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      SARS-CoV-2 in Children with Cancer or Following Haematopoietic Stem Cell Transplant: An Analysis of 131 Patients

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          Abstract

          Purpose

          There are limited data on SARS-CoV-2 (COVID-19) infection in children with cancer or following hematopoietic stem cell transplant (HSCT). We describe severity and outcomes of SARS-COV-2 in these patients and identify factors associated with severe disease.

          Methods

          Multi-national, observational study of children (<19y) with cancer or HSCT and SARS-CoV-2 confirmed by polymerase chain reaction. COVID-19 was classified as asymptomatic, mild, moderate, severe, or critical (≥1 organ support). Exact polytomous regression was used to determine relationship between clinical variables and disease severity.

          Results

          One-hundred-and-thirty-one patients with COVID-19 across 10 countries were identified (median age 8y). Seventy-eight (60%) had leukemia/lymphoma, 48 (37%) solid tumour and 5 primary immunodeficiency and HSCT. Fever (71%), cough (47%) and coryza (29%) were the most frequent symptoms. The median duration of detectable virus was 16 days (range, 1-79d). Forty-nine patients (37%) were hospitalized for COVID-19 symptoms and 15 (11%) required ICU-level care. Chemotherapy was delayed/modified in 35%. COVID-19 was asymptomatic in 32% of patients, mild in 47%, moderate in 8%, severe in 4% and critical in 9%. In 124 patients (95%), a full recovery was documented and four (3%) died due to COVID-19. Any co-morbidity (odds ratio, 2.94; 95% CI, 1.81-5.21), any co-infection (1.74; 95% CI1.03-3.03) and severe baseline neutropenia (1.82; 95% CI1.13-3.09) were independently and significantly associated with increasing disease severity.

          Conclusion

          While most children with cancer had asymptomatic/mild disease, 13% had severe COVID-19 and 3% died. Co-morbidity, co-infection and neutropenia may increase the risk of severe disease. Our data may help management decisions in this vulnerable population.

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          Most cited references30

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          Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

          China and the rest of the world are experiencing an outbreak of a novel betacoronavirus known as severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). 1 By Feb 12, 2020, the rapid spread of the virus had caused 42 747 cases and 1017 deaths in China and cases have been reported in 25 countries, including the USA, Japan, and Spain. WHO has declared 2019 novel coronavirus disease (COVID-19), caused by SARS-CoV-2, a public health emergency of international concern. In contrast to severe acute respiratory system coronavirus and Middle East respiratory syndrome coronavirus, more deaths from COVID-19 have been caused by multiple organ dysfunction syndrome rather than respiratory failure, 2 which might be attributable to the widespread distribution of angiotensin converting enzyme 2—the functional receptor for SARS-CoV-2—in multiple organs.3, 4 Patients with cancer are more susceptible to infection than individuals without cancer because of their systemic immunosuppressive state caused by the malignancy and anticancer treatments, such as chemotherapy or surgery.5, 6, 7, 8 Therefore, these patients might be at increased risk of COVID-19 and have a poorer prognosis. On behalf of the National Clinical Research Center for Respiratory Disease, we worked together with the National Health Commission of the People's Republic of China to establish a prospective cohort to monitor COVID-19 cases throughout China. As of the data cutoff on Jan 31, 2020, we have collected and analysed 2007 cases from 575 hospitals (appendix pp 4–9 for a full list) in 31 provincial administrative regions. All cases were diagnosed with laboratory-confirmed COVID-19 acute respiratory disease and were admitted to hospital. We excluded 417 cases because of insufficient records of previous disease history. 18 (1%; 95% CI 0·61–1·65) of 1590 COVID-19 cases had a history of cancer, which seems to be higher than the incidence of cancer in the overall Chinese population (285·83 [0·29%] per 100 000 people, according to 2015 cancer epidemiology statistics 9 ). Detailed information about the 18 patients with cancer with COVID-19 is summarised in the appendix (p 1). Lung cancer was the most frequent type (five [28%] of 18 patients). Four (25%) of 16 patients (two of the 18 patients had unknown treatment status) with cancer with COVID-19 had received chemotherapy or surgery within the past month, and the other 12 (25%) patients were cancer survivors in routine follow-up after primary resection. Compared with patients without cancer, patients with cancer were older (mean age 63·1 years [SD 12·1] vs 48·7 years [16·2]), more likely to have a history of smoking (four [22%] of 18 patients vs 107 [7%] of 1572 patients), had more polypnea (eight [47%] of 17 patients vs 323 [23%] of 1377 patients; some data were missing on polypnea), and more severe baseline CT manifestation (17 [94%] of 18 patients vs 1113 [71%] of 1572 patients), but had no significant differences in sex, other baseline symptoms, other comorbidities, or baseline severity of x-ray (appendix p 2). Most importantly, patients with cancer were observed to have a higher risk of severe events (a composite endpoint defined as the percentage of patients being admitted to the intensive care unit requiring invasive ventilation, or death) compared with patients without cancer (seven [39%] of 18 patients vs 124 [8%] of 1572 patients; Fisher's exact p=0·0003). We observed similar results when the severe events were defined both by the above objective events and physician evaluation (nine [50%] of 18 patients vs 245 [16%] of 1572 patients; Fisher's exact p=0·0008). Moreover, patients who underwent chemotherapy or surgery in the past month had a numerically higher risk (three [75%] of four patients) of clinically severe events than did those not receiving chemotherapy or surgery (six [43%] of 14 patients; figure ). These odds were further confirmed by logistic regression (odds ratio [OR] 5·34, 95% CI 1·80–16·18; p=0·0026) after adjusting for other risk factors, including age, smoking history, and other comorbidities. Cancer history represented the highest risk for severe events (appendix p 3). Among patients with cancer, older age was the only risk factor for severe events (OR 1·43, 95% CI 0·97–2·12; p=0·072). Patients with lung cancer did not have a higher probability of severe events compared with patients with other cancer types (one [20%] of five patients with lung cancer vs eight [62%] of 13 patients with other types of cancer; p=0·294). Additionally, we used a Cox regression model to evaluate the time-dependent hazards of developing severe events, and found that patients with cancer deteriorated more rapidly than those without cancer (median time to severe events 13 days [IQR 6–15] vs 43 days [20–not reached]; p<0·0001; hazard ratio 3·56, 95% CI 1·65–7·69, after adjusting for age; figure). Figure Severe events in patients without cancer, cancer survivors, and patients with cancer (A) and risks of developing severe events for patients with cancer and patients without cancer (B) ICU=intensive care unit. In this study, we analysed the risk for severe COVID-19 in patients with cancer for the first time, to our knowledge; only by nationwide analysis can we follow up patients with rare but important comorbidities, such as cancer. We found that patients with cancer might have a higher risk of COVID-19 than individuals without cancer. Additionally, we showed that patients with cancer had poorer outcomes from COVID-19, providing a timely reminder to physicians that more intensive attention should be paid to patients with cancer, in case of rapid deterioration. Therefore, we propose three major strategies for patients with cancer in this COVID-19 crisis, and in future attacks of severe infectious diseases. First, an intentional postponing of adjuvant chemotherapy or elective surgery for stable cancer should be considered in endemic areas. Second, stronger personal protection provisions should be made for patients with cancer or cancer survivors. Third, more intensive surveillance or treatment should be considered when patients with cancer are infected with SARS-CoV-2, especially in older patients or those with other comorbidities.
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            Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak

            In a study of 105 patients with cancer and 536 without, all with confirmed COVID-19, cancer was predictive of more severe disease, with stage IV cancer, hematologic cancer, and lung cancer being associated with worse outcomes.
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              Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients

              Abstract Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients <60 years (RR, 1.82; 95% CI, 1.45-2.27; N = 1169). The risk of death in pediatric patients was 4% (95% CI, 1-9; N = 102). RR of death comparing patients with recent systemic anticancer therapy to no treatment was 1.17 (95% CI, 0.83-1.64; N = 736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients ≥60 years have significantly higher mortality; pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

                Author and article information

                Journal
                Eur J Cancer
                Eur J Cancer
                European Journal of Cancer
                Elsevier Ltd.
                0959-8049
                1879-0852
                9 October 2021
                9 October 2021
                Affiliations
                [a ]Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
                [b ]NHMRC National Centre for Infections in Cancer, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
                [c ]The Paediatric Integrated Cancer Service, Parkville, Victoria State Government, Australia
                [d ]Infection Diseases Unit, Department of General Medicine, Royal Children’s Hospital, Parkville, Victoria, Australia
                [e ]Murdoch Children's Research Institute, Parkville, Australia
                [f ]Paediatric Hematology and Oncology, Department of Paediatrics, Inselspital, Bern University Hospital, Bern, Switzerland
                [g ]Kinderaerzte KurWerk, Burgdorf, Switzerland
                [h ]Paediatric Oncology Institute, GRAACC/Federal University of Sao Paulo, Sao Paulo, Brazil
                [i ]Infectious Disease Research Program, Center for Bone Marrow Transplantation, Department of Paediatric Hematology and Oncology, University Children’s Hospital Münster, Münster, Germany
                [j ]Paediatric Infectious Disease, Faculty of Medicine, Hebrew University of Jerusalem; Hadassah Medical Center, Jerusalem, Israel
                [k ]Infectious Diseases Unit, Department of Paediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
                [l ]Leeds Teaching Hospital, NHS Trust, Leeds; University of York, York, United Kingdom
                [m ]Department of Paediatric Intensive Care, Centro Infantil Boldrini, Campinas, SP, 13083-210, Brazil
                [n ]Dmitry Rogachev Federal Scientific-Clinical Center of Children's Hematology, Oncology and Immunology, Moscow, Russia
                [o ]Paediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
                [p ]Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, Germany
                [q ]Center for Paediatrics and Adolescent Medicine, Department of Paediatric Hematology and Oncology, Faculty of Medicine, Medical Center - University of Freiburg, Germany
                [r ]Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
                [s ]Paediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe University, Frankfurt
                Author notes
                [] Corresponding author. , Murdoch Children’s Research Institute, Flemington Rd, Parkville, Australia. Tel.: +61393481391
                Article
                S0959-8049(21)01127-8
                10.1016/j.ejca.2021.09.027
                8501219
                34736044
                e9294532-55e8-41a1-864d-d676a83c3e80
                © 2021 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 23 August 2021
                : 15 September 2021
                : 22 September 2021
                Categories
                Original Research

                Oncology & Radiotherapy
                child,cancer,sars-cov-2,covid-19,chemotherapy,hematopoietic stem cell transplantation

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