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      Collateral effects of COVID‐19 pandemic in pediatric hematooncology: Fatalities caused by diagnostic delay

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          Abstract

          To the Editor: Coronavirus disease COVID‐19 has deeply modified national health services with a profound impact on hospitals, and in particular emergency and intensive care unit (ICU) activities. As recently reported in Italy, pediatric emergency accesses substantially decreased likely due to the instructions to prevent overcrowding in emergency rooms and spread of SARS‐CoV‐2 infection and to fear of the infection. 1 At the Santobono‐Pausilipon Hospital (Naples), pediatric emergency accesses in March 2020 were only one‐fifth of those registered in 2019 in the same period. Likewise, a marked reduction of consultations also occurred in family pediatric clinics. 2 We report here three children who arrived at hospital with life‐threatening conditions at the onset of acute lymphoblastic leukemia (ALL) between March 14 and April 10, 2020. First case: A 2‐year‐old child arrived at the emergency department with a 15‐day history of fatigue, pallor, and dyspnea, in a comatose state with severe anemia, respiratory distress, hematemesis, and metabolic acidosis. Chest X‐ray showed interstitial pneumonia. Blood tests showed the following results: hemoglobin 2.7 g/dL, WBC count 185 000/μL, platelets (PTL) 10 000/μL, and LDH 3609 U/L. Peripheral blood was diagnostic for CD10, CD19, and CD58 positive ALL (B‐lineage ALL). The patient, admitted at the ICU, intubated, transfused with RBC, PTL, and plasma, died 12 h after arrival at the hospital due to progressive worsening of clinical conditions. The nasal swab was negative for SARS‐CoV‐2 and positive for adenovirus. Second case: A 5‐year‐old child arrived at the emergency department with a 1‐month history of respiratory distress. Imaging showed a mediastinal mass compressing the brachiocephalic vein, the aorta, the pulmonary trunk, and the left pulmonary artery; tracheal deviation;compression of the left main bronchus; left lung atelectasis; and pleural effusion. Blood tests showed the following results: hemoglobin 14.5 g/dL, WBC count 37 000/μL, PTL 294 000/μL, LDH 6153 U/L, creatinine 1.9 mg/dL. Peripheral blood was diagnostic for CD5, CD7, CyCD3, and CD8 positive ALL (T‐ALL). Steroid treatment was started. Clinical conditions deteriorated rapidly with cardiac and renal failure. The patient, admitted to ICU 2 h after arrival at the hospital and intubated, died 24 h later. The nasal swab was negative for SARS‐CoV‐2. Third case: A 4‐year‐old child arrived at the hospital with 1‐month history of fever, cough, and shortness of breath, treated at home with antibiotics and steroids without improvement. Imaging showed a mediastinal mass compressing the left brachiocephalic, azygos and superior cava veins, and right pulmonary artery and vein; mild tracheal deviation; compression of the left main bronchus; pericardial and pleural effusion; nephro‐hepato‐splenomegaly and ascites. Due to signs of cardiac tamponade, pericardiac and pleural drainage were placed and the patient was admitted to ICU and intubated. Blood tests showed the following results: normal hemoglobin, WBC, and PTL counts; LDH 2732 U/L, creatinine 2.98 mg/dL, K 8 mEq/L, and Ca 5.4 mEq/L. Bone marrow was diagnostic for CD2, CD5, CD7, CD99, and CyCD3 positive ALL (T‐ALL). Treatment with steroids was started. Due to progressive renal failure, hemodialysis was performed for 9 days. Clinical conditions improved with rapid shrinking of mediastinal masses and resolution of pericardial and pleural effusion. The patient was thus extubated and treatment for ALL was instituted with good response to induction therapy. The nasal swab was negative for SARS‐CoV‐2. The three cases of ALL are described here, two of them fatal, arrived at the hospital in critical condition, most likely as a consequence of fear of COVID‐19. Delay in diagnosis of neoplastic disease is a well‐known problem in low‐ to middle‐income countries (LMIC), but is quite rare in high‐income countries (HIC). Actually, this combination of events never occurred in the past at the Santobono‐Pausilipon Hospital, where, at the time of writing, no SARS‐CoV‐2‐positive cases have been identified among children treated for cancer. Considering low prevalence of virus spreading in children and that SARS‐CoV‐2‐positive children are generally asymptomatic or have a very mild course of the disease, there is a substantial risk that collateral effects of COVID‐19 pandemic, that is, delays in diagnosis, chemotherapeutic treatments, and treatment of chemotherapy complications, may be worse than those posed by the disease itself. 3 , 4 , 5 Recently, the major pediatric cancer scientific associations have expressed great concern on the risk that fear to access to medical care raised by COVID‐19 may cause these delays not only in LMIC but also in HIC with dramatic consequences we are not used to face. 6 , 7 Our experience confirms the occurrence of these collateral effects, indicating that there is a need of awareness of this risk and careful medical attention to assure timely diagnoses and adequate treatment adherence in childhood cancer. CONFLICT OF INTEREST The authors declare that there is no conflict of interest.

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          The COVID‐19 pandemic: A rapid global response for children with cancer from SIOP, COG, SIOP‐E, SIOP‐PODC, IPSO, PROS, CCI, and St Jude Global

          Abstract The COVID‐19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarize general principles for continuing multidisciplinary care during the SARS‐CoV‐2 (COVID‐19) pandemic. With contributions from the leadership of the International Society for Pediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global program, and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families, and cancer services in low‐ and middle‐income countries. Therefore, we have brought together the relevant clinical leads from SIOP Europe, COG, and SIOP‐PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g., extreme social distancing), and how to prepare for the anticipated recovery period.
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            Flash Survey on SARS-CoV-2 Infections in Pediatric Patients on anti-Cancer Treatment

            Introduction Since the beginning of COVID-19 pandemics, it is known that the severe course of the disease occurs mostly among elderly, whereas it is rare among children and young adults. Comorbidities, in particular diabetes and hypertension, clearly associated with age, besides obesity and smoke are strongly associated with the need of intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Along the same line, anecdotal information from Wuhan, China mentioned a severe course of COVID-19 in a child treated for leukemia. Aim and methods We made a flash survey on COVID19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short web based survey. Results We received reports from 25 countries, where approximately 10,000 patients at risk are followed. At the time of the survey, over 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken as well as treatment options in immunocompromised children with COVID-19. Conclusion Thus, even children receiving anti-cancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.
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              Effect of the COVID-19 pandemic on cancer treatment and research

              The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly escalated into a global pandemic. Patients with haematological and other cancers,1, 2 and recipients of haematopoietic stem cell transplantation (HSCT), could be at particular risk from COVID-19, since they tend to be older, have multiple comorbidities, and are often immunosuppressed by their disease or therapy. A retrospective analysis of 355 patients who died of COVID-19 in Italy showed that 20% had active cancer, 3 and a study from 2013–17 of 678 patients who had an HSCT found that 112 (17%) developed human coronavirus infection, of whom 34 had lower respiratory tract infection. 4 However, evidence regarding the effect of COVID-19 on patients with cancer is inadequate. The influx of a large number of patients with COVID-19 requiring intensive monitoring and mechanical ventilation has resulted in overloading of hospital systems in the affected regions and countries, disrupting routine treatment of haematology and cancer patients who constitute an especially fragile and vulnerable population, and whose outcomes are likely to be negatively affected if the usual standard of care is delayed. Travel restrictions, patient concerns, regulatory guidance, and sequestering of oncology staff have resulted in many cancer outpatient visits being replaced by telephone consultation, and deferral of some routine therapy, tests, and procedures. Estimating the risk versus benefit of administering potentially immunosuppressive treatment to patients with cancer with a scarcity of knowledge about this novel disease, and balancing individual versus societal benefits in the new reality of stretched resources, poses acute ethical dilemmas to oncologists. Investigators, government agencies, and professional societies have provided initial experiences and guidance on managing the continued care of patients with cancer during the current period of crisis. 5 Routine visits should be done via telephone or rescheduled, oral medications should be delivered to the patient's home to cover the peak period of the pandemic, and biological samples should be collected and processed at a local facility near the patient's residence. Cancer multidisciplinary team meetings should be done via a virtual platform, and changes should be made to individual treatment plans as needed for the duration of the pandemic. Patients with leukaemia, lymphoma, or myeloma; those receiving radical radiotherapy for lung cancer, cytotoxic chemotherapy, immunotherapy, antibodies, protein kinase inhibitors, or poly ADP ribose polymerase (PARP) inhibitors; and those with recent bone marrow or stem cell transplants could be especially vulnerable to COVID-19. 5 The European Society of Medical Oncology and National Health Service England have suggested a tiered approach for categorising patients into different priorities for receiving active cancer therapy during the pandemic. 5 Higher priority should be given if the patient's condition is immediately life threatening or clinically unstable, or the intervention is expected to result in substantial overall survival gain or improvement of quality of life. Oncologists should consider changing intravenous treatments to subcutaneous or oral routes, using longer intervals between immunotherapy regimens, deferring non-urgent supportive therapies, using granulocyte-colony stimulating factor as primary prophylaxis, and discussing treatment breaks for patients on long-term therapy. 5 Radiation treatment should be prioritised for patients with rapidly proliferating tumours and those whose planned radiotherapy has already begun, and hypofractionation should be considered to shorten the treatment duration. Patients with cancer who develop COVID-19 should be treated in the respiratory or intensive care units rather than in the oncology or radiotherapy units. 2 The COVID-19 pandemic has had a serious and disruptive effect on the conduct of haematology and oncology clinical trials, with both immediate and delayed consequences. In the short term, research staff and resources have been reassigned to manage the rush of patients with COVID-19 at many academic institutions and participating hospitals, and routine clinical research activities have been suspended. Trials testing treatments for COVID-19 have been prioritised. Research-related appointments to hospitals for site selection or qualification, source data verification, drug accountability, audit, and site staff training by contract research organisations (CROs) and sponsors have been cancelled because of travel restrictions. A sharp reduction in recruitment to ongoing trials and a delay in the planned launch of new haematology and oncology studies might be expected during the peak of the pandemic. A delay can also be anticipated in data entry into clinical trial databases owing to study coordinators working remotely with reduced access to the source data. As hospital radiology departments and laboratories are stretched during the pandemic, and to reduce the risk of SARS-CoV-2 infection to trial subjects, some protocol-mandated visits and study procedures, such as tumour assessments and biopsies, have been delayed or cancelled. A delay in imaging will impact progression-free endpoints of ongoing studies, while quality of life endpoints will be affected if patients miss study visits. Most regulatory authorities require that COVID-19 infection and related (serious) adverse events, such as dyspnoea and acute respiratory distress syndrome, be specifically captured and reported. 6 Site staff and monitors will need to be trained in this regard. In the medium to longer term, recruitment delays resulting from the pandemic will negatively affect drug development timelines, with damaging financial implications and potential delays in getting promising drugs to patients. An increase in protocol deviations over the duration of the pandemic can be expected, potentially affecting patient safety because of missing or late reporting of adverse events. COVID-19-related deaths could potentially affect survival endpoints in some studies. Cytokine release syndrome is a known toxicity of chimeric antigen receptor T-cell therapy and also occurs in a subgroup of patients with COVID-19, 7 but the effect on ongoing immunotherapy trials is presently unknown. Regulatory agencies such as the US Food and Drug Administration, European Medicines Agency, and the UK Medicines and Healthcare products Regulatory Agency have issued guidelines on managing clinical trials during the COVID-19 pandemic, stressing the importance of pragmatism and flexibility in tumour assessments and visits (via protocol amendments as necessary), protecting patient safety, clearly documenting protocol deviations, and disallowing prospective protocol waivers.8, 9, 10 Ensuring patient safety during the pandemic is of utmost priority. Training courses on COVID-19 symptoms, management, and use of personal protective equipment should be implemented. A phone contact with the trial participant should be made the day before the planned visit, to enquire if they have any COVID-19 symptoms. Hospital access should be restricted for vendors, visitors, trial monitors, and auditors. Virtual support services should be implemented for trial participants, and where feasible, remote access to relevant medical charts should be granted to trial monitors to review, verify, and raise queries. Such systems should have robust security and audit trails. Several CROs are responding to this new reality by adapting their usual processes and developing new methods of remote, secure trial monitoring, site staff training, drug accountability, and source data verification and review, while recognising and respecting the disparities in national legislation in different countries with regard to remote access to medical records by CROs and direct shipment of medication to patients. A discussion between investigators and sponsors should take place to consider withdrawal of optional trial procedures (eg, biopsies), and to allow laboratory and radiological assessments to be done at an accredited facility closest to the patient. For some investigational products, such as oral medications typically distributed for self-administration, alternative safe delivery methods should be implemented to avoid hospital visits by patients. The implementation of such alternative processes should be as consistent with the protocol as possible, and sponsors and clinical investigators should document the reasons for any contingency measures adopted. Sponsors and clinical investigators should clearly document how restrictions related to COVID-19 led to the changes in study conduct, the duration of those changes, and which trial participants were affected and how. Since radiology services are likely to be stretched during the pandemic, central imaging review should be instituted to ensure good quality of data for clinical trial patients. COVID-19 has had a huge and negative effect on cancer treatment and research. We hope that with the support of all stakeholders, patients with cancer and trial participants can receive the best possible care even in these exceptionally difficult times. © 2020 Sputnik/Science Photo Library 2020 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.
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                Author and article information

                Contributors
                rparasol64@gmail.com
                Journal
                Pediatr Blood Cancer
                Pediatr Blood Cancer
                10.1002/(ISSN)1545-5017
                PBC
                Pediatric Blood & Cancer
                John Wiley and Sons Inc. (Hoboken )
                1545-5009
                1545-5017
                11 June 2020
                : e28482
                Affiliations
                [ 1 ] Department of Pediatric Hemato‐Oncology Santobono‐Pausilipon Hospital Naples Italy
                [ 2 ] Pediatric Hemato‐Oncology University of Milano‐Bicocca Fondazione MBBM/Hospital San Gerardo Monza Italy
                [ 3 ] Intensive Care Unit Santobono‐Pausilipon Hospital Naples Italy
                [ 4 ] Nephrology Unit Santobono‐Pausilipon Hospital Naples Italy
                [ 5 ] Emergency Unit Santobono‐Pausilipon Hospital Naples Italy
                Author notes
                [*] [* ] Correspondence

                Rosanna Parasole, Department of Pediatric Hemato‐Oncology, Santobono‐Pausilipon Hospital, Via Posillipo 226, 80123 Naples, Italy.

                Email: rparasol64@ 123456gmail.com

                Author information
                https://orcid.org/0000-0003-3350-5286
                Article
                PBC28482
                10.1002/pbc.28482
                7300556
                32525616
                825312b2-16cf-4d88-bfa5-0ff949f60bd7
                © 2020 Wiley Periodicals LLC

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 20 May 2020
                : 20 May 2020
                Page count
                Figures: 0, Tables: 0, Pages: 2, Words: 1089
                Categories
                Letter to the Editor
                Letter to the Editor
                Custom metadata
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                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:18.06.2020

                Pediatrics
                Pediatrics

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