Demographic and clinical characteristics of patients
Records of 3,057 patients with confirmed Coronavirus disease 2019 (COVID-19) infection were collected from the Wuhan Huoshenshan Hospital between February 4 and April 11, 2020. Thirteen patients (0.43%) who suffered from lung cancer and 52 matched patients were enrolled. The demographic and clinical features of these patients are shown in Table 1. The median (IQR) age of lung cancer patients was 65 (63-72) years, and 10 (76.9%) of them were men. The most common comorbidities were hypertension and diabetes observed in 30.8% patients. No significant differences were found in age, sex, and main symptoms and signs between the case and control groups. Further, the most prevalent symptom among the 65 enrolled patients was fever (n=50, 76.9%), followed by cough (n=41, 63.1%), fatigue (n=30, 46.2%), and shortness of breath (n=26, 40.0%).
Lung cancer patients were more likely to have dyspnea (15.4% vs. 1.9%; P=0.040) than the other groups (Table S1). Five of these patients were long-term survivors, and none of them was diagnosed with stage IV cancer. All patients received at least one kind of antitumor treatment, including surgery (n=7, 53.8%), chemotherapy (n=6, 46.2%), epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy (n=2, 15.4%), anti-angiogenesis therapy (n=1, 7.7%), and radiotherapy (n=2, 15.4%), while none of the long-term survivors received treatment within past 3 months. The percentage of long-term survivors who underwent surgery was four-fold higher than that of short-term survivors (100.0% vs. 25.0%, P=0.011). No difference was observed in comorbidities and symptoms between long- and short-term survivors (Table S1).
During treatment, development of severe infection was more common among lung cancer patients (Wilcoxon’s rank-sum test, P=0.064) (Table 2). The duration of symptoms before hospital admission in lung cancer patients was 10.5 (10.0-17.5) days, which was significantly shorter than that observed in other patients (30.0 [14.0-35.0]; Wilcoxon’s rank-sum test, P=0.016) (Table 2). Moreover, the average time to clinical improvement in lung cancer patients was 12 (11.0-18.0) days, which was 4 days longer than that observed in non-cancer patients (5.8-14.0) (Wilcoxon’s rank-sum test, P=0.020) (Table 2). The mortality (7.7%, 1/13) observed in our study was higher than that reported in the general population (2.3%) and lower than that (18.18%; 4/22) noted in a multicenter study1,2. There were no differences among indicators such as time from symptoms to hospitalization and symptom remission time between long-term and short-term survivors (Table S2). These findings suggested that lung cancer patients represent a highly vulnerable group to the current COVID-19 outbreak.
ACE2 and TMPRSS2 are overexpressed at resection margins of lung cancer patients
Several studies have shown that coronaviruses enter cells via binding of the viral spike (S) proteins to cellular receptors ACE2 and following S protein priming by host cell proteases. TMPRSS2 as a transmembrane protease can induce the virus-plasma membrane fusion3,4. Hoffmann and coworkers recently demonstrated that Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming5,6. ACE2 is broadly expressed in epithelial cells7. We then evaluated if resection margins of lung cancer harbor more epithelial cells. We collected three resection margin tissues from lung cancer and three other non-cancerous lung tissues (Table S3). We performed IHC to investigate the population of epithelial cells among the two groups, and found that the percentage of the stained area was much higher in the resection margin tissues than in the non-cancerous tissues (Figure 1A, B).
We analyzed single-cell sequencing data from the existing research8 and found that the epithelial cells at the resection margin of lung cancer were more likely to highly activate the genes related to lung cancer, such as KRAS, MET, and EGFR (Figure 1C, D). The genomic instability of these cells inferred by inferCNV in the resection margin was much higher than that in the normal tissues (Figure 1E), and these cells had stronger capability for invasion and infiltration (Figure 1F). These findings suggested that the cells at the margin of resection were more likely to be a sort of tumor-like cells.
The proportion of epithelial cells expressing ACE2 and TMPRSS2 was higher at the resection margin of lung cancers than in normal tissues (Figure 1G), suggesting that the resection margins of lung cancer tissues were still more susceptible to COVID-19 infection. We also analyzed the expression of ACE2 in resection margin tissues of lung cancer survivors and normal lung tissues from general individuals using The Cancer Genome Atlas (n=110) and GTEx (n=288) databases and found that the mRNA expression of ACE2 was higher in lung cancer patients than in general individuals (Wilcoxon’s rank-sum test, P=0.013) (Figure 1H). The expression of TMPRSS2, the co-factor of ACE2, was also significantly higher in lung cancer patients than in the general population (Wilcoxon’s rank-sum test, P<0.001) (Figure 1H), suggesting that patients with lung cancer were more likely to be susceptible to COVID-19.