Malignancy history had no marked effect on the prognosis of COVID-19: A cohort study

Background Primary disease inuenced the prognosis of coronavirus disease 2019 (COVID-19), but the clinical characters of patients accompanied with tumor were few reported. Methods We enrolled 528 COVID-19 patients. Date of laboratory tests and outcome were divided to corresponding groups to compare the risk factors of disease severity, progression and survival. Results The disease severity at hospitalization, progression rate (51.43% vs 54.42%) and mortality (19.51% vs 11.91%) were equal between tumor and non-tumor group. In both groups, lymphopenia was negatively related to the severity grading (OR = 0.019 and 0.168 separately), NLR was positively correlated with the poor outcome (OR = 1.371 and 1.155 separately), and CRP was relevant to the disease progression and survival (OR = 1.334 and 1.303 separately). history may have no marked effect on the severity and prognosis of COVID-19. Lymphopenia, NLR and CRP levels could be regarded as indicators to determine severe cases, and predict progression and survival. lymphocyte count and albumin. Lymphopenia was negatively related to the determination of severity at hospitalization both in patients with and without tumor; NLR was positively correlated with the poor outcome in either group. CRP was relevant to the disease progression and survival. ALB was related to disease progression in tumor group, and severity in non-tumor group.


Introduction
Since December 2019, the Wuhan city, in the center of China, was attacked by a novel coronavirus which was later designated as severe acute respiratory syndrome coronavirus 2, (SARS-CoV-2). This coronavirus Infect patients of all ages, exhibiting multiple systemic in ammations, included severe viral pneumonia with respiratory failure and even death, called coronavirus disease 2019 (COVID-19) by WHO 1-3 (Huang C, Chen N, Guan WJ). Until July 21th 2020, there were 12579569 con rmed cases of SARS-CoV-2 infection worldwide, including 559049 deaths 4 .
With increasing understanding of this pandemic, a large amount of publications have precisely described the demographic, clinical features, illness severity grading and prognosis of COVID-19. Noteworthily, comorbidities were frequently present in 30-40% of patients, while the most common were hypertension, diabetes and coronary heart disease 5 . These comorbidities were con rmed as predictors to assess the clinical severities. Among which, malignancy was little mentioned and rarely reported, as their minor proportion in hospitalized COVID-19 patients. As Guan at al. reported, together with chronic obstructive pulmonary disease (COPD), hypertension and diabetes, malignancy was one of the risk factors of disease severity 6 . While another Meta-analysis suggested that there was no correlation between malignant tumor and COVID-19 patients' aggravation 7 . Few studies only reported the epidemiological data or overall outcome of this particular population [8][9][10] . Here we focused on this minor population to explore the distinguishing laboratory feature in SARS-CoV-2 infected patients with tumor.

Study design and participants
This retrospective cohort study included 528 COVID-19 patients from February 5 to March 10, 2020,

Data Collection
Demographic, clinical, laboratory and outcome data were extracted from electronic medical records using a standardized data collection form. All data were collected by experienced clinicians and checked by two researchers independently.
Procedures SARS-CoV-2 infection was con rmed by positive next-generation sequencing or real-time RT-PCR methods of respiratory specimens as previously described 12 . Routine laboratory examinations included blood examinations, coagulation and biochemical tests. The clinical outcomes were evaluated by two experienced clinicians.

De nitions
The disease severity of COVID-19 was de ned according to the guideline of Chinese NHC 11 . Brie y, moderate grade was de ned as patients with fever, respiratory symptoms and lung CT changed, but oxygen saturation exceeded 93% without oxygen; severe grade signi es respiratory frequency ≥ 30 times/minute, blood oxygen saturation ≤ 93%, oxygenation index ≤ 300 mmHg, and/or lung in ltration progression > 50% within 24 to 48 hours; and critical grade was de ned as appearance of respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Poor progression included moderate grade progressed to severe or critical grades and even death. Statistical Analysis SPSS software (version 22.0) was used to analyze the data. Shapiro wilktest method was used to determine the distribution of continuous variables. Student-t test was used to test the score difference of each group in the normal distribution, and rank sum test was used to compare the difference in the normal distribution. The normal distribution measurement data is expressed by mean ± standard deviation (SD), and median (interquartile Range IQR) for the non-normal distribution data. Frequency (percentage) was used to express the counting data. Chi-square test was used to compare the distribution differences among groups. When the number of predicted cases was less than 5, Fisher accurate probability method was applicated. The signi cant factors of univariable analysis were included into multivariable logistic regression model. A two-sided α of less than 0.05 was considered statistically signi cant.  1). The gender distribution didn't show signi cant difference. As for the Laboratory ndings, tumor group showed signi cant higher levels of white blood count (WBC), neutrophil count (NEUT), neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) than non-tumor group, but lymphocyte count (LY) and the level of serum albumin were lower in tumor group (table 1). The level of D-dimer in tumor group was elevated than non-tumor group, however, it did not showed any signi cance in the multivariable regression analyze (data not shown). Of the 35 (85.37%) moderate patients in tumor group, 18 (51.43%) experienced poor progression during subsequent hospitalization; while in non-tumor group, this proportion was 240 (54.42%) progression in 441 (90.55%) moderate patients. We observed no obvious difference in disease progression between two groups. In terms of mortality, our data still showed no signi cant difference (19.51% vs 11.91%, p=0.16, table 1).

Different characteristics of moderate and severe patients on admission
As in the early stage of COVID-19, most patients were mild or moderate, and the majority of mild patients were admitted to the Fangcang shelter hospitals. So almost all the patients admitted in our hospital during this period were moderate or severe cases. We explored the differences between moderate and severe patients at admission separately in patients with tumors and without tumors (  [11.34-13.30], p=0.031). Based on the results of univariable logistic regression, factors with p <0.05 were included for the multivariable logistic regression, only LY was negatively related to the severity (p=0.044). In non-tumor group, the levels of LY, NLR, D-dimer, CRP, and serum albumin were all signi cant different between moderate and severe patients. Then we did the multivariable regression and found only lower levels of LY and serum albumin were associated with the severity in COVID-19 patients without tumor.
Risk factors associated with poor progression among moderate patients It was reported that almost 20% of COVID-19 patients with mild or moderate early presentation can develop severe or critical grade 13 . To further con rm the risk factors associated with poor progression among early moderate patients, we enrolled 476 moderate patients including 35 (7.35%) patients with tumor and 441 (92.65%) patients without tumor (table 1). According to the disease development, they were divided into two subgroups, stabilization and poor progression group (  (table 3).

Risk factors associated with death in-hospital
We divided patients into survivor group and non-survivor group. The mortality was 19.51% in tumor group (table 1). The median age of non-survivors was 72 years old (IQR 71-80), elder than survivors (63, IQR 55-70) (p=0.006, table 4). But in multivariable logistic regression, this difference was meaningless; while higher NLR and CRP level were risk factors associated with death in-hospital among tumor patients (p=0.027 and 0.029 separately). In patients without tumor, older age, male, higher NLR and CRP were risk factors related to death in-hospital (table 4).

Discussion
In this retrospective study, we analyzed the data of 528 COVID-19 infected cases admitted in our hospital, which were divided into two groups, 41 patients accompanied with different tumors and 487 patients without tumor. The objective of this study was to compare the laboratory characteristics of these two groups and to explore risk factors for disease progression and survival separately.
Recent studies have indicated that lymphocyte count played a key role of severe or critical COVID-19 patients 14,15 . Lymphopenia is a common feature and thought to be a critical factor associated with disease severity and mortality 16 . In our study, we found severe patients were more likely accompanied by lymphopenia on admission, con rmed by univariable and multivariable logistic regression analyze, which is consistent with the results of Qin et al 17 . Absolute counts of lymphocytes on admission were lower in severe patients when compared to moderate patients both in tumor group and non-tumor group. We found lymphopenia was valuable in determination the severity of COVID-19 patients. Besides, lymphocytes count was signi cant lower in tumor group related to non-tumor group.
The NLR in peripheral blood was a well-known marker of systemic in ammatory responses. Even though the underlying mechanisms are not fully known, it has been con rmed that circulating neutrophil counts were elevated above the normal range in tumor patients 18 . Elevated NLR has been observed in multiple solid cancers, including pancreas cancer 19 , non-small cell lung cancer 20 , cervical adenocarcinoma 21 , glioma 22 , and thought to be related to poorer survival, as well as to predict tumor grade 23 and distinguish between tumor recurrence and pseudoprogression in high-grade gliomas 24 .
As it has been reported that the increase of NLR was associated with more serious infections 17,25 , and identi ed as an independent risk factor for COVID-19 patients with severe illness 26 . Our results con rmed the increase of NLR was positively correlated with the poor outcome both in tumor and non-tumor group by multivariable logistic regression analysis. In general, the NLR in tumor group was signi cantly elevated in contrast to the other group.
Kaya et al. reported the in ammatory cytokines secreted by tumor cells caused the neutrophil count to increase, both in tumor stroma and in peripheral blood. The increase in the neutrophil count may cause a decrease in lymphocytes and lymphocyte apoptosis, as a result cellular immunity is depressed 27 . This interaction between neutrophils and lymphocytes probably explained the increased neutrophil and NLR level with decreased lymphocyte count in tumor group.
Serum albumin is an indicator of nutritional status, and hypoalbuminemia re ects undernourished state in the elderly, patients with chronic diseases and cancer 28 . In patients with in ammatory conditions, serum albumin levels were signi cantly reduced and negatively correlated with disease severity 29 . We showed coherent result in non-tumor group by univariable and multivariable logistic regression analyze. Tumor patients are frequently combined with cachexia in various degrees according to tumor type and stage 30 . One of the most characteristic biochemical indicators of cachexia is hypoalbuminemia. It has been reported that patient with serum-albumin < 35 g/L was associated with reduced quality of life and immune function, while serum-albumin < 32 g/L with shorter survival 29,31 . Logically, we found reduced serum albumin in tumor group in our study, and albumin level was negatively related to in ammatory progression in COVID-19 patients with tumor.
Serum CRP, a sensitive and acute-phase protein synthesized by hepatocytes following stimulation by various cytokines, including tumor necrosis factor-α and interleukin (IL)-6, markedly increase within several hours of infection or in ammation. CRP ≥ 5 mg/dl was considered as an important evidence of severe in ammation. Elder patients with higher CRP had higher in-hospital mortality with a RR of 2 compared with lower CRP group 32 . Furthermore, CRP level is regarded as a useful marker of systemic in ammation and a key feature of cancer cachexia. CRP > 1 mg/dl was associated with reduced immune function and shorter survival in tumor patient 31 . The production of CRP was elevated in tumor patients with cachexia 30 . Similarly in our results, CRP was positively associated with poor progression and death in both tumor and non-tumor group. CRP level of non-survivors and progression cases in tumor group was superior to 5 mg/dl (median of 10.44 and 5.19 separately). It's worth mentioning that tumor cells could also affect the production of CRP, which caused more incidence of hyper in ammation. Studies showed that pro-in ammatory cytokines are produced not only by in ammatory cells, but also by tumor cells. Among which, IL-6 was widely involved 33 . In consequence, CRP level in tumor patients was logically elevated.
Our data represented that COVID-19 patients with tumor showed elevated NLR, CRP levels and more severe lymphopenia and hypoalbuminemia compared with patients without tumor. All these biochemical indicators signi ed higher probability of infection progression possibility and mortality. Actually in our study, we showed discordant results: we observed the tendency of increased mortality in tumor group (19.5% vs 11.9%), but was not statistically signi cant. Meanwhile, the severity grading and progression rate was similar in COVID-19 patients with and without tumors. One explanation might be that patients with cancer could experience systemic immunosuppressive states caused by both cancer and anticancer

Conclusion
Our analyze showed the disease severity at hospitalization, progression rate and mortality were equal between tumor and non-tumor group. As one of combined diseases, malignancy history may have no marked effect on the severity and prognosis of COVID-19. Nevertheless, leucocyte count, neutrophil count, NLR, CRP and D-dimer levels were elevated in COVID-19 patients with cancer, with lower level of lymphocyte count and albumin. Lymphopenia was negatively related to the determination of severity at hospitalization both in patients with and without tumor; NLR was positively correlated with the poor outcome in either group. CRP was relevant to the disease progression and survival. ALB was related to disease progression in tumor group, and severity in non-tumor group.
There were some limitations in this study. First, due to the rapid pandemic outbreak and the shortage of medical workers, not all historical electronic medical records of patients were completely connected, thus a main limitation was the self-report of medical history by patients on admission. The clinical staging and precise treatment protocols were imprecise or even unavailable. We could not conclude the effect of forepassed application of radiotherapy (especially in lung cancer) or chemotherapy agent to the progression the COVID-19. Secondly, the time from onset to progression couldn't be analyzed as a risk factor because of the incomplete data about the length of time before hospital admission. Besides, due to the retrospective study design, not all laboratory tests were performed in each patient, immunological indicators as IL-6, IL-17A, CD4 + T cell, and CD8 + T cell in particular. Therefore, profound immunological alterations were not concluded. Moreover, our study was single-central and small-sized with biased patient characteristics, these may make it di cult to generalize the result, larger sample population of multiple centers will be more representative.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
There was no funding for the study.