Cancer patients/survivors, lymphocytes, and severe COVID-19

doi:10.21203/rs.3.rs-22283/v1

There is a heated debate on whether the cancer survivors have worse outcomes in corona virus disease 2019 (COVID-2019). This study showed that both cancer survivors and cancer patients have decreased lymphocytes, partially explaining why these patients were associated with poorer prognosis in severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) in principle. Therefore, patients with cancer history, whether they are going active treatment or not, deserve special attention.

Oncology

Infectious Diseases

SARS-CoV-2

cancer survivors

cancer patients

decreased lymphocytes

The coronavirus disease 2019 (COVID–2019) has become a pandemic, causing 823,626 confirmed cases and 40,598 deaths according to WHO, as of Apr 1, 2020.¹ Previously we published a nationwide study in China indicating that cancer patients were associated with poorer outcomes during COVID–19 caused by SARS-CoV–2 infection.² Seventy-five percent (12/16) of COVID–19 patients in our study were cancer survivors who received no active treatments, which was similar to the proportion (58.3%, 7/12) reported recently by Yu et al.³ A considering number of scholars have proposed that cancer patients or cancer survivors receiving no active treatment might not have significant immune suppression, therefore, these patients are not predisposed to the higher susceptibility or poorer prognosis of COVID–19.^3–5Hence, we sought to investigate the immune level among these patients.

In the healthy population, we observed a negative linear correlation between age and lymphocyte count (r = –0.74, r² = 0.54, Figure S1).. The changes in lymphocyte count and NLR of each patient were summarized in Figure S2. The average lymphocyte count and NLR of each category were shown in Table S1 and were illustrated in Figure 1A–1C. We found that, within 6 months after surgery for lung cancer, lymphocytes decreased significantly, then recovered gradually, but lower than the preoperative levels. Similar trends were observed among patients with or without adjuvant chemotherapy. In contrast, there was no short-term decline in patients with benign pulmonary nodules after surgery

By studying the 16 cases with cancer history in the nationwide cohort of COVID–19 (baseline features shown in Table S2),, we found that the cancer survivors had a high risk of critical illness after adjusting other confounders compared with patients with no cancer history, and had a prognosis closer to cancer patients rather than non-cancer patients (cancer survivors: HR 3.55, 95% CI, 1.43 to 8.82; cancer patients, HR 4.92, 95% CI 1.12–21.6; Figure 1D, Table 1)..

We have acknowledged that age was the most important determinant of prognosis among COVID–19 patients. In the healthy population, we observed a negative linear correlation between age and lymphocyte count, which provided an indirect support for using lymphocyte count to assess the risk of severe COVID–19.

The lymphocyte count from postoperative cancer survivors and from patients with advanced lung cancer were both lower than healthy people. This implied that the immunity of cancer survivors was compromised, which persisted over time, regardless of receiving adjuvant chemotherapy or not. The uncontrolled virus infection in immune-compromised patients will cause extensive cell damages and induce T cell exhaustion even cytokine storm, which are common reasons for critical illness. Some recent studies showed that the cytokines were negatively associated with lymphocyte count.^6,7 Interestingly, there was no short-term decline in patients with benign pulmonary nodules after surgery, suggesting that this decline in immunity may not be related to the surgery per se. Taken together, we assumed that this was due to the interaction between cancer and surgical trauma, which warrants further investigation.

In summary, we showed that both cancer survivors and patients might have reduced lymphocytes, partially explaining why these patients were associated with poorer prognosis in SARS-CoV–2 infection in principle. Patients with cancer history who are not undergoing active treatment should also deserve special attention.

To study the immune level of patients in different status, we have collected the pre-and post-operative complete blood counts (CBCs) of patients who underwent resection for stage I to IIIA lung cancer (N = 4,313) or benign non-infection pulmonary nodules (N = 52) in our center from 2013 to 2018. In addition, CBCs from healthy patients (retrieved from annual checkup reports) (N = 144,983) and patients with advanced lung cancer before and after chemotherapy (N = 3,238) during the same period were used as controls. Postoperative CBCs tested after cancer recurrence were excluded.

We analyzed the absolute lymphocyte count and neutrophil-to-lymphocyte ratio (NLR), which can be considered as one of the measures for immune status, because lymphocytes are essential to our defense against virus and cancer, and both lymphocyte count and NLR have been proved as important prognostic factors in patients with cancers or virus infection.^8–11

In addition, to illustrate the prognosis of cancer survivors who had COVID–19, we collected and analyzed a nationwide cohort of 1,590 COVID–19 cases from 575 hospitals in China as of Jan 31^st. Details in data collection and processing were provided in previous publication² and the appendix (p1).. A cox regression model was used to study the impact of cancer status on risk for critical illness with adjustment for age, other comorbidity, and smoking.

Acknowledgements

We declare no competing interests. This study was approved by the ethics committee of the First Affiliated Hospital of Guangzhou Medical University. Because this is a retrospective study,the ethical committee approved the study and waived the informed consent requirement. We sincerely thank all the hospital for providing data, on behalf of China Medical Treatment Expert Group for COVID–19. We thank Meng Shu in Janssen Research and Development, Qiang Lin and Wei Shen in Yitu Technology for the great support in processing the data. This study is supported by the China National Science Foundation (grant no 81871893) and the Key Project of Guangzhou Scientific Research Project (grant no 201804020030).

Author Contributions

H. J. and L. W. conceived of and designed the study. L. W., L. C. and L. J. developed the methodology. H. J., L. W., L. C., L. J., X. S., Z. R., C. B., O. L., C. Z., H. Q., X. Z. and L. J. acquired the data. L. W., L. C., L. J., and X. S. analyzed and interpreted the data. L. W., L. C., L. J. and X. S. wrote the manuscript.

Competing Interests statement

All authors declare no competing interests.

WHO. Novel coronavirus (COVID–19) situation reports. Available: https://www.who.int/emergencies/diseases/novel-coronavirus–2019/situation-reports [Accessed 1 Apr 2020]
Liang W. et al. Cancer patients in SARS-CoV–2 infection: a nationwide analysis in China. Lancet Oncol. 21, 335–337 (2020).
Yu J. et al. SARS-CoV–2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China. Jama Oncol. Published online March 25, 2020. doi:10.1001/jamaoncol.2020.0980
Xia Y, Jin R, Zhao J, Li W, Shen HH. Risk of COVID–19 for cancer patients. Lancet Oncol. Published online: March 3, 2020. doi:10.1016/S1470–2045(20)30150–9
Wang HP, Zhang L. Risk of COVID–19 for patients with cancer. Lancet Oncol. Published online: March 3, 2020. doi:10.1016/S1470–2045(20)30149–2
Liu J. et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV–2 infected patients. Medrxiv.org. Preprint at https://doi.org/10.1101/2020.02.16.20023671
Wan SX, Yi QJ, Fan SB, et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). Medrxiv.org. Preprint at https://doi.org/10.1101/2020.02.10.20021832
Sarraf KM. et al. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg. 137, 425–8 (2009).
Feng F. et al. Low lymphocyte count and high monocyte count predicts poor prognosis of gastric cancer. BMC Gastroenterol. 18, 148 (2018).
Wu KS. et al. Comparison of clinical characteristics of amebic liver abscess in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. J Microbiol Immunol Infect. 41, 456–61 (2008).
Zhang Y. et al. Neutrophil-lymphocyte ratio as an early new marker in AIV-H7N9-infected patients: a retrospective study. Ther Clin Risk Manag, 15, 911–919 (2019).

Table 1. Cox regression for risk factors of critically-ill COVID-19

Variables	Hazard ratio	95% confidence interval		P value
		lower	upper
Cancer history				0.003
No cancer (reference)
Cancer survivors	3.548	1.426	8.824	0.006
Current cancer patients	4.917	1.119	21.597	0.035
Age	1.039	1.025	1.053	0
Any other comorbidity (yes vs. no)	1.978	1.335	2.929	0.001
Smoking (yes vs. no)	1.519	0.902	2.559	0.116

*, other comorbidities include chronic obstructive pulmonary disease (COPD), diabetes mellitus, hypertension, coronary heart disease, cerebrovascular disease, viral hepatitis type B, chronic kidney disease and immunodeficiency.

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Cancer patients/survivors, lymphocytes, and severe COVID-19

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Abstract

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Introduction

Results

Discussion

Methods

Declarations

Acknowledgements

Author Contributions

Competing Interests statement

References

Table

Supplementary Files

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