key: cord-0741398-9d5g5xaw authors: Hrusak, Ondrej; Kalina, Tomas; Wolf, Joshua; Balduzzi, Adriana; Provenzi, Massimo; Rizzari, Carmelo; Rives, Susana; del Pozo Carlavilla, María; Valerio Alonso, Maria Eli; Domínguez Pinilla, Nerea; Bourquin, Jean-Pierre; Schmiegelow, Kjeld; Attarbaschi, Andishe; Grillner, Pernilla; Mellgren, Karin; Ten Bosch van der Werff, J.; Pieters, Rob; Brozou, Triantafyllia; Borkhardt, Arndt; Escherich, Gabriele; Lauten, Melchior; Stanulla, Martin; Smith, Owen; Juh Yeoh, Allen Eng; Elitzur, Sarah; Vora, Ajay; Li, Chi-Kong; Ariffin, Hany; Kolenova, Alexandra; Dallapozza, Luciano; Farah, Roula; Lazic, Jelena; Manabe, Atsushi; Styczynski, Jan; Kovacs, Gabor; Ottoffy, Gabor; Felice, Marisa; Buldini, Barbara; Conter, Valentino; Stary, Jan; Schrappe, Martin title: Flash Survey on SARS-CoV-2 Infections in Pediatric Patients on anti-Cancer Treatment date: 2020-04-07 journal: Eur J Cancer DOI: 10.1016/j.ejca.2020.03.021 sha: 1532f63a9a38d108746ba7a374ed1987c9f8d952 doc_id: 741398 cord_uid: 9d5g5xaw 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. 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. 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. 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. The outbreak of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causing the Coronavirus Disease (COVID-19) pandemic in 2020 was identified in December, 2019. By March 17, 2020 it has affected 200,000 cases in 163 countries and in several foci the numbers rise exponentially [World Health Organization, "Rolling updates on coronavirus disease (COVID-19)" https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen]. In spite of high mortality rate, the spectrum of COVID-19 includes asymptomatic infection, upper respiratory tract infection, lower respiratory tract infection through severe respiratory failure, as well as other problems such as myocarditis, sepsis 1 , and diarrhea (Pan et al, Am. J. Gastroenterol., In Press). The age distribution of the more severe course of the disease is strikingly skewed towards older patients, especially those over 65 years of age 1,2 . In contrast, pediatric patients rarely develop critical illness. [3] [4] [5] [6] [7] In one study, only 5% and 0.6% of 2141 evaluable children with confirmed COVID-19 had severe or critical illness respectively. 7 The biology underlying this disparity in severity is unknown. The possibility that more severe disease associated with immunosenescence, along with an increased risk of severe disease in adults with cancer, and a single case report of a critically ill child who developed COVID-19 during myelosuppressive chemotherapy, has raised the concern that COVID-19 among immunosuppressed children might be a much more severe illness than is seen in otherwise healthy children. 2, [8] [9] [10] This is consistent with data for other coronaviruses, which do cause more severe infections in immunocompromised children. 11 To evaluate this, we used a flash survey to determine whether there was current evidence that pediatric patients with cancer in SARS-CoV-2 affected areas had been tested for this virus or had developed severe COVID-19 disease. On March 16, 2020, we circulated a simple survey on COVID-19 incidence and diagnostic and preventative measures. A web-based form was sent by email to 89 addressees, who work in pediatric hematology/oncology (PH/O) departments in many countries. Data was collected one day later. In total, 32 centers or countries provided data on COVID-19 incidence in children treated with chemotherapy or intensive immunosuppression in their institutions or countrywide ( Table 1) . The results are shown together with the COVID-19 incidences in general population. Briefly, of more than 200 patients who were tested for SARS-CoV-2 in these PH/O departments, which care for close to 10,000 at-risk patients, only eight cases of proven infection were identified. Given that there is no general recommendation regarding testing of asymptomatic individuals, many centers only tested symptomatic patients, so the true rate of infection is not known. None of the reported cases required intensive care because of COVID-19. Case 1 was a febrile adolescent after mediastinal radiotherapy for osteosarcoma, no information was available regarding prior chemotherapy. Case 2 was a 16year girl with febrile neutropenia after adjuvant chemotherapy for hepatoblastoma. She received azithromycin and granulocyte colony stimulating factor (G-CSF), no pulmonary involvement was present and after 5 days she was free of both neutropenia and fever. Also case 3 had febrile neutropenia, after chemotherapy for a cervical rhabdoid tumor. There were no radiologic signs of pulmonary involvement but she required oxygen for nightly desaturations. She received G-CSF and azithromycin and after 10 days she was dismissed from hospital. Case 4 was a 6-year boy admitted in a hospital for a cisplatin cycle for hepatoblastoma, with a COVID-19-positive swab after the end of therapy; he was discharged without therapy and remained in a good condition. Cases 1-4 were also mentioned elsewhere (Balduzzi et al, submitted). Case 5 was a child with metastatic Ewing sarcoma who developed febrile neutropenia after their 5 th cycle of chemotherapy. Case 6 was a child with Wilms' tumor who presented with fever and diarrhea after 6 weeks of chemotherapy; this child did have lymphopenia but not neutropenia. None of these two patients had respiratory symptoms, and both became afebrile within 12-24 hours. Both received hydroxychloroquine, and Case 5 also received Lopinavir-Ritonavir (LPV/r). Two more cases were reported two days after the survey responses were collected. One of them (case 7) was in febrile neutropenia treated for ALL and no data on outcome is available yet. The other one (case 9) was on maintenance treatment for ALL without typical symptoms, tested because his parents were COVID-19-positive; the anti-leukemic maintenance treatment was interrupted until two negative results will be obtained. To our knowledge, this is the first survey of pediatric oncology centers in SARS-CoV-2 affected areas. We found that the number of infected patients appears to be low, and that the few who were identified had mild and possibly self-limited infection. The low rate of identified infection is somewhat surprising, as it is reasonable to assume that the pediatric patients with cancer would be at least as susceptible to infection with SARS-CoV-2 infection as their healthy peers. The SARS-CoV-2 does infect children in general, although lower severity of the infection makes children prone to be underreported 3, 6 . Thus, at least in the countries with high COVID-19 incidence, either the transmission of SARS-CoV-2 was prevented by standard infection prevention measures, or cases remained undiagnosed as the course of the infection did not raise a suspicion of COVID-19. In some areas, the devastating overall situation made the diagnostics of mild cases a low priority. The mild disease experienced by the three children in this study is in direct contrast to the only previously published case of which we are aware. An 8 year old child undergoing myelosuppressive chemotherapy for T-cell acute lymphoblastic leukemia in ALL in a Wuhan hospital developed respiratory failure over the course of 3 weeks, eventually requiring mechanical ventilation; the patient had not recovered at the time of the report 8 (and included in 3, 9 ) . During the course of that patient's disease, CRP and IL-6 were only mildly elevated but ferritin levels were high (6417-15,758 ug/L). This is reminiscent of features of hemophagocytic lymphohistiocytosis, which has been previously described to co-occur with infections 12 . Possible correlation between the severity of infection and the composition and intensity of chemotherapy should be studied in larger cohorts. The participating countries are gradually strengthening general preventative measures, usually aiming at social distancing, quarantines for the infected and contacts, clean hands and surfaces and cautious checking for possible symptoms -similarly to measures successfully applied in Hong Kong during the SARS epidemic in 2003 13 . In PH/O departments, precautions are always taken to protect patients from any infections. The degree of these precautions typically depends on the severity of immunosuppression and differs among hospitals 14 . Although our study portrays symptomatic COVID-19 as a rare finding among heavily immunocompromised children, at least in the first weeks of pandemics, other viruses do occasionally infect these patients in hospital wards despite these precautions 15 . The responders to this survey recommend taking additional measures during the COVID-19 epidemic to protect patients and staff from being either infected or in quarantine. As the epidemiological situation develops, only scientifically supported measures should remain in place, not to cause unwanted delays in the treatment of the underlying malignancies. The overall experience with daily life in hospitals during the peak COVID-19 epidemics has been thoroughly described by Italian physicians (Balduzzi et al, submitted). There are large differences among countries regarding the specific measures recommended. Most commonly, social contact is being minimized in the general population during high epidemic risk. Whole hospitals or hospital areas in Italy and Spain are designated as "dirty" (suspected or proven SARS-CoV-2 infection) and "clean" (no suspicious symptoms or SARS-CoV-2 test is negative) areas. Facial masks are recommended for all care givers and, if possible, for patients any time during personal contacts. Health professionals taking care of immunocompromised patients are separated into teams without mutual physical contact, to avoid simultaneous infection or preventative quarantine in the entire staff. This can be done by working on alternate days (unless the workload forbids it) or weeks and not sharing offices and common areas. Fewer or no in-person conferences take place. Children with respiratory symptoms are screened for SARS-CoV-2 before entering PH/O units. Outpatient visits for long-term surveillance patients are postponed. Immunosuppressed children are recommended to be isolated from general pediatric patients, where possible. Although these infection prevention measures might reduce the risk of SARS-CoV-2 transmission, they can also directly or indirectly complicate patient care. It can cause a shortage of clinical doctors, nurses, diagnosticians, and technical supportive staff, drug shortages, higher stress in accompanying parents, logistic problems with transfusion and transplant products, and organizational inaccuracies in clinical decision making process due to lack of meetings. In conclusion, heavily immunocompromised patients in the PH/O wards remain at high potential risk of acquiring infectious diseases, including COVID-19. In a striking contrast, the current number of reported cases of COVID-19 among these patients is limited to a single previously reported case from China plus the four cases reported here. More research is needed to better understand the epidemiology of SARS-CoV-2 infection and COVID-19 in pediatric patients with cancer or other immunocompromised children. More cases are expected as the pandemic is only just unfolding in many countries. This flash survey, although providing a very early picture of COVID-19, shows that the disease may have a mild course even in children receiving anticancer chemotherapy. The risk of severe disease with COVID-19 in profoundly immunocompromised children is still unknown, and predictors of asymptomatic infection, mild disease or severe and life-threatening infection would help support the development of approaches to prevent as well as to optimize treatment of COVID-19 in this vulnerable patient population. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. 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