Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, retrospective, cohort study
In this multicentre, retrospective, cohort study, we included all adult patients (aged ≥18 years) with any type of malignant solid tumours and haematological malignancy who were admitted to nine hospitals in Wuhan, China, with laboratory-confirmed COVID-19 between Jan 13 and March 18, 2020. Enrolled patients were statistically matched (2:1) with patients admitted with COVID-19 who did not have cancer with propensity score on the basis of age, sex, and comorbidities. Demographic characteristics, laboratory examinations, illness severity, and clinical interventions were compared between patients with COVID-19 with or without cancer as well as between patients with cancer with non-severe or severe COVID-19. COVID-19 disease severity was defined on admission on the basis of the WHO guidelines. Univariable and multivariable logistic regression, adjusted for age, sex, comorbidities, cancer type, tumour stage, and antitumour treatments, were used to explore risk factors associated with COVID-19 disease severity. This study was registered in the Chinese Clinical Trial Register, ChiCTR2000030807.Findings Between Jan 13 and March 18, 2020, 13077 patients with COVID-19 were admitted to the nine hospitals in Wuhan and 232 patients with cancer and 519 statistically matched patients without cancer were enrolled. Median follow-up was 29 days (IQR 22–38) in patients with cancer and 27 days (20–35) in patients without cancer. Patients with cancer were more likely to have severe COVID-19 than patients without cancer (148 [64%] of 232 vs 166 [32%] of 519; odds ratio [OR] 3·61 [95% CI 2·59–5·04]; p<0·0001). Risk factors previously reported in patients without cancer, such as older age; elevated interleukin 6, procalcitonin, and D-dimer; and reduced lymphocytes were validated in patients with cancer. We also identified advanced tumour stage (OR 2·60, 95% CI 1·05–6·43; p=0·039), elevated tumour necrosis factor α (1·22, 1·01–1·47; p=0·037), elevated N-terminal pro-B-type natriuretic peptide (1·65, 1·03–2·78; p=0·032), reduced CD4+T cells (0·84, 0·71–0·98; p=0·031), and reduced albumin–globulin ratio (0·12, 0·02–0·77; p=0·024) as risk factors of COVID-19 severity in patients with cancer.Interpretation Patients with cancer and COVID-19 were more likely to deteriorate into severe illness than those without cancer. The risk factors identified here could be helpful for early clinical surveillance of disease progression in patients with cancer who present with COVID-19.
DiscussionIn face of the COVID-19 pandemic, research is urgently needed to guide the implementation of effective pre-vention and control measures for susceptible populations. Here, by integrating clinical data from nine hospitals, we found that patients with cancer infected with SARS-CoV-2 have an increased risk of developing severe COVID-19. Furthermore, in addition to previously reported risk factors for this population, such as older age and elevated IL-6, procalcitonin, and D-dimer, we identified novel risk factors including advanced tumour stage, elevated TNF-α and NT-proBNP, and decreased CD4+ T cells and albumin–globulin ratio.Our enrolled patients without cancer were statistically matched to those with cancer, which helped to minimisethe effects of common confounders such as age, sex, and other comorbidities on the severity of COVID-19. The lower prevalence of sore throat and coryza and increased prevalence of dyspnoea and expectoration in patients with cancer compared with those without cancer are in line with the findings of previous studies,13 and might be due to patients’ subjective perception of their disease severity. Moreover, in most situations, CT images of chest lesions in patients with COVID-19 pneumonia is explicitly different from those of lung cancer or metastasis in distribution, density, and size.14 Notably, all patients in our current study were symptomatic for COVID-19; therefore, a screening or an epidemiological study in the patients with cancer is warranted to understand the rate of asymptomatic infection.We used unconditional logistic regression methods to explore the factors related with COVID-19 severity in patients with cancer. Risk factors reported previously in patients without cancer, such as older age; elevated IL-6, procalcitonin, D-dimer, and C-reactive protein; and decreased lymphocytes were validated in patients withcancer. Additionally, we identified several risk factors for COVID-19 severity in patients with cancer, including advanced tumour stage, elevated TNF-α and NT-proBNP, and decreased CD4+ T cells and albumin–globulin ratio. Older age has previously been reported as an important independent predictor of mortality in severe acute respiratory syndrome (SARS), Middle East respiratory syndrome, and COVID-19.15–17 Moreover, we observed that advanced tumour stage aggravates COVID-19 pro-gression, which might be due to the tumour burden. Among the measured cytokines, elevation of IL-6 was most pronounced, consistent with recent published studies.18,19 It is known that IL-6 plays multifaceted roles in regulation of vascular leakage, complement activation, and coagulation pathways, which ultimately causes poor outcomes for acute respiratory distress syndrome, multiple organ dysfunction syndrome, and SARS.20–22TNF-α, a potential novel biomarker for COVID-19 identified here, has been reported to facilitate the apoptosis of both lung epithelial cells and endothelial cells, ultimately resulting in vascular leakage, alveolar oedema, and hypoxia.23 TNF-α has also been reported to mediate airway hyper-responsiveness and pathogenesis in influenza and SARS-CoV infection.24 Additionally, TNF-α was originally identified as an effective medi-ator inducing haemorrhagic necrosis in tumours.25Collectively, these findings help to explain our results showing that TNF-α, compared with indicators such as C-reactive protein and D-dimer, might be more predictive for COVID-19 severity, especially in patients with cancer.Reduced CD4+ T cells in patients with COVID-19 has been confirmed by Qin and colleagues, revealing that an immunosuppression feature is pronounced in severe COVID-19 cases.19 A rapid and well coordinated innate immune response is the first line of defence against viral infections. CD4+ T cells can enhance the ability of cytotoxic T cells to clear pathogens.26 However, persistent stimulation by the virus might induce T-cell exhaustion and facilitate host immune response disorders, causing excessive inflammation and even death.23,27 Notably, in addition todysregulated inflammatory and immune responses, organ damage biomarkers such as elevated NT-proBNP and decreased albumin–globulin ratio, were also associated with COVID-19 severity, as has been confirmed by other studies.28 Collectively, these findings suggest that aggravated inflammatory storm, dysregulated immune responses, and multiple-organ damage appear to be possible mechanisms in patients with cancer with severe COVID-19.Successful standardised treatment protocols for patients with COVID-19, especially with severe disease, must be recommended globally to curb poor outcomes. Here, we found that clinical interventions, especially ventilation treatments (high-flow nasal cannula oxygen or mechanical ventilation), were more intensive in patients with cancer than in patients without cancer.In particular, more than 75% of patients with cancer and COVID-19 received antiviral treatment and antibiotics, and approximately a third of patients received immuno-modulators. Several clinical trials are underway to define potential roles for antiviral agents (remdesivir, lopinavir, or ritonavir)29 and specific immunomodulators such as IL-6 receptor blockade (tocilizumab; ChiCTR2000029765) in COVID-19. Interactions between several chemotherapy agents and antiviral drugs need to be considered when treating patients with cancer and COVID-19;30 the sample size in our study was too small to permit this analysis. In view of the uncontrolled inflammatory responses, impaired adaptive immune responses, and multiple-organ dysfunction in patients with cancer and COVID-19—especially those with severe COVID-19—the current management of COVID-19 should be focused on inflammatory reaction and immune dysfunction, sup-portive care including ventilatory support, and treatment of complications.Based on our findings, three major strategies for the management of patients with cancer during this COVID-19 crisis are warranted. First, robust personal protection provisions should be made for medical staff, patients with cancer, and cancer survivorsto avoid cross-infection. Second, intentional postponement of adjuvant chemotherapy or elective surgery for stable cancer should be considered in endemic areas, but oral medications should continue to be administered. Third, more inten-sive surveillance should be considered for patients admitted with COVID-19 who have cancer, especially older patients or those with other comorbidities.Our study has several limitations. First, owing to its retrospective design, it lacks dynamic clinical and laboratory data. Second, the potential mechanisms of dysregulated inflammatory cytokines and immune responses were not fully explored and need to be further investigated. Third, our study recruited all available patients with any type of malignant solid tumours and haematological malignancy, but included two patients with basal cell carcinoma and three cancer survivors who had disease-free survival for more than 5 years. Finally, the enrolled patients with cancer represent a mixed sample of multiple cancer types; further studies by cancer type are still needed.To our knowledge, this study is the largest multicentre cohort study so far among patients with cancer and COVID-19, providing detailed clinical and laboratory information. This study highlights that risk factors including elevated TNF-α and NT-proBNP and decreased CD4+ T cells or albumin–globulin ratio would be helpful for early surveillance of disease progression, in addition to previously reported risk factors of older age; elevated IL-6, procalcitonin, and D-dimer; and decreased lymphocytes.
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