key: cord-0719058-19cpgkb2 authors: Madhusoodhan, P. Pallavi; Pierro, Joanna; Musante, Jordan; Kothari, Prachi; Gampel, Bradley; Appel, Burton; Levy, Adam; Tal, Adit; Hogan, Laura; Sharma, Archana; Feinberg, Shari; Kahn, Alissa; Pinchinat, Ashley; Bhatla, Teena; Glasser, Chana L.; Satwani, Prakash; Raetz, Elizabeth A.; Onel, Kenan; Carroll, William L. title: Characterization of COVID‐19 disease in pediatric oncology patients: The New York‐New Jersey regional experience date: 2020-12-18 journal: Pediatr Blood Cancer DOI: 10.1002/pbc.28843 sha: 1009b98c837fbb3e39ad998d3f56fba44af36de6 doc_id: 719058 cord_uid: 19cpgkb2 PURPOSE: Pediatric oncology patients undergoing active chemotherapy are suspected to be at a high risk for severe disease secondary to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection; however, data to support this are lacking. We aim to describe the characteristics of coronavirus disease 2019 (COVID‐19) in this population and also its impact on pediatric cancer care in the New York region during the peak of the pandemic. PATIENTS AND METHODS: This multicenter, retrospective study included 13 institutions. Clinical and laboratory information on 98 patients ≤21 years of age receiving active anticancer therapy, who tested positive for SARS‐CoV‐2 by nasopharyngeal swab polymerase chain reaction (PCR), was collected. RESULTS: Of the 578 pediatric oncology patients tested for COVID‐19, 98 were positive, of whom 73 were symptomatic. Most experienced mild disease, 28 required inpatient management, 25 needed oxygen support, and seven required mechanical ventilation. There is a slightly higher risk of severe disease in males and obese patients, though not statistically significant. Persistent lymphopenia was noted in severe cases. Delays in cancer therapy occurred in 67% of SARS‐CoV‐2‐positive patients. Of four deaths, none were solely attributable to COVID‐19. The impact of the pandemic on pediatric oncology care was significant, with 54% of institutions reporting delays in chemotherapy, 46% delays in surgery, and 30% delays in transplant. CONCLUSION: In this large multi‐institutional cohort, we observed that mortality and morbidity from COVID‐19 amongst pediatric oncology patients were low overall, but higher than reported in general pediatrics. Certain subgroups might be at higher risk of severe disease. Delays in cancer care due to SARS‐CoV‐2 remain a concern. anticancer therapy, who tested positive for SARS-CoV-2 by nasopharyngeal swab polymerase chain reaction (PCR), was collected. Results: Of the 578 pediatric oncology patients tested for COVID-19, 98 were positive, of whom 73 were symptomatic. Most experienced mild disease, 28 required inpatient management, 25 needed oxygen support, and seven required mechanical ventilation. There is a slightly higher risk of severe disease in males and obese patients, though not statistically significant. Persistent lymphopenia was noted in severe cases. Delays in cancer therapy occurred in 67% of SARS-CoV-2-positive patients. Of four deaths, none were solely attributable to COVID-19. The impact of the pandemic on pediatric oncology care was significant, with 54% of institutions reporting delays in chemotherapy, 46% delays in surgery, and 30% delays in transplant. In this large multi-institutional cohort, we observed that mortality and morbidity from COVID-19 amongst pediatric oncology patients were low overall, but higher than reported in general pediatrics. Certain subgroups might be at higher risk of severe disease. Delays in cancer care due to SARS-CoV-2 remain a concern. K E Y W O R D S chemotherapy, COVID-19, immunocompromised, immunotherapy, pediatric oncology, SARS-CoV-2 The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which causes coronavirus disease 2019 (COVID- 19) , has led to a global pandemic, with significant morbidity and mortality in high-risk populations. Due to their immunocompromised state, children undergoing cancer-directed therapy have been suspected to be at a higher risk for complications of COVID-19; however, data to support this are lacking. Early reports from China on adult oncology patients suggested a higher risk of severe disease in these patients, lending support to this theory. 1 Children undergoing cancer-directed therapy have been similarly suspected to be at higher risk for complications of COVID-19. Early data on pediatric patients in China suggested that malignancy and chemotherapy may be a risk factor for severe disease. Of 171 children who were positive for SARS-CoV-2, only three required mechanical ventilation, one of whom was receiving therapy for acute lymphoblastic leukemia (ALL). 2 In the United States, the New York region was an early epicenter of the pandemic, providing the opportunity to study the behavior of the disease even within a niche population like pediatric oncology. Investigators formed a rapid data collection collaborative of 13 institutions with the overarching goal to describe the clinical characteristics and natural history of the disease to help devise surveillance and treatment guidelines. This was a multicenter retrospective cohort study. Data were collected utilizing two REDCap questionnaires. where applicable in an effort to minimize confounding factors. Individual charts were also reviewed for age-adjusted body mass index (BMI), and patients were classified as underweight, healthy, overweight, or obese as per Center for Disease Control (CDC) guidelines. 10 Chemotherapeutic regimens were graded as mildly, moderately, or severely immunosuppressive based upon relative risk of fever and neutropenia. In cases of nonstandard or experimental therapy, the level of immunosuppression was assigned by the treating institution. Details can be found in the Supporting Information. Patients were assigned a "disease severity score" (DSS) by categorizing them into one off our groups, asymptomatic, mild, moderate, or severe disease as detailed in Table 1 . The cross-sectional information was presented using standard descriptive statistics. Frequency, percentage, and Fisher's exact test were pro-vided for categorical variables (Table S2) . We estimated median and interquartile range (IQR) for continuous variables, which were tested using Kruskal-Wallis test as appropriate (Table S3 ). All the tests were two-sided at a significance level of .05. We assessed normality of the continuous variables, and log-transformation of the data was made to render it appropriate for parametric testing. Several laboratory variables were collected from three time points in this study: diagnosis, peak or nadir during course of illness, and resolution. Cross-sectional analyses at each time point and longitudinal analyses were performed. A linear mixed-model approach, accounting for correlation of the data from the same source (patient) across time points, was used for the longitudinal data. 11 All analyses were conducted using SAS Institute 9.4 software (Cary, NC). 12 Of the 98 SARS-CoV-2-positive patients among 578 tested, 32 were asymptomatic at the time, of whom seven ultimately developed symptoms, while 66 (65.7%) were tested due to symptoms of COVID-19 ( Figure 1) Clinical characteristics of pediatric oncology patients undergoing active anti-cancer therapy with SARS-CoV-2 positivity by nasopharyngeal swab PCR are outlined above. *Other COVID-19 symptoms included (N) increased supplemental O2 support from baseline (2), congestion (4), headache (5), rhinorrhea (3), irritability (1) and anorexia (1). ± Other complications of COVID-19 included fungemia, aspiration pneumonia, seizures, thromboembolism and one case of suspected "hyperinflammatory syndrome" (as reported by one institution). # No death was solely attributed to COVID-19. P = .56, respectively). However, when comparing obese patients to nonobese, there was a statistically significant difference in distribution across disease severity groups (P = .0088) ( Figure 2B ). Overall, four deaths were reported in the cohort. Of these three had relapsed/refractory disease and one had newly diagnosed acute myeloid leukemia (AML) with hyperleukocytosis, none of whom were in remission. Thus, while the all-cause mortality in this cohort was 4.08% Laboratory parameters were collected at three time points: diagnosis, peak or nadir during course of illness, and resolution. None significantly correlated with a more severe course of illness. While previous reports found a correlation of absolute neutrophil count (ANC) to absolute lymphocyte count (ALC) ratio with disease severity, 13 we did not observe this in our cohort (P = .12). However, while testing mixed F I G U R E 2 Relationship of age and obesity to disease severity. A, Distribution of age groups within disease severity groups, showing a predominance of older patients in the moderate and severe disease groups. B, Distribution of disease severity within obese patients as compared to nonobese patients showing a trend toward more severe disease in obese patients model effects, we observed a statistically significant difference in lymphocyte counts between COVID-19 disease severity groups (P = .02). This difference is also impacted by time point (P = .03). The ALC counts at diagnosis were variable and did not correlate to clinical severity, but patients with severe disease had 2.5 times the risk of lymphopenia at recovery which was statistically significant (95% CI: 1.35-4.9, P = .01) ( Figure 3 ). Alanine transaminase levels were significantly higher among obese patients at all time points (diagnosis P = .006; peak P = .02; resolution P = .001). Among the small number of patients for whom this data were available, inflammatory markers such as CRP, D-dimer, and interleukin-6 did not correlate with disease severity (Table S4 ). Pediatric oncology patients straddle an interesting clinical space in the SARS-CoV-2 world, one in which their age would predict a mild course but their underlying malignancy and treatment may increase the risk of severe disease. The observations captured in this study shed considerable light on this debate and suggest that while overall risk of severe F I G U R E 3 Median blood counts amongst disease severity groups at time of COVID-19 diagnosis, peak or nadir during course of COVID-19 illness, and at COVID-19 resolution disease is less than predicted, the risk may be higher than healthy children and with certain demographic and disease features. Patients of Hispanic/Latino ethnicity and male gender were a majority in this cohort, but it is difficult to comment on whether this is truly reflective of disease impact or is purely a reflection of institutions' general population, because data on the overall demographics of the patient population at these institutions were not collected. Published literature on COVID-19 supports that these patients are at a higher risk. [14] [15] [16] The median for measures such as LOS (12) Correlating laboratory values with prognosis in this group has been challenging, given the impact of their malignant diagnosis and its therapy upon these values. Despite this, the persistent lymphopenia noted in the severe disease group, is noteworthy. Lymphopenia has recurrently been discussed as a risk factor for severe disease in COVID-19 in adults, 22 While this study provides important information on SARS-CoV-2 infection in these patients, there are several limitations. First, the study was conceived early in the pandemic when hospital resources were strained due to explosive growth of the pandemic in the New York/New Jersey area and prior to the availability of antibody testing or the description of the multisystem inflammatory syndrome. Screening for SARS-CoV-2 was not population based, and therefore could have selection biases for the patients who were tested. The PCR testing for SARS-CoV-2 was also not centralized and is subject to variability in technique between institutions. Additionally, due to differences between management among institutions, lab values were not consistently available for all patients, further limiting analysis. In conclusion, while pediatric oncology patients on active therapy appear to have higher risk of severe disease and need for critical care support as compared to the general pediatric population, this risk may be lower than initially perceived and is far lower than observed in their adult oncology counterparts. However, certain subgroups might be at higher risk for severe disease (males, older age, and obesity). Delays in therapy were common in our cohort due to uncertainties about the impact of the virus and the strain on hospital resources, but our data indicate that this approach may be indicated only in select symptomatic cases. The ultimate impact of the unprecedented COVID-19 pandemic on pediatric oncology patients will be assessed through prospective studies that are underway. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China SARS-CoV-2 infection in children COVID-19 in pediatric oncology from French pediatric oncology and hematology centers: high risk of severe forms? Pediatr Blood Cancer Severe COVID-19 disease in two pediatric oncology patients COVID-19 in children with cancer in New York City COVID-19 disease in New York City pediatric hematology and oncology patients COVID-19 Registry in Hematology. ASH Research Collaborative The Pediatric COVID-19 Cancer Case Report Global Registry of COVID-19 in Pediatric Cancer Healthy Weight, Nutrition and Physical Activity Applied Longitudinal Analysis SAS Institute Inc. SAS/ACCESS® 9 Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage Hospitalization rates and characteristics of children aged <18 years hospitalized with laboratoryconfirmed COVID-19 -COVID-NET, 14 States Sex differences in case fatality rate of COVID-19: insights from a multinational registry Palabindala V. COVID-19 disparity among racial and ethnic minorities in the US: a cross sectional analysis UK Coronavirus Cancer Monitoring Project team. The UK Coronavirus Cancer Monitoring Project: protecting patients with cancer in the era of COVID-19 COVID-19 mortality risk in Down syndrome: results from a cohort study of 8 million adults Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid Epidemiology of COVID-19 among children in China Early experience of COVID-19 in a US children's hospital Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a systemic review and meta-analysis COVID-19 in 7780 pediatric patients: a systematic review Korea Centers for Disease Control and Prevention. Findings from Investigation and Analysis of Re-Positive Cases. KDCA The authors would like to acknowledge the contributions of the follow- Additional supporting information may be found online in the Supporting Information section at the end of the article.