RDV group, which included more aggressive COVID-19 forms, and No-RDV group could be related to the RDV they had received. Similar results were observed in young adults and pediatric cohorts. 10, 16 To date, there is insufficient data regarding the safety of RDV below the age of 12, but we did not observe serious adverse events even in younger patients. 28 Zheng et al. discussed disease severity as a factor that correlates with the duration to viral clearance, with a median of 21 days in severe disease compared to 14 days in mild disease; p = 0.04). 31 Similarly, all our critical patients either had not reached viral clearance within 2 weeks or had died before clearing the virus. The importance of this prospective study lies in the fact that it describes the clinical course of SARS-COV-2 in a considerable number of pediatric oncology patients with more than half of them have received the same antiviral therapy. In addition, we managed to achieve good outcome and to conduct well-timed follow up PCR tests and CT scans despite our limited resources. However, one main limitation of this study is that it is based on data from a single centre. In addition, some logistic problems related to the availability of PCR kits at the start of the crisis might have led to selection bias as only symptomatic patients being screened. Criteria for hospital admission and treatment were not properly tailored according to the clinical severity and radiological findings of each patient. More The RDV group included more severe and critical patients compared to the No-RDV group, yet OS was comparable in both groups with no serious adverse events observed in all age groups. The present work was funded by the Children's Cancer Hospital Foundation and ssociation of Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults COVID-19 in pediatric oncology from French pediatric oncology and hematology centers: High risk of severe forms? Pediatr Blood Cancer Lessons after the early management of the COVID-19 outbreak in a pediatric transplant and hemato-oncology center embedded within a COVID-19 dedicated hospital in Lombardia, Italy. Estote parati Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study Global Registry of COVID-19 in Pediatric Cancer The Pediatric COVID-19 Cancer Case Report Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Impact of the First Wave of COVID-19 on Pediatric Oncology and Hematology: A Report from the French Society of Pediatric Oncology. Cancers (Basel) Clinical strategies for treating pediatric cancer during the outbreak of 2019 novel coronavirus infection Compassionate use of remdesivir in children with COVID-19 Remdesivir for the Treatment of Covid-19 -Final Report FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome Treatment of children with COVID-19: position paper of the Italian Society of Pediatric Infectious Disease COVID-19 in Children With Cancer COVID-19 infection in febrile neutropenic pediatric hematology oncology patients. Pediatr Blood Cancer COVID-19 infection in children and adolescents with cancer in Madrid Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment Characterization of COVID-19 disease in pediatric oncology patients: The New York-New Jersey regional experience Epidemiology of COVID-19 Among Children in China Poor clinical outcomes for patients with cancer during the COVID-19 pandemic COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis The UK Coronavirus Cancer Monitoring Project: protecting patients with cancer in the era of COVID-19 Impact of the coronavirus disease 2019 (COVID-19) pandemic on pediatric oncology care in the Middle East, North Africa, and West Asia region: A report from the Pediatric Oncology East and Mediterranean (POEM) group Delayed cancer diagnoses and high mortality in children during the COVID-19 pandemic Compassionate Use of Remdesivir for Patients with Severe Covid-19 Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease Infant With SARS-CoV-2 Infection Causing Severe Lung Disease Treated With Remdesivir Remdesivir during induction chemotherapy for newly diagnosed paediatric acute lymphoblastic leukaemia with concomitant SARS-CoV-2 infection Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China Abbreviations: Anti-IL6, anti-interleukin-6 ARDS, acute respiratory distress syndrome; CNS, central nervous system; CT, computed tomography; NRM, non-rebreather mask Simple oxygen mask * Others: eosinophilic granuloma. **Excluding patients without radiological findings in their baseline chest computed tomography Median, range (days) We would like to acknowledge the Children's Cancer Hospital Foundation and ssociation of Friends of the National Cancer-free Initiative (AFNCI) for giving us the logistic and financial support to complete this work.