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Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak

In a study of 105 patients with cancer and 536 without, all with confirmed COVID-19, cancer was predictive of more severe disease, with stage IV cancer, hematologic cancer, and lung cancer being associated with worse outcomes.


INTRODUCTION
A new acute respiratory syndrome coronavirus, named SARS-CoV-2 by the World Health Organization (WHO), has rapidly spread around the world since its first reported case in late December 2019 from Wuhan, China (1). As of March 2020, this virus has affected more than 200 countries and territories, infecting more than 800,000 individuals and causing more than 40,000 deaths (2).
With more than 18 million new cases per year globally, cancer affects a significant portion of the population. Individuals affected by cancer are more susceptible to infections due to coexisting chronic diseases, overall poor health status, and systemic immunosuppressive states caused by both cancer and anticancer treatments (3). As a consequence, patients with cancer who are infected by the SARS-CoV-2 coronavirus may experience more difficult outcomes than other populations. Until now, there is still no systematic evaluation of the effects that the SARS-CoV-2 coronavirus has of patients with cancer in a representative population. A recent study reported a higher risk of severe events in patients with cancer when compared with patients without cancer (4); however, the small sample size of SARS-CoV-2 patients with cancer used in the study limited how representative it was of the whole population and made it difficult to conduct more insightful analyses, such as comparing clinical characteristics of patients with different types of cancer, as well as anticancer treatments (5,6).
Using patient information collected from 14 hospitals in Hubei Province, China, the epicenter of the 2019-2020 COVID-19 outbreak, we describe the clinical characteristics and outcomes [death, intensive care unit (ICU) admission, development of severe/critical symptoms, and utilization of invasive mechanical ventilation] of patients affected by the SARS-CoV-2 coronavirus for 105 hospitalized patients with cancer and 536 patients without cancer. We document our findings for different cancer types and stages, as well as different types of cancer treatments. We believe the information and insights provided in this study will help improve our understanding of the effects of SARS-CoV-2 in patients with cancer.

Patients Characteristics
In total, 105 COVID-19 patients with cancer were enrolled in our study for the time period January 1, 2020, to February 24, 2020, from 14 hospitals in Wuhan, China. COVID-19 patients without cancer matched by the same hospital, hospitalization time, and age were randomly selected as our control group. Our patient population included 339 females and 302 males. Patients with cancer [median = 64.00, interquar-tile range (IQR) = 14.00], when compared with those without cancer (median = 63.50, IQR = 14.00) had similar age distributions (by design), experienced more in-hospital infections [20 (19. 1A). We also conducted survival analysis on occurrence of any severe condition which included death, ICU admission, having severe symptoms, and utilization of invasive mechanical ventilation (see cumulative incidence curves in Fig. 1B). In general, patients with cancer deteriorated more rapidly than those without cancer. These observations are consistent with logistic regression results ( Supplementary Fig. S1), after adjusting for age, sex, smoking, and comorbidities including diabetes, hypertension, and chronic obstructive pulmonary disease (COPD). According to our multivariate logistic regression results, patients with cancer still had an excess OR of 2.17 (P = 0.06) for death ( Supplementary Fig. S1A Table  S1). The consistency of observed ORs between the multivariate regression model and unadjusted calculation reassures the association between cancer and severe events even in the presence of other factors such as age differences.

Cancer Types
Information regarding potential risks of severe conditions in SARS-CoV-2 associated with each type of cancer was calculated. We compared different conditions among cancer types (

Timeline of Severe Events
To evaluate the time-dependent evolution of the disease, we conducted the timeline of different events for COVID-19 patients with cancer ( Fig. 2A ) and COVID-19 patients without cancer ( Fig. 2B ) with death and other severe events marked in the fi gure. COVID-19 patients with cancer had a mean length of stay of 27.01 days (SD 9.52) and patients without cancer had a mean length of stay of 17.75 days (SD 8.64); the difference is signifi cant (Wilcoxon test, P < 0.01). To better clarify the contributing factors that might infl uence outcomes, we also included logistic regression of COVID-19 patients with cancer adjusted by immunosuppression levels in Supplementary Table S5. However, no signifi cant association between immunosuppression and severe outcomes was observed from the analysis (with all P > 0.05).

DISCUSSION
The fi ndings in this study suggest that patients with cancer infected with SARS-CoV-2 tend to have more severe outcomes when compared with patients without cancer. Patients with hematologic cancer, lung cancer, and cancers in metastatic stages demonstrated higher rates of severe events compared with patients without cancer. In addition, patients who underwent cancer surgery showed higher death rates and higher chances of having critical symptoms.
The SARS-CoV-2 virus has spread rapidly globally; thus, many countries have not been ready to handle the large volume of people affected by this outbreak due to a lack of knowledge about how this coronavirus affects the general population. To date, reports on the general population infected with SARS-CoV-2 suggest elderly males have a higher incidence and death rate ( 7,8 ). Limited information is known about the outcome of patients with cancer who contract this highly communicable disease. Cancer is among the top causes of death. Asia, Europe, and North America have the highest incidence of cancer in the world ( 9 ), and at the moment of the writing of this study the SARS-CoV-2 virus is mainly spreading in these three areas (referred from https://www.cdc.gov/ media/releases/2020/s0226-Covid-19-spread.html ; https://www. nytimes.com/2020/02/27/world/coronavirusnews.html ). Although COVID-19 patients with cancer may share some epidemiologic features with the general population with this disease, they may also have additional clinical characteristics. Therefore, we conducted this study on patients with cancer with coexisting COVID-19 disease to evaluate the potential effect of COVID-19 on patients with cancer.
On the basis of our analysis, COVID-19 patients with cancer tend to have more severe outcomes when compared with the noncancer population. Although COVID-19 is reported to have a relatively low death rate of 2% to 3% in the general population ( 10 ), patients with cancer and COVID-19 not only have a nearly 3-fold increase in the death rate than that Cancer Research.
on November 18, 2021. © 2020 American Association for cancerdiscovery.aacrjournals.org Downloaded from of COVID-19 patients without cancer, but also tend to have much higher severity of their illness. Altogether, these findings suggest that patients with cancer are a much more vulnerable population in the current COVID-19 outbreak. Our findings are consistent with those presented in a previous study based on 18 patients with cancer (4). Because of the limited number of patients with cancer in the previous study, the authors concluded that among patients with cancer, age is the only risk factor for the severity of the illness. On the basis of our data on 105 patients with cancer, we have discovered additional risk factors, including cancer types, cancer stage, and cancer treatments, which may contribute to the severity of the disease among patients with cancer.
Our data demonstrate that the severity of SARS-CoV-2 infection in patients is significantly affected by the types of tumors. From our analysis, patients with hematologic cancer have the highest severity and death rates among all patients with cancer, and lung cancer follows second. Patients with hematologic cancer in our study include patients with leukemia, myeloma, and lymphoma, who have a more compro-mised immune system than patients with solid tumors (11). These patients all had a rapidly deteriorating clinical course once infected with COVID-19. Because malignant or dysfunctional plasma cells, lymphocytes, or white blood cells in general in hematologic malignancies have decreased immunologic function (12)(13)(14), this could be the main reason why patients with hematologic cancer have very high severity and death rates. All patients with hematologic cancer are prone to the complications of serious infection (12)(13)(14), which can exacerbate the condition which could have worsened in patients with COVID-19. In our study, 55.56% of patients with hematologic cancer had severe immunosuppression, which may be the main reason for deteriorated outcomes. Although the small sample size limits representativity of the observation, we believe our finding can serve as an informative starting point for further investigation when a larger cohort from a wide range of healthcare providers becomes available. Among solid tumors, lung cancer is the highest risk category disease in patients with SARS-CoV-2 infection (Fig.  1C). Decreased lung function and severe infection in patients  Cancer Research.
on November 18, 2021. © 2020 American Association for cancerdiscovery.aacrjournals.org Downloaded from with lung cancer could contribute to the worse outcome in this subpopulation (15,16).
In our analysis, we classified the SARS-CoV-2 infectionrelated high risk factors based on death, severe or critical illness, ICU admission, and the utilization of invasive mechanical ventilation. Using these parameters, we detected a multi-fold increase in risk in the cancer population, in contrast to the noncancer population. If there were primary or metastatic tumors in the lungs, patients were more prone to a deteriorated course in a short time. Intriguingly, when patients with cancer had only early-stage disease without metastasis, we did not observe any difference between the cancer and noncancer population in terms of COVID-19related death rate or severity (Fig. 1E). The stage of cancer diagnosis seemed to play a significant role in the severity and death rate of COVID-19.
Patients with cancer received a wide range of treatments, and we also found that different types of treatments had different influences on severity and death when these patients contracted COVID-19. Recently, immunotherapy has assumed a very important role in treating tumors, which aids in treatment of cancer by blocking the immune escape of cancer cells. But in our study, in contrast to patients with cancer with other treatments, patients with immunotherapy had the highest death rate and the highest severity of illness, a very puzzling finding. According to pathologic studies on the patients with COVID-19, there were desquamation of pneumocytes and hyaline membrane formation, implying that these patients had acute respiratory distress syndrome (ARDS; ref. 17). ARDS induced by cytokine storm is reported to be the main reason for death of SARS-CoV-2-infected patients (18). It is possible that in this setting, immunotherapy induces the release of a large amount of cytokines, which can be toxic to normal cells, including lung epithelial cells (19)(20)(21), and therefore lead to a more severe illness. However, in this study the number of patients with immunotherapy was too small; further research with a large case population needs to be conducted in the future.
In addition, COVID-19 patients with cancer who are under active treatment or not under active treatment do not show differences in their outcomes, and there is a significant difference between COVID-19 patients with cancer but not with active treatment and patients without cancer (Supplementary Table S2). These results indicate that COVID-19 patients with both active treatment and just cancer history have a higher risk of developing severe events than noncancer COVID-19 patients. The possible reasons could be due to some known cancer-related complications, for example, anemia, hypoproteinaemia, or dyspnea in early phase of COVID-19 (22). We considered that cancer had a lifetime effect on patients and that cancer survivors always need routine follow-up after primary resection. Therefore, in clinical COVID-19 patient management, equivalent attention needs to be paid to those with cancer whether they are under active therapeutics or not during the outbreak of COVID-19.
This study has several limitations. Although the cohort of COVID-19 patients with cancer is one of the largest in Hubei province, China, the epicenter of the initial outbreak, a larger cohort from the whole country or even from multiple countries will be more representative. Large-scale national and international research collaboration will be necessary to achieve this. At the initial stage of the outbreak, data collection and research activities were not a priority of the hospitals. Therefore, it was not possible to record and collect some data that are potentially informative for our analysis in a timely manner. In addition, due to the urgency of clinical treatment, medical data used in this study were largely disconnected from the patients' historical electronic medical records, which are mostly stored with a different healthcare provider than the medical center providing COVID-19 care. This left us with limited information about each patient.
Our study is the midsize cohort study on this topic and will provide much-needed information on risk factors of this population. We hope that our findings will help countries better protect patients with cancer affected by the ongoing COVID-19 pandemic.

Study Design and Patients
We conducted a multicenter study focusing on the clinical characteristics of confirmed cases of COVID-19 patients with cancer in 14 hospitals in Hubei province, China; all of the 14 hospitals served as government-designated hospitals for patients diagnosed with COVID-19 (listed in the Supplementary Data). COVID-19 was diagnosed according to the WHO interim guidance (23). Patients with cancer confirmed with COVID-19 who were hospitalized from January 1, 2020, to February 24, 2020, were enrolled. SARS-CoV-2-infected patients without cancer matched by the same hospital and hospitalization time were randomly selected as our control group. In addition, as age is one of the major predictors of severity of respiratory diseases like COVID-19 (4), we excluded from our analysis 117 younger COVID-19 patients without cancer so that median ages of patients with cancer (median = 64.0, IRQ = 14.00) and patients without cancers (median = 63.5, IQR = 14.00) would be comparable. Four clinical outcomes were monitored up to February 24, 2020, the final date of follow-up. This case series was approved by the Institutional Ethics Board of Zhongnan Hospital of Wuhan University (Wuhan, Hubei, China, No. 2020029). It is worth pointing out that because of limited resources and information available in early stages of this outbreak, sample sizes of some subgroups were small and collection of data for patients with better matched clinical characteristics was not possible. This limited this study design.

Procedures
Medical records of patients were acquired by the data collection team of the above 14 hospitals. A team of physicians who had been taking care of patients with SARS-CoV-2 infection reviewed the data. We used a standardized case-report form to collect clinical data. Primary cancer characteristics and detailed treatment information were extracted from past medical records by oncologists in the Hubei Anti-Cancer Association. Data were entered into a computerized database. Cases with insufficient records of previous disease history were excluded. Information collected included demographic data, medical history, comorbidities, symptoms, vital signs, routine blood test, and chest CT scans. Only cancer treatments within 40 days before the onset of COVID-19 symptoms were considered for this study. Each patient's medical record was reviewed by at least two oncologists. Our institutional ethics review board approved the study and waived the need for informed consent.

End Points and Assessments
There were four primary outcomes analyzed in this study: death, admission into the ICU, development of severe or critical symptoms, and utilization of invasive mechanical ventilation. The clinical definition of severe/critical symptoms follows the 5th edition of the 2019 Novel Coronavirus Disease (COVID-19) Diagnostic Criteria published by the National Health Commission in China, including septic shock, ARDS, acute kidney injury, disseminated intravascular coagulation, and rhabdomyolysis.

Statistical Analysis
The aim of this study was to report clinical outcomes of COVID-19 patients with cancer. For categorical data, percentages of patients in each category were calculated. The Wilcoxon rank sum test was used to compare continuous data, and the Fisher exact test was used to compare categorical data from different categories without multitest adjustment. Multivariate logistic regression was used to estimate ORs and 95% CIs of each factor of interest with outcomes after data was normalized using Z-scores. The ORs were adjusted by age, sex, diabetes, hypertension, smoking, and COPD at admission. Time from onset of symptoms to severe outcomes was investigated using survival analysis, with follow-up from initial onset of symptoms until February 24, 2020. Multivariate Cox regression was conducted to estimate the HRs and their corresponding 95% CI. Similar to logistic regression, Cox regression was adjusted by age, sex, diabetes, hypertension, smoking, and COPD at admission. The Kaplan-Meier product-limit estimator was used to conduct survival analysis. All survival analyses were conducted using Lifelines 0.24.0 in Python environment.