key: cord-0756112-i1nehm61
authors: Wei, Xiuqi; Su, Jingyu; Yang, Kunyu; Wei, Jiazhou; Wan, Huimin; Cao, Xiaoling; Tan, Wenbin; Wang, Hui
title: Elevations of serum cancer biomarkers correlate with severity of COVID‐19
date: 2020-04-29
journal: J Med Virol
DOI: 10.1002/jmv.25957
sha: 1f2ac1962470a0b7888ed913363c5cc5fad35670
doc_id: 756112
cord_uid: i1nehm61

In this retrospective study, we evaluated the levels of a series of serum biomarkers in coronavirus disease 2019 (COVID‐19) patients (mild: 131; severe: 98; critical: 23). We found that there were significant increases in levels of human epididymis protein 4 (HE4) (73.6 ± 38.3 versus 46.5 ± 14.7, p<0.001), cytokeratin‐19 fragment (CYFRA21‐1) (2.2 ± 0.9 versus 1.9 ± 0.8, p<0.001), carcinoembryonic antigen (CEA) (3.4 ± 2.2 versus 2.1 ± 1.2, p<0.001), carbohydrate antigens (CA) 125 (18.1 ± 13.5 versus 10.5 ± 4.6, p<0.001) and 153 (14.4 ± 8.9 versus 10.1 ± 4.4, p<0.001) in COVID‐19 mild cases as compared to normal control subjects; their levels showed continuous and significant increases in severe and critical cases (HE4, CYFRA21‐1 and CA125: p<0.001; CEA and CA153: p<0.01). Squamous cell carcinoma antigen (SCC) and CA199 increased significantly only in critical cases of COVID‐19 as compared with mild and severe cases and normal controls (p<0.01). There were positive associations between levels of C‐reactive protein and levels of HE4 (R= 0.631, p<0.001), CYFRA21‐1(R= 0.431, p<0.001), CEA (R= 0.316, p<0.001), SCC (R= 0.351, p<0.001), CA153 (R= 0.359, p<0.001) and CA125 (R= 0.223, p=0.031). We concluded that elevations of serum cancer biomarkers positively correlated with the pathological progressions of COVID‐19, demonstrating diffuse and acute lung injuries. This article is protected by copyright. All rights reserved.

The coronavirus disease 2019 (COVID-19) pandemic has become a global threat to public health. 1 The disease is believed to be of zoonotic origin. 2, 3 Snakes, pangolins, and turtles are speculated to be intermediate host(s). 4 Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is the causative organism for COVID-19. 5 

Betacoronavirus, which is based on the most conserved sequence of coronavirus genome, that is, the open reading frame 1a/1b (ORF1a/1b) responsible for replicases encoding. 6 The RNA genome has 29,891 nucleotides and share 79% sequence identity with SARS-COV and 50% sequence identity with Middle East respiratory syndrome coronavirus (MERS-COV). 6, 7 The phylogeny of this Accepted Article coronavirus show that it is most close to the bat coronavirus (BatCoV) RaTG13, with 96.3% sequence identity. 3 The SARS-COV2 Spike (S) protein is thought to mediate the virus entering host cells via surface angiotensin converting enzyme 2 (ACE2). 7, 8 COVID-19 patients can be asymptomatic or symptomatic. The incubation period for symptomatic development in COVID-19 is approximately 4-7 days. 9 Based on the severity of symptoms, COVID-19 can be classified into three categories. 1, 2, 10 Mild cases are marked by the onset of symptoms such as fever, cough, fatigue, headache, diarrhea, and so forth, with or without mild pneumonia. Severe cases demonstrate dyspnea, acute respiratory stress, decrease in blood oxygen saturation, lung infiltrates, multiple peripheral ground-glass opacities on both lungs, and so forth. Critical cases present symptoms such as respiratory or multiple organ failure and septic shock. The mortality rate of COVID-19 is estimated to be about 2.3%, with a range from 6 to 41 days from the onset of symptoms to death. 10, 11 COVID-19 patients also develop dyslipidemia which is associated with the disease severity. 12, 13 Many cancer biomarkers such as carcinoembryonic antigen (CEA) and carbohydrate antigens (CA) have shown an elevation in various inflammatory conditions in the lungs. [14] [15] [16] We posit that SARS-CoV-2-induced acute lung injuries may be associated with elevations of some cancer biomarkers. In this study, we performed a thorough investigation of the pathological profiles of COVID-19 from a series of laboratory serum tests; these profiles may reflect the progression of the disease. We found that the levels of a panel of serum cancer This article is protected by copyright. All rights reserved.

biomarkers were positively associated with the severity of COVID-19, demonstrating the diffuse and acute lung injuries in patients. 

Statistical analyses were performed with the SPSS software (IBM, Armonk, NY, USA). Differences among groups were analyzed by Chi square. A Mann-Whitney U test was used to compare differences between two groups. A Pearson correlation analysis was used to calculate the correlation coefficiency. The data was presented as "Mean ± standard deviation (S.D.)" or "Mean ± 95% confident interval (CI)". p<0.05 was considered as statistical significance. Table 2) . Patients showed a significant lymphopenia with a degree associated with the disease severity (mild: 1.6 ± 0.6; severe: 1.4 ± 0.7; critical: 0.9 ± 0.5; in g/L; p<0.001) ( Table 2) . IL-6 levels dramatically increased in all categories of cases ( Table 2) . IL-4 and IFN-γ levels increased in critical cases. Changes in WBC, IL2, IL10, TNF-α, and many other metabolic profiles in patients were not in evidence ( Table 2, supplementary Table 2 ). This article is protected by copyright. All rights reserved.

There were significant increases in levels of HE4 (73.6 ± 38. 3 with levels in the normal subjects (Fig 1) . The levels of all these biomarkers exhibited significantly gradual increases in patients across cases in all categories ( Fig 1, Table 2 , p<0.02). NSE, SCC, and CA199 levels increased significantly only in critical cases as compared with levels in normal subjects, mild and critical cases ( Fig 1F, Table 2, p<0.05) . We had all female subjects in normal control group of HE4, which data had a gender bias. In order to determine whether the gender was a potential factor contributing to the elevation of HE4 in patients, we divided the cohort based on genders in each category. Both female and male patients with mild COVID-19 showed significant higher levels of HE4 as compared with the normal subjects (Fig 1A, p<0.05) ; they also showed gradual increases in HE4 levels in correlation with the disease severity, regardless of genders (Fig 1A, p<0.05 ).

The number of lymphocytes was inversely correlated with levels of HE4 (R= -0.375, p<0.001) in COVID-19 patients (Fig 2A) , but was not associated with other cancer biomarkers we examined in this study (data not shown). CRP levels were positively correlated with HE4 (R= 0.631, p<0.001, Fig 2B) , CYFRA21-1 (R= This article is protected by copyright. All rights reserved. 0.431, p<0.001, Fig 2C) , CEA (R= 0.316, p<0.001, Fig 2D) , CA125 (R= 0.223, p=0.031, Fig 2E), CA153 (R= 0.359, p<0.001, Fig 2F) , SCC (R= 0.351, p<0.001, Fig 2G) , and NSE (R= 0.316, p<0.001, Fig 2H) , respectively.

In this study, we retrospectively summarized a series of clinical laboratory tests on serum from COVID-19 patients, including metabolic panels and a set of 13 cancer biomarkers. This is the first report with such a substantial evaluation of cancer biomarkers on a large patient population of COVID-19. Our data demonstrate that levels of serum HE4, CYFRA21-1, CEA, CA125, CA153, SCC and NSE are positively associated with CRP, a crucial factor in correlation with the severity of the disease. Our findings provide insights into the detailed pathological evolution of COVID-19 in patients; this will not only aid in understanding the disease's molecular pathology, and facilitate early diagnosis, but will also help in assessing long-term outcomes.

In this study, we did not include any patients with cancer diagnoses; therefore, the elevation of these cancer biomarkers was not related to preexisting conditions of tumorigenesis. Many studies have shown that cancer biomarkers such as CEA and carbohydrate antigens are also elevated in various inflammatory conditions in the lungs. For example, CEA is increased in smoking subjects; 14 CYFRA21-1 is increased in pulmonary alveolar proteinosis; 15 and CA125 is increased in chronic obstructive pulmonary disease. 16 HE4 levels are correlated with the severity of cystic fibrosis. 17 More interestingly, a recent study This article is protected by copyright. All rights reserved.

has shown that carbohydrate antigens such as CA199 can cause rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor signaling and promote pancreatic cancer in an animal model. 18 Many studies have shown that cancer biomarkers such as CEA and carbohydrate antigens and HE4 are also elevated in various inflammatory conditions in the lungs. 15-17 A potential mechanism underlying our data is that upregulation of HE4, CEA, and CYFRA21-1 can reflect an acute alveolar injury. CRP is an inflammatory marker.

The positive correlations between CRP and CEA or CA biomarkers have been found in other diseases such as gastric and colon cancer, and Parkinson's disease. 19, 20 CRP is a crucial factor associated with the severity of COVID-19. 12, 13 The positive correlations between CRP and series cancer biomarkers we showed in this study demonstrate that these cancer biomarkers can present the diffuse and acute lung injuries in COVID-19.

There are several limitations of this study. First, a long-term follow-up is needed in order to determine whether elevated cancer biomarkers in patients are transient or long-term as a risk of tumorigenesis. Second, surveillance of these serum markers during treatment is very important in order to provide a molecular basis for how this disease responds to various treatments. Third, the normal control subjects for HE4 were all female, which data had a gender bias. Data are presented as mean (SD). Chi square was used for comparisons. n.s., no significance. *data were measured from the normal subjects in each control group in supplementary Table 1 .

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