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      Delayed cancer diagnoses and high mortality in children during the COVID‐19 pandemic

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          Abstract

          To the Editor, Although the effects of the SARS‐CoV‐2 virus on infected patients are increasingly documented, the indirect consequences for uninfected patients are less well described. 1 We report five cases of children who presented critically ill to two U.S. tertiary referral centers (Children's Hospital of Philadelphia [CHOP] and Lucile Packard Children's Hospital at Stanford [LPCH]) in April 2020. All patients tested SARS‐CoV‐2 negative and experienced delays in cancer diagnosis due to the COVID‐19 pandemic with grave consequences. Each patient required emergent life‐saving interventions shortly after presentation (Table 1), including resuscitation following cardiac arrest (N = 2), emergent intubation (N = 4), and emergent pericardiocentesis for tamponade (N = 1). Two patients died within days of presentation. Although pediatric cancers can present with severe initial findings, the clustered frequency and acuity of these recent initial presentations is striking. TABLE 1 Clinical characteristics, presentation, and outcomes of children who presented in critical condition and were subsequently diagnosed with cancer # Visits prior to diagnosis Patient Age (years) Sex Symptoms at presentation Onset of symptoms Tele‐health PMD/urgent care ED Presumed diagnosis Time from initial presentation to diagnosis Oncologic diagnosis SARS‐CoV‐2 RT‐PCR assay Notable laboratory/radiologic findings Clinical course Survival status 1 4 F Fevers, emesis, hallucinations 3 weeks 2 1 1 Viral syndrome 2 weeks B‐cell ALL Negative × 2 WBC 1,000 /μL Blasts 1.6% Hgb 2.3 g/dL Platelets 3,000 /μL Lactate 13 mmol/L Uric acid 19 mg/dL Blood culture positive for Group G strep Many clusters of bacterial organisms on BMA Presented in shock. Cardiac arrest with multisystem organ failure. Brain herniation. Hemodialysis delayed due to COVID‐19‐related staffing shortages. Deceased (HD 5) 2 16 M Fevers, cough, emesis, diarrhea, dyspnea 4.5 weeks 0 1 2 Asthma flare and acute otitis media 4 weeks B‐cell ALL Negative × 3 WBC 1,000 /μL Blasts 26% Hgb 3 g/dL Platelets 77 ,000 /μL Lactate 15 mmol/L Uric acid 11.5 mg/dL Presented in respiratory distress. Cardiac arrest with multisystem organ failure. Small cerebral hemorrhages. Alive 3 17 F Abdominal pain, cough, palpitations 2.5 weeks 4 0 1 Gastritis 2 weeks Stage III DLBCL Negative × 1 Echocardiogram: large circumferential pericardial effusion with right atrial and ventricular collapse CT chest: large anterior mediastinal mass Presented in cardiac tamponade. 1.5 L malignant pericardial fluid emergently drained. Alive 4 10 F Shortness of breath, lethargy and cyanosis 3 days Reported parental reluctance to present to care 3 days T‐cell lymphoblastic lymphoma Negative × 2 pH of 6.9 pCO2 100 Lactate of 9.2 CT chest: large anterior mediastinal mass Presented in respiratory distress and obtunded. Emergently intubated Alive 5 8 M Fevers, throat pain, pallor, bruising, vomiting, fatigue, and eye pain 4 weeks 0 2 0 Tonsillitis 4 weeks AML Negative × 1 WBC 365,000 /μL Blasts 89% Hgb 6.1 g/dL Platelets 28,000 /μL INR 1.7 Fibrinogen 191 Presented with altered mental status. Status epilepticus and emergent intubation. Intracranial hemorrhage and herniation. Deceased (HD 5) AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; BMA, bone marrow aspirate; DLBCL, diffuse large b‐cell lymphoma; ED, emergency department; EMS, emergency medical services; HD, hospital day; Hgb, hemoglobin; PMD, primary medical doctor; WBC, white blood cell. John Wiley & Sons, Ltd. 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. Coinciding with the rapid rise in regional COVID‐19 cases and initiation of stay‐at‐home orders, both institutions noted significant changes in the timing and severity of new patient presentations. The first COVID‐19 case in Pennsylvania was reported on March 6, 2020. Despite a five‐year historical mean of 2.96 days between new leukemia patients, CHOP did not see any patients with a new leukemia diagnosis for 35 days (March 2, 2020, to April 6, 2020). Comparatively, the longest gap from 2015 to 2019 was 18 days. Thus, it was notable when two patients subsequently diagnosed with acute lymphoblastic leukemia (ALL) presented on consecutive days to the pediatric intensive care unit (PICU) after having cardiac arrests at local hospitals in April. Similarly, LPCH noted an increase in the percentage of patients requiring prolonged PICU care at diagnosis. In April 2020, 75% of new leukemia/lymphoma diagnoses required PICU care, compared with a historic monthly average of 12% during 2018–2019 (previous maximum 40%). Pediatric cancers are relatively rare, and thus delays in diagnosis can occur. 2 However, our experience suggests that additional factors specific to the ongoing COVID‐19 pandemic contributed to care delays and higher patient acuity. The family of one patient expressed reluctance to seek care due to fear of COVID‐19 exposure. The other four patient families had repeated contact with the healthcare system prior to ultimate diagnosis. This suggests that healthcare system factors may play a role, including decreased referrals to emergency departments or laboratories, and transition to alternative evaluation methods such as telemedicine. Diagnostic bias may also occur, since presenting signs of malignancy (fever, malaise, and respiratory symptoms) can initially be mistaken for symptoms of COVID‐19. Furthermore, endemic areas have reported that children are less likely to become critically ill from COVID‐19 disease as compared with adults, 3 which may delay referral of children for emergency services or laboratory studies. Two patients had multiple telehealth visits prior to in‐person evaluations. Telemedicine utilization among primary and acute care providers is increasing during the pandemic. 4 The limitations of telemedicine, including lack of ability to detect critical physical exam findings such as unstable vital signs, pallor, and hepatosplenomegaly, are underscored by these cases. For example, after two telehealth visits and one visual assessment outside the primary care provider's office, patient 1 re‐presented hours later to a local emergency department with overwhelming sepsis that progressed to cardiac arrest and brain death. Such an outcome is particularly difficult given the extremely favorable prognosis of childhood ALL. Indeed, the pediatric cancer diagnoses presented here are highly curable in North America with expected cure rates ranging from 67% to over 95% depending on diagnosis. 5 These cases illustrate the indirect impact of this pandemic on morbidity in COVID‐19–negative patients for whom care delays can be fatal. We highlight the unintended consequences of a pandemic‐transformed healthcare system for a vulnerable pediatric population. More work is critical to quantify these consequences and to develop solutions that protect severely ill but treatable children, while also balancing public health and the needs of those infected during this COVID‐19 pandemic. CONFLICTS OF INTEREST The authors have no conflicts of interest/financial relationships relevant to this article to disclose.

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          Most cited references4

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          Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China

          To identify the epidemiological characteristics and transmission patterns of pediatric patients with the 2019 novel coronavirus disease (COVID-19) in China.
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            Virtually Perfect? Telemedicine for Covid-19

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              Delayed access or provision of care in Italy resulting from fear of COVID-19

              During Italy's national lockdown for coronavirus disease 2019 (COVID-19), official hospital statistics in the period March 1–27, 2020, show substantial decreases—ranging from 73% to 88%—in paediatric emergency department visits compared with the same time period in 2019 and 2018 (figure ). Similarly, family paediatricians widely report a considerable reduction in clinic visits, although this is difficult to measure precisely. Figure Visits to paediatric emergency departments across five hospitals in Italy, March 1–27, 2020, compared with the same period in 2018 and 2019 Data are official hospital statistics (courtesy of the authors). Schools and sports activities have been closed since March 1 in Italy, so it is understandable that the numbers of acute infections and traumas among children are lower than usual. In addition, relatively few cases of COVID-19 among children have been reported. 1 As of April 2, the 1624 cases in the paediatric population ( 39°C) and the other presented with severe anaemia (haemoglobin 4·2 mg/dL) and respiratory distress after emergency department access was delayed. One of these patients died several days after hospital admission. One child presented with long-lasting convulsions after three previous episodes of convulsions had been treated at home without medical assistance; the patient was eventually diagnosed with bacterial pneumonia. A 3-year-old girl was admitted to hospital after 6 days at home with very high fever (>39°C), with a sepsis secondary to a pyelonephritis. A neonate was kept home despite vomiting for several days because of hypertrophic pyloric stenosis and arrived in the emergency department in hypovolaemic shock. Another child, aged 2 years, had been vomiting for several days and unable to eat before presenting with severe hypoglycaemia. One child arriving in the emergency department having been unable to pass faeces for more than a week was diagnosed with an abdominal mass of 15 cm diameter, later diagnosed as Wilm's tumour; the diagnosis by telephone from his paediatrician had been functional constipation. An adolescent with cerebral palsy and severe malnutrition got in touch with the hospital after 10 days of fever at home with increased oxygen needs, and died in the ambulance on the way to the hospital. The precise cause of fever and death was not ascertained but the adolescent was negative for COVID-19 infection. Another child with cerebral palsy, tracheotomy, and enteral nutrition died on route to the hospital after 3 days of bloody stools. A child with Mowat Wilson syndrome, in dialysis for chronic renal insufficiency, arrived at the hospital after 3 days of being “less active than usual” with capillary refill time of 4 s, heart rate of 50 beats per min, oxygen saturation level not detectable, mixed acidosis, and creatine 4 mg/dL; the child died after 4 days in the ICU. Of this small series of 12 cases, half of the children were admitted to an ICU and four died. In all cases, parents reported avoiding accessing hospital because of fear of infection with SARS-CoV-2. Furthermore, in five cases, the family had contacted health services before accessing care, but their health provider was unavailable because of the COVID-19 epidemic, or hospital access was discouraged because of the possible risk of infection. All cases were either negative for SARS-CoV-2 or had a clinical presentation (eg, diabetes) that did not justify a diagnostic test according to the national criteria. Notably, no death occurred in the same hospitals during the same period in 2019, and the total yearly number of paediatric deaths in these hospitals ranges from zero to three. These cases are clearly a small sample compared with the overall number of paediatric visits recorded in the five hospitals during this week (12 [2%] of 502). However, since delay in access to care was not monitored systematically, this small case series might underestimate the problem. We believe that further monitoring of access to routine clinical care is needed during the COVID-19 pandemic. There is a need to prevent delays in accessing hospital care and to increase provision of high-quality coordinated care by health-care providers. Both of these aspects should be considered as part of the overall public health impact of the COVID-19 pandemic, as evident in other epidemics,3, 4 and must be adequately monitored. Both the general population and health-care workers need clear guidance and information. Specifically, parents should be made fully aware that the risks of delayed access to hospital care for emergency conditions can be much higher than those posed by COVID-19. Specific duties and obligations of different types of health-care professionals should be clearly defined, taking into consideration the risk level of the working environment, the health-care worker's specialty, the probable harms and benefits of treatment, and competing obligations deriving from workers' multiple roles.4, 5
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                Author and article information

                Contributors
                dingy@email.chop.edu
                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
                26 June 2020
                : e28427
                Affiliations
                [ 1 ] Division of Oncology and Center for Childhood Cancer Research Children's Hospital of Philadelphia Philadelphia Pennsylvania
                [ 2 ] Lucile Packard Children's Hospital Stanford Palo Alto California
                Author notes
                [*] [* ] Correspondence

                Yang‐Yang Ding, Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 4020, Philadelphia, PA 19104.

                Email: dingy@ 123456email.chop.edu

                [†]

                Y. Ding and S. Ramakrishna contributed equally as co‐first authors to this manuscript.

                Author information
                https://orcid.org/0000-0003-1588-2571
                https://orcid.org/0000-0002-0391-1673
                https://orcid.org/0000-0001-8025-6767
                Article
                PBC28427
                10.1002/pbc.28427
                7361231
                32588960
                6701705c-9de0-4162-9e3d-49cdab3a11c7
                © 2020 Wiley Periodicals, Inc.

                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
                : 02 May 2020
                : 04 May 2020
                Page count
                Figures: 0, Tables: 1, Pages: 3, Words: 1265
                Categories
                Letter to the Editor
                Letter to the Editor
                Custom metadata
                2.0
                corrected-proof
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:15.07.2020

                Pediatrics
                Pediatrics

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