key: cord-288070-qwax5tg9 authors: Robilotti, E. V.; Babady, N. E.; Mead, P. A.; Rolling, T.; Perez-Johnston, R.; Bernardes, M.; Bogler, Y.; Caldararo, M.; Figueroa-Ortiz, C.; Glickman, M.; Joanow, A.; Kaltsas, A.; Lee, Y. J.; Lucca Bianchi, A.; Mariano, A.; Morjaria, S.; Nawar, T.; Papanicolaou, G. A.; Predmore, J.; Redelman-Sidi, G.; Schmidt, E.; Seo, S. K.; Sepkowitz, K.; Shah, M.; Wolchok, J. D.; Hohl, T. M.; Taur, Y.; Kamboj, M. title: Determinants of Severity in Cancer Patients with COVID-19 Illness date: 2020-05-08 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2020.05.04.20086322 sha: doc_id: 288070 cord_uid: qwax5tg9 New York State had 180,458 cases of SARS-CoV-2 and 9385 reported deaths as of April 10th, 2020. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher COVID-19 death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-19 disease4. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. Since March 10th, 2020 Memorial Sloan Kettering Cancer Center performed diagnostic testing for SARS-CoV-2 in symptomatic patients. Overall, 40% out of 423 patients with cancer were hospitalized for COVID-19 illness, 20% developed severe respiratory illness, including 9% that required mechanical ventilation, and 9% that died. On multivariate analysis, age [≥] 65 years and treatment with immune checkpoint inhibitors (ICI) within 90 days were predictors for hospitalization and severe disease, while receipt of chemotherapy within 30 days and major surgery were not. Overall, COVID-19 illness is associated with higher rates of hospitalization and severe outcomes in patients with cancer. Association between ICI and COVID-19 outcomes will need interrogation in tumor-specific cohorts. New York State had 180,458 cases of SARS-CoV-2 and 9385 reported deaths as of April 10 th , 2020. Patients with cancer comprised 8.4% of deceased individuals 1 Italy suggested a higher COVID-19 death rate in patients with cancer 2,3 , although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-19 disease 4 . This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. Since March 10 th , 2020 Memorial Sloan Kettering Cancer Center (MSKCC) performed diagnostic testing for SARS-CoV-2 in symptomatic patients. Overall, 40% out of 423 patients with cancer were hospitalized for COVID-19 illness, 20% developed severe respiratory illness, including 9% that required mechanical ventilation, and 9% that died. On multivariate analysis, age ≥ 65 years and treatment with immune checkpoint inhibitors (ICI) within 90 days were predictors for hospitalization and severe disease, while receipt of chemotherapy within 30 days and major surgery were not. Overall, COVID-19 illness is associated with higher rates of hospitalization and severe outcomes in patients with cancer. Association between ICI and COVID-19 outcomes will need interrogation in tumorspecific cohorts. The characterization of COVID-19 in patients with cancer remains limited in published studies and nationwide surveillance analyses. Reports from outside the US show a higher risk of COVID-19 related severe events in patients on active therapy, those with lung cancer and ICI recipients [4] [5] [6] . In this study, we report on the epidemiology of COVID-19 illness experienced at our cancer center over the last month, during the height of incident cases in New York City, and offer an analysis of risk factors for severe infection that is pertinent to cancer patient populations. From March 10, 2020, until April 7, 2020, SARS-CoV-2 was detected in 530 (26%) of 2035 patients tested (Figure 1) . The final study population included 423 patients, with the following exclusions: outpatients with missing information (n = 77) and asymptomatic individuals tested as part of diagnostic screening protocols before surgery or myeloablative chemotherapy (n = 30). The MSKCC Institutional Review Board granted a HIPAA waiver of authorization to conduct the study. All rights reserved. No reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Next, we assessed risk factors for hospitalization and severe respiratory illness, defined as the requirement for high-flow oxygen supplementation or mechanical ventilation. In the multivariate analysis, the following risk factors were independently associated with hospitalization: age > 65 years, non-white race, hematologic malignancy, a composite measure of chronic lymphopenia and/or corticosteroid use, and treatment with ICI therapy. Hypertension and/or chronic kidney disease trended towards significance as predictors of hospitalization in the multivariate model ( Table 2 ). The risk factors for severe respiratory illness due to COVID-19 were overlapping with those for hospitalization, but not identical. Severe illness was significantly more common with age > 65 years. Of note, treatment with ICI also remained an independent predictor of severe respiratory illness. Metastatic disease, recent receipt of chemotherapy, or major surgery within the previous 30 days did not show a significant association with either hospitalization or severe respiratory illness (Table 3) . Given the apparent association of ICI with COVID-19 severity, we explored this further by calculating stratum-specific rates of hospitalization and severe respiratory illness (Table 4 ). Since PD-1, a type of ICI, is commonly used to treat lung cancer, we examined the occurrence of outcomes by ICI use and underlying cancer (lung vs non-lung). The frequency of severe illness and hospitalization was higher in both ICI treated groups. In a separate prediction model, clinical All rights reserved. No reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which this version posted May 8, 2020. . https://doi.org/10.1101/2020.05.04.20086322 doi: medRxiv preprint presentation with new onset dyspnea and diarrhea were most predictive of hospitalization and severe illness (Supplemental Table 2 ). Patients with cancer are among those most vulnerable to severe illness from respiratory viral infections. 7 Our early experience with COVID-19 at a large tertiary care cancer center demonstrated severe disease in 20% of patients diagnosed with COVID-19 illness, with an overall CFR of 9%. Similar to other studies in the general population, we found that age, non-white race, cardiac disease, hypertension, and chronic kidney disease correlated with severe outcomes. 8, 9 Contrary to previous reports, receipt of chemotherapy within 30 days before COVID-19 diagnosis was not associated with a higher risk of complications. 6 Recent major surgery and metastatic disease also did not confer a significant risk of severe COVID-19 disease. Treatment with ICI predicted both hospitalization and severe disease, although there was considerable heterogeneity in ICI treated tumor types, and disease-specific confounding factors could not be specifically addressed. COVID-19 illness among children with cancer exhibited a milder course, consistent with reports in children without cancer, but represented a small portion of the evaluated population (7, 2%). 10 Immunotherapy was an independent risk factor in our study involving 31 ICI-treated patients, 12 of 31 had lung cancer, while the remaining reflected a combination of multiple primary tumor groups. While we observed more severe COVID-19 illness in ICI recipients with underlying lung cancer, non-lung cancer patients treated with ICI also demonstrated severe outcomes (Table 4) . A possible explanation for this observation is an exacerbation of ICI-related lung injury, or ICI-triggered immune dysregulation by T cell hyperactivation, that in turn may facilitate acute respiratory distress syndrome, a dreaded COVID-19 disease complication. 11 This finding should be interpreted with caution due to the limitations of our ICI dataset. It is possible that patients with lung cancer have confounding from other risk factors beyond ICI treatment (e.g., surgery, preexisting lung disease, radiotherapy, prior smoking) that contributed to the finding of increased disease severity and were not fully evaluable in our population. Until more extensive studies are available, it is prudent not to alter treatment decisions, but consider SARS CoV -2 testing for patients initiating or continuing treatment with ICIs irrespective of symptoms. All rights reserved. No reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. There are several other limitations to our study. First, we describe a single center retrospective analysis in a heterogeneous group of patients with cancer. Second, outcomes may have been incomplete, given the short follow-up period and the possibility of reporting delays; 49 patients remain hospitalized at the time of this report. Third, many patients received an array of medications, including hydroxychloroquine, remdesivir, corticosteroids, and IL-6 inhibitors, according to the decision of the primary team caring for the patient. The effectiveness of these experimental therapeutics was not explicitly evaluated. Finally, with the postponement of all non-essential cancer care during the study period, COVID-19 testing practices were mostly targeted towards symptomatic patients that needed medical evaluation, potentially overestimating the overall severity of COVID-19. In summary, the outcome of COVID-19 illness is worse among those with underlying conditions, including cancer. Our group of 423 patients with cancer had substantially higher rates of severe outcomes with COVID-19 illness when compared to published worldwide rates of severe disease (6.1-31.4%) and death (2.3-7.2%). 3, [12] [13] [14] In addition, as was seen with the SARS epidemic in 2003, the ongoing risk of contracting the illness and indirect consequences of treatment disruptions are expected to have a lasting effect on the health and safety of patients undergoing treatment for cancer. 15 Continuous preparedness is paramount as routine cancer care is resumed in the coming weeks and months amidst the unpredictable threat posed by COVID-19. Informed approaches with universal screening, aggressive testing, and rigorous control measures will be essential for the safe ongoing delivery of oncologic care. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Immune checkpoint inhibitor (ICI) a 31 (7) All rights reserved. No reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. None c 287 (68) High-flow oxygen 45 (11) Death All rights reserved. No reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which this version posted May 8, 2020. . https://doi.org/10.1101/2020.05.04.20086322 doi: medRxiv preprint was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which this version posted May 8, 2020. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. From March 10, 2020, until April 7, 2020, all consecutive adult and pediatric cases of symptomatic and laboratory-confirmed SARS-CoV-2 infection were included. The only exceptions were asymptomatic subjects tested before surgery or prior to receipt of select myeloablative chemotherapy regimens. Identification of case-patients, their medical background, and clinical course during COVID-19 illness, were abstracted from electronic medical records. Nasopharyngeal swab samples were collected using flocked swabs (Copan Diagnostics) and placed in viral transport media. SARS-CoV-2 RNA was detected using the Centers for Disease Control and Prevention (CDC) protocol targeting two regions of the nucleocapsid gene (N1 and N2), with the following modifications: Nucleic acids were extracted from specimens using the NUCLISENS EasyMag (bioMérieux, Durham, NC) following an off-board, pre-lysis step. 16, 17 Real-time reverse transcription PCR was performed on the ABI 7500 Fast (Applied Biosystems Foster City, CA) in a final reaction volume of 20-µL, including 5 µL of extracted nucleic acids. Samples were reported as positive if both the N1 and N2 targets were detected. We first assessed patient risk factors for hospitalization as part of the management for COVID-19 illness, using logistic regression. Patients with nosocomial infection (n=12) were excluded from this analysis. Next, we assessed risk factors for severe respiratory illness, defined as the requirement for high-flow oxygen supplementation or mechanical ventilation. Cause-specific Cox proportional hazard modeling was All rights reserved. No reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which this version posted May 8, 2020. . https://doi.org/10.1101/2020.05.04.20086322 doi: medRxiv preprint applied for this. Analysis time began at the time of COVID-19 diagnosis and continued until one of the following endpoints was achieved:30 days since diagnosis, the end of the study follow-up period (April 17, 2020), or death. For the outcomes described above, the following clinical variables were assessed: age, sex, race, diabetes, hypertension cardiovascular disease (myocardial infarction, heart failure, heart valve replacement, or cardiomyopathy), chronic obstructive pulmonary disease, asthma, chronic kidney disease, obesity (body mass index >30), smoking status, underlying cancer, chronic lymphopenia (absolute lymphocyte count less than 500 per microliter for at least five measurements, immediately preceding positive COVID-19 PCR test), chronic corticosteroid use (prednisone of 20 mg per day or equivalent, for at least ten days), systemic parenteral chemotherapy within 30 days, and major surgery within 30 days, treatment with an immune checkpoint inhibitors (ICI) within 90 days. In addition to past underlying conditions, new symptoms at the time of testing were assessed: fever, cough, shortness of breath, and diarrhea. For both outcomes, predictors were first analyzed separately in a univariate analysis. Predictors with a univariate p-value of less than 0.25 were incorporated into a multivariate model. All study analyses were performed on R version 3.5 (R Development Core Team, Vienna, Austria). The MSKCC Institutional Review Board granted a HIPAA waiver of authorization to conduct the study. All rights reserved. No reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which this version posted May 8, 2020. . https://doi.org/10.1101/2020.05.04.20086322 doi: medRxiv preprint New York State Department of Health. 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