key: cord-1006256-2j4yn868
authors: Peng, Junnan; Qi, Di; Yuan, Guodan; Deng, Xinyu; Mei, Ying; Feng, Longhua; Wang, Daoxin
title: Diagnostic value of peripheral hematologic markers for coronavirus disease 2019 (COVID‐19): A multicenter, cross‐sectional study
date: 2020-07-17
journal: J Clin Lab Anal
DOI: 10.1002/jcla.23475
sha: 3d9b54de9d687ff2202c1a456c6f3a4e70ae10f0
doc_id: 1006256
cord_uid: 2j4yn868

BACKGROUND: To determine the diagnostic value of hematologic markers for coronavirus disease 2019 (COVID‐19) and explore their relationship with disease severity. METHODS: Subjects included 190 COVID‐19 patients, 190 healthy subjects, and 105 influenza pneumonia (IP) patients. COVID‐19 patients were divided into the ARDS and non‐ARDS groups. Routine blood examination, biochemistry indicator, days in hospital, body temperature, pneumonia severity index (PSI), CURB‐65, and MuLBSTA were recorded. Correlations between variables were assessed using Spearman's correlation analysis. Receiver operating characteristic (ROC) curves were used to study the accuracy of the various diagnostic tests. RESULTS: Compared with healthy subjects, COVID‐19 patients had lower white blood cell (WBC), lymphocyte, platelet, and hemoglobin levels; higher percentages of neutrophils and monocytes; lower percentages of lymphocytes and higher neutrophil‐to‐lymphocyte ratio (NLR), monocyte‐to‐lymphocyte ratio (MLR), and platelet‐to‐lymphocyte ratio (PLR) values (P < .05). COVID‐19 patients had higher WBC and neutrophil levels and lower percentages of lymphocytes compared to IP (P < .05). ROC curve analysis revealed that MLR had a high diagnostic value in differentiating COVID‐19 patients from healthy subjects, but not from IP patients. NLR showed significant positive correlations with PSI, CURB‐65, and MuLBSTA. Lymphocyte count was lower in the ARDS group and yielded a higher diagnostic value than the other variables. CONCLUSIONS: Monocyte‐to‐lymphocyte ratio showed an acceptable efficiency to separate COVID‐19 patients from healthy subjects, but failed to rule out IP patients. NLR may be a reliable marker to evaluate the disease severity of COVID‐19. Lymphocyte count may be useful to establish the early diagnosis of ARDS in the COVID‐19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS- and the disease it causes, coronavirus disease 2019 (COVID- 19) , were first reported in Wuhan, the capital of Hubei Province, and have quickly spread to different regions of China and other countries, including the United States, Japan, South Korea, and

Thailand. 1, 2 The World Health Organization (WHO) has declared that the outbreak of SARS-CoV-2 can be characterized as a global pandemic, and as of May 5, 2020, the number of confirmed COVID-19 cases surged above 3 570 000, with nearly 250 000 deaths. 3 Several published reports of early clinical descriptions of COVID-19 found that 26%-33% of patients required intensive care and 4%-15% died. 1, [4] [5] [6] Subsequently, a report of 72 314 cases estimated that approximately 19% of people with COVID-19 have severe or critical disease, with a case fatality rate of 2.3%. 7 Early identification and management are the most effective ways to improve the curative efficacy, which is a challenging task for physicians in clinical practice.

Currently, a positive result on high-throughput sequencing or real-time reverse transcription polymerase chain reaction (RT-PCR) of nasal and pharyngeal swab specimens is considered an optimal standard of COVID-19. Chest computerized tomography (CT) is widely used as an important diagnostic tool of COVID-19, and some CT manifestations may be associated with the progression and prognosis of COVID-19. 8 However, their clinical application is restricted by many factors, such as limited medical resources and high examination costs. Thus, convenient and cost-effective indicators are urgently required to simplify the diagnostic process and evaluate the disease severity.

Hematologic markers, including neutrophils, lymphocytes, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR), have been proposed as indicators to assist in the diagnosis, early warning, and risk stratification of infectious diseases. 9 NLR has been demonstrated as an informative biomarker of diagnosis and disease severity in community-acquired pneumonia and bacteremia. 10, 11 MLR and PLR have also been recognized as a surrogate biological marker for the diagnosis of influenza virus infection in patients with respiratory tract infection. [12] [13] [14] However, few studies have focused on the diagnostic value of hematologic markers for Therefore, this study aimed to examine neutrophils, lymphocytes, monocytes, platelets, NLR, MLR, and PLR in COVID-19 patients, determine their diagnostic value for COVID-19, and explore their relationship with disease severity. 

Data including demographic information, medical history, clinical manifestations, laboratory findings, radiologic images, and days in hospital were collected from the patients' medical and nursing records. Laboratory results included WBCs, neutrophils, lymphocytes, monocytes, platelets, hemoglobin (HGB), C-reactive protein (CRP), Lymphocyte count may be useful to establish the early diagnosis of ARDS in the COVID-19 patients.

coronavirus disease 2019, diagnostic value, lymphocyte, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio erythrocyte sedimentation rate (ESR), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), and creatine kinase isoenzyme (CKMB). NLR, MLR, and PLR were calculated by dividing the absolute neutrophil, monocyte, and platelet counts by the absolute lymphocyte counts. The pneumonia severity index (PSI), CURB-65, and MuLBSTA 16 were determined within 24 hours after admission by standardized forms. The diagnosis of acute respiratory distress syndrome (ARDS) was based on the Berlin definition. 17 Two senior physicians independently reviewed the data.

Continuous variables are presented as the mean ± standard de- A two-sided P-value of <.05 was considered significant. (normal range: <20.00 mm/h), CRP was 29.12 ± 31.21 mg/L (normal range < 10.00 mg/L), and PCT was 0.057 ± 0.055 ng/mL (normal range < 0.050 ng/mL) in the COVID-19 patients. In addition, the length of hospital stay was 13.91 ± 1.84 days, the body temperature was 37.38 ± 0.87°C, ALT was 28.77 ± 24.87 U/L (normal range: 7.00-40.00 U/L), AST was 27.82 ± 18.28 U/L (normal range: 13.00-35.00 U/L), CREA was 68.93 ± 19.10 µmol/L (normal range: 41.00-81.00 µmol/L), CKMB was 11.59 ± 16.74 ng/mL (normal range: <5.00 ng/mL), PSI was 61.77 ± 27.03, CURB-65 was 0.51 ± 0.62, and MuLBSTA was 7.09 ± 2.50 in the COVID-19 group.

There were no statistical differences in laboratory findings between COVID-19 and IP groups except for the WBC counts (5.45 ± 2.16 vs 6.04 ± 2.31 × 10 9 /L, P = .013), neutrophil counts (3.53 ± 1.97 vs 3.97 ± 2.16 × 10 9 /L, P = .043), and the percentages of lymphocytes (25.52 ± 10.31 vs 23.07 ± 11.58%, P = .032; Table 1 ). However, when comparing patients with COVID-19 to those with IP, the AUC was lower than 0.600 in all the hematologic markers examined ( Figure 1 and Table 2 ). (Table 3) .

According to the Berlin definition, 17 COVID-19 patients were divided into the non-ARDS (n = 159) and ARDS (n = 31) groups, and the differences between the two groups were analyzed. There were no significant differences of age and gender between the two groups. The results showed that when compared with those of the non-ARDS group, the lymphocyte and platelet counts were markedly decreased (0.83 ± 0.35 vs 1.40 ± 0.55 × 10 9 /L, P < .001;

147. 23 

Receiver operating characteristic curve analysis was carried out to evaluate the accuracy, specificity, and sensitivity of the hematologic markers, PSI, CURB-65, and MuLBSTA for the diagnosis of ARDS in the COVID-19 patients. The results showed that a lymphocyte level <0.87 × 10 9 /L was an optimal cutoff for predicting ARDS in COVID-19 patients with 88.05% specificity and 70.97% sensitivity, which was higher than that of other variables (Table 5 and Figure 2 ). Note: Data are presented as mean ± standard deviation (SD) and n (%). P 1 : Compared between COVID-19 and healthy subjects; P 2 : Compared between COVID-19 and IP.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKMB, creatine kinase isoenzyme; COVID-19, coronavirus disease 2019; CREA, creatinine; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IP, influenza pneumonia; MLR, monocyte-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PCT, procalcitonin; PLR, platelet-to-lymphocyte ratio; PSI, pneumonia severity index; WBC, white blood cell. that some serum cytokines (IL-6 and IFN-α) and chemokines (IL-8, CXCL-10, and CCL-5) are correlated with increased peripheral blood monocytes in patients with MERS, suggesting a possible effect on increasing the MLR. 23 Notably, the differences in monocyte count between the two groups were not statistically significant in our study, although the COVID-19 group indeed had a higher mean value and wider range than the healthy control group. One possi- Data are presented as mean ± standard deviation (SD) and n (%).

Abbreviations: ARDS: acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MLR, monocyte-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PCT, procalcitonin; PLR, platelet-to-lymphocyte ratio; PSI, pneumonia severity index. This study has several limitations. First, it was of retrospective nature. All included patients were obtained from hospital medical systems after satisfying a series of criteria, which could introduce a selection bias. Second, we only used one measure in time rather than a longitudinal measure because of insufficient data. Third, although some of the conditions were adjusted, we could not have completely removed all the confounding factors that might influence the level of hematologic markers. Forth, all our patients were Asian descent, and as these hematologic markers have racial differences, the study findings may not be applicable to the white and black populations. 34, 35 Therefore, an additional large-scale multicenter, randomized control study will be required to further confirm our findings. and was in accordance with the Declaration of Helsinki.

The manuscript is approved by all authors for publication.

The datasets used during the current study are available from the corresponding author on reasonable request.

https://orcid.org/0000-0001-8327-3650

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