key: cord-0971015-zkicli3a
authors: Tao, Zheying; Xu, Jing; Chen, Wei; Yang, Zhitao; Xu, Xiaoman; Liu, Ling; Chen, Ruwu; Xie, Jingyuan; Liu, Mingyu; Wu, Jingyi; Wang, Huiming; Liu, Jialin
title: Anaemia is associated with severe illness in COVID‐19: a retrospective cohort study
date: 2020-08-19
journal: J Med Virol
DOI: 10.1002/jmv.26444
sha: 86c76a50f09d1d9c2839f858bf6df6ce67006345
doc_id: 971015
cord_uid: zkicli3a

BACKGROUND AND OBJECTIVE: Anaemia commonly aggravates the severity of respiratory diseases, whereas thus far, few study has elucidated the impact of anaemia on Corona Virus Disease 2019 (COVID‐19). The aim of this study was to evaluate the clinical characteristics of patients with anaemia, and to further explore the relationship between anaemia and the severity of COVID‐19. METHODS: In this single‐center, retrospective, observational study, a total of 222 confirmed patients admitted to Wuhan Ninth Hospital from December 1, 2019 to March 20, 2020 were recruited, including 79 patients with anaemia and 143 patients without anaemia. Clinical characteristics, laboratory findings, disease progression and prognosis were collected and analyzed. Risk factors associated with the severe illness in COVID‐19 were established by univariable and multivariable logistic regression models. RESULT: In our cohort, compared to patients without anaemia, patients with anaemia were more likely to have one or more comorbidities and severe COVID‐19 illness. More patients demonstrated elevated levels of C‐reactive protein (CRP), procalcitonin (PCT) and creatinine in anaemia group. Levels of erythrocyte sedimentation rate (ESR), D‐dimer, myoglobin, T‐pro brain natriuretic peptide (T‐pro‐BNP) and urea nitrogen (BUN) in patients with anaemia were significantly higher than those without. In addition, the proportion of patients with dyspnoea, elevated CRP and PCT was positively associated with the severity of anaemia. The Odd Ratio (OR) of anaemia related to the severe condition of COVID‐19 was 3.47(95% CI: 1.02‐11.75, P=0.046) and 3.77 (95% CI:1.33‐10.71, P=0.013) after adjustment for baseline date and laboratory indices, respectively. CONCLUSION: Anaemia is an independent risk factor associated with the severe illness of COVID‐19, and healthcare professionals should be more sensitive to the haemoglobin levels of COVID‐19 patients on admission. Awareness of anemia as a risk factor for COVID‐19 was of great significance. TRIAL REGISTRATION: Ethics committee of Wuhan University People's Hospital (wdry2020‐k064) This article is protected by copyright. All rights reserved.

. The median age of the patients was 55 years (IQR, 42-66 years); there were with 80 (36.0%) male and 142 (64.0%) women. Overall, 81 (36.5%) patients had one or more comorbidities, of which hypertension (28.6%) was the most common one, followed by diabetes (12.2%), cardiovascular disease (CVD) (7.7%), and chronic obstructive pulmonary disease (COPD) (3.6%). The most common symptom at the onset of the illness was fever (59.5%), followed by cough (54.1%), expectoration (23.0%), weakness (18.0%), chest pain (15.3%), and dysponea (13.5%). A minority of patients initially presented with diarrhoea (9.9%), myalgia (1.8%), and pharyngula (1.4%). Based on the guideline described previously, disease severity was graded as severe or non-severe, respectively. As reported by previous studies, compared with non-severe patients, severe cases were significantly older (54 years vs 65 years, P=0.004) and significantly more likely to suffer from underlying disorders (31.7% vs 85.0%, P=0.000), such as hypertension, CVD, and COPD.

Laboratory tests of COVID-19 patients were conducted at the time of admission, and the results are shown in Table2. Patients with COVID-19 presented with an inflammatory response combined with functional impairment of major organs. Differences were observed between the subgroups. Compared with Accepted Article blood routine including white blood cell count (WBC), lymphocyte, neutrophils, eosinophils, red blood cell count (RBC), haematocrit, and platelet count were prominently lower in the anaemic group compared to the non-anaemic group (all P<0.05) ( Figure 1F ).

The severity of anaemia was established based on the WHO definitions [10] . Among the 222 patients in our study, 46 patients were classified as having mild anaemia, whereas 29 and 4 patients were classified as having moderate and severe anaemia, respectively. Haemoglobin levels of the three groups were 116 g/ L, 103 g/ L, and 72 g/L, respectively. Compared with the mild anaemia group, patients with moderate to severe anaemia were more likely to present with dyspnoea (24.2% vs 6.5%, P=0.025), and had lower levels of PaO2 and SaO2 than patients with mild anaemia (both P<0.05)，while no significant difference was found in the age, sex, comorbidities, proportion of severe patients, and mortality between the anaemia subtypes (As is shown in Table 3 , Figure 1B , Supplementary Table S1 ). For laboratory indices, we found that the severity of anaemia was positively associated with inflammatory responses and coagulation disorders, whereas no significant relationship with organ injuries was observed. The prevalence of CRP, PCT beyond the normal range, and elevated levels of ESR and D-dimer, were prominently higher in patients with moderate to severe anaemia compared to patients with mild anaemia ( Figure 1C, 1D) .

Moreover, the absolute values of WBC, lymphocyte count ( Figure 1E ), eosinophils, RBC, platelet count, haematocrit, SO 2, and PO 2 gradually and significantly decreased as the anaemia grade increased (all P<0.05).

To assess whether anaemia is a risk factors for the severe illness of COVID-19, logistic regression analysis was performed. Based on the recent studies and our statistical results, some variables among the Accepted Article baseline data and laboratory findings were included in the logistic regression model. As summarised in Figure 2 and Supplementary Table S2, in univariate analysis, baseline data including age ≥60 years, anaemia, any com comorbidities, hypertension, CVD, COPD, and laboratory indices containing CRP ≥10 mg/ L, LDH ≥250 U/L, and D-dimer ≥0.5 mg/L, Creatinine ≥133 μmol/L were significantly associated with the increased disease severity in patients with COVID-19. We further screened and selected the variables to be included in the multivariable logistic regression model. The multivariable analysis indicated that anaemia remained significant as an independent risk factor for patients with severe COVID-19, even after adjusting for baseline data (OR: 3.47, 95%CI: 1.02-11.75, P=0.046) and laboratory indexes (OR:3.77, 95%CI: 1.33-10.71, P=0.013). However, anaemia showed an insignificant relationship with the overall mortality of COVID-19 patients in univariate analysis (P=0.996), possibly because of the limited death toll in our cohort.

We reported 222 patients with COVID-19 in this cohort. The clinical and laboratory features of COVID-19 patients were similar to those in other series [11] . In this retrospective cohort study, we mainly identified that COVID-19 patients with anaemia were more likely to develop severe conditions. It was shown that more patients dead in the anaemic group when compared to non-anaemiac group, however none significant relationship was found between anaemia and death in univariate regression analysis.

Comorbidities were more commonly seen in patients with anaemia. In addition, anaemic patients were older and had a higher risk of severe inflammatory responses and organ injuries. Moreover, the severity of anaemia was positively and strongly associated with more serious inflammatory responses. Our research also demonstrated that anaemia is an independent risk factor associated with severe illness of COVID-19.

Anaemia is common among patients suffering from pneumonia, with nearly 7-12% in Accepted Article community-acquired pneumonia and 31.8% in severe influenza A. [6, 11] Zhou et al. [12] in which 191 patients were enrolled, found that the frequency of anaemia in COVID-19 patients was 15%. In a cohort of 267 patients with severe acute respiratory syndrome, 16% had anaemia at presentation, whereas the incidence increased to 53% during hospitalization. [13] In our study, the prevalence of anaemia in hospitalised COVID-19 patients was up to 35.5%, which is much higher than that reported by Zhou et al. Due to the limited literature on anaemia among COVID-19 patients, the accurate prevalence of anaemia in patients with COVID-19 remains unclear.

Anaemia commonly aggravates the severity of respiratory diseases, and it has been documented that respiratory diseases combined with anaemia are associated with poor outcomes and increased mortality [6, 7] .

Hitherto, few research has noted the clinical characteristics of COVID-19 patients with anaemia as well as the direct correlation between anaemia and disease severity in patients with COVID-19. It is worth noting the clinical characteristics in patients with and without anaemia as well as in patients with different severities of anaemia. Our study is the first investigation that exclusively and systematically focuses on anaemia in COVID-19 patients. We first described the clinical and laboratory characteristics of COVID-19 patients with anaemia and then further evaluated the impact of anaemia on patients with COVID-19.

The physiological mechanisms of the direct correlation observed in our cohort between anaemia and COVID-19 severity remained elusive. Previous investigations have revealed that anaemic patients had poorer lung function than non-anaemic patients [14] .Additionally, it is well acknowledged that anaemia and low haemoglobin could decrease oxygen delivery. Therefore, it is plausible to speculate that COVID-19 patients with anaemia were more susceptible to severe illness due to worse pulmonary function and poor tissue oxygenation. Despite the lack of significant differences in lung function-related parameters between anaemic patients and non-anaemic patients in our study, patients with moderate to severe anaemia Accepted Article rate; CK-MB: creatine kinase-MB; LDH: lactate dehydrogenase; T-pro-BNP: T-pro brain natriuretic peptide; ALT: glutamic-pyruvic transaminase; AST: glutamic oxiracetam transaminase; ALP: alkaline phosphatase; GGT: gamma glutamyl transpeptidase; BUN: urea nitrogen; WBC: white blood cell count;

RBC: red blood cell count: IQR: inter-quartile range; OR: odd ratio; CI: confidence interval.

The study was approved by The Ethics Commission of Wuhan University People's Hospital (wdry2020-k064), and written informed consent was obtained from all participants before enrolment.

The authors declare that they have no conflict of interests.

This study was supported by National Natural Science Foundation of China (8177010121) 

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We would like to thank all the patients and guardians of those patients for their participation in the study.We would also like to acknowledge the professors and colleagues from Shanghai Jiaotong University and This article is protected by copyright. All rights reserved.