key: cord-0933866-4npd6ovd
authors: Du, Yong; Lu, Zhanjun; Jin, Jing; Shi, Tianyun; Ding, Yi; Qian, Ling; He, Wei; Huang, Qihui; Feng, Jingjing; Jiang, Rong; Chen, Xuru; Jiang, Handong; Jie, Zhijun
title: Hematological characteristics of patients with novel coronavirus pneumonia in intensive care unit
date: 2021-04-20
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2021.107697
sha: cef01c0a01c56e9ccb035d18e921c4c71dc8a562
doc_id: 933866
cord_uid: 4npd6ovd

Background Toward the end of December 2019, a novel type of coronavirus (2019-nCoV) broke out in Wuhan, China. Here, the hematological characteristics of patients with severe and critical 2019-nCoV pneumonia in intensive care unit (ICU) were investigated, which may provide the necessary basis for its diagnosis and treatment. Methods We collected data on patients with confirmed 2019-nCoV pneumonia in the ICU of Leishenshan Hospital in Wuhan from February 25 to April 2, 2020. Real-time reverse-transcription polymerase chain reaction was used to confirm the presence of 2019-nCoV, and various hematological characteristics were analyzed. Results All patients tested positive for 2019-nCoV using nasopharyngeal swabs or sputum after admission, and interstitial pneumonia findings were noted on chest computed tomography. Sex, age and comorbidities were not significantly different between the severe and critical groups. In terms of prognosis, the survival rate of patients in the severe group reached 100%, whereas that of patients in the critical group was only 13.33% after positive treatment. Furthermore, lymphocyte percentage, blood urea nitrogen, calcium, D-dimer, myohemoglobin, procalcitonin, and IL-6 levels were high-risk factors for disease progression in critical patients. Finally, lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels were closely associated with patient prognosis. Conclusions 2019-nCoV pneumonia should be considered a systemic disease. Patients with more complications were more likely to develop critical disease. Lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels can be monitored to prevent progression critical disease.

Wuhan, China. This infectious disease spread rapidly to other parts of the country and then to several countries abroad. Thereafter, the Chinese Center for Disease Control (CDC) announced the inclusion of the disease into national "class B" and adopted "class A" prevention and control measures [1] . According to the national CDC official website (http://2019ncov.chinacdc.cn/nCoV/), a total of 84,547 patients were diagnosed with this disease and 4,645 patients had died as of May 27, 2020.

During the initial stages of 2019-nCoV pneumonia, severe acute respiratory infection symptoms occur, with some patients rapidly developing acute respiratory distress syndrome, acute respiratory failure, and other serious complications [2] . As a result, most patients with severe 2019-nCoV pneumonia require hospital admission or treatment in the intensive care unit (ICU) [3] . To date, several investigations have established the characteristics of patients with coronavirus disease 2019 (COVID- 19) , including epidemiological, clinical, laboratory, and radiological characteristics; treatment; and clinical outcomes [2, 4, 5] . However, the findings of these studies were mainly focused on the general population, and the clinical characteristics of patients with varying degrees of severity of this disease in the ICU are less known.

In this study, we analyzed the hematological characteristics of patients with 2019-nCoV pneumonia admitted to the ICU of Leishenshan Hospital in Wuhan and explored the clinical significance of changes in blood routine examination, blood biochemistry examination, coagulation function, myocardial injury markers, and inflammatory markers.

A total of 51 patients with severe and critical 2019-nCoV pneumonia (severe and critical groups, respectively) who were admitted to the ICU of Leishenshan Hospital in Wuhan from February 25 to April 2, 2020, were enrolled in this retrospective analysis. The sex and age of each patient were recorded. We also recorded the comorbidities of each enrolled patient in detail, including the history of chronic systemic diseases (cardiovascular, respiratory, endocrine, liver, kidney, cerebrovascular), malignancies and autoimmune diseases to explore the impact of Shanghai Jiao Tong University, and written informed consent was obtained from the patients before enrollment when their data were collected.

Under limosis condition, vein blood samples were obtained early in the morning after admission to the hospital to examine blood routine parameters, blood biochemistry parameters (including liver function, renal function, and electrolyte levels), coagulation function, myocardial injury markers, and inflammatory markers [such as serum inflammatory factor interleukin-6 (IL-6)]. Among these indicators, IL-6 was detected by enzyme-linked immunosorbent assay.

Statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, USA). The demographic and clinical characteristics of patients with severe and critical 2019-nCoV pneumonia were compared using the χ2 test and Student's t-test. 6 0.012, and 0.043, respectively). In terms of blood sodium level, severe patients showed hyponatremia as the main characteristic (38.1% vs. 10%), whereas critical patients showed hypernatremia (36.67% vs. 9.52%). No significant differences were observed in serum alanine aminotransferase and aspartate aminotransferase, blood potassium, and blood chlorine levels between the two groups (P = 0.357, 0.694, 0.371, and 0.127, respectively). In terms of coagulation function, significant differences were noted in prothrombin time, activated partial thromboplastin time, and D-dimer levels between the two groups (P = 0.001, 0.002, and 0.023, respectively), whereas no significant difference was observed in fibrinogen levels (P = 0.561). In terms of myocardial injury markers, creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, hypersensitive troponin I, myohemoglobin, and brain natriuretic peptide levels were significantly higher in critical patients than in severe patients (P = 0.000, 0.014, 0.048, 0.038, 0.000, and 0.042, respectively). Finally, significant differences were noted in terms of inflammatory marker levels, including hypersensitive C-reactive protein, procalcitonin, and IL-6 levels, between the two groups (P = 0.000, 0.000, and 0.000, respectively).

Furthermore, multivariate logistic regression analysis revealed that lymphocyte percentage and blood urea nitrogen, blood calcium, D-dimer, myohemoglobin, procalcitonin, and IL-6 levels were high-risk factors for progression into critical disease (P = 0.008, 0.011, 0.021, 0.037, 0.005, 0.012, and 0.035, respectively; odds ratio [OR] = 3.342, 1.468, 2.012, 1.931, 2.382, 1.712, and 2.743, respectively) ( Table   3) . Table 4 , lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels were closely related to the prognosis of patients (P = 0.001, 0.04, 0.038, 0.000, and 0.023, respectively).

Coronavirus is a large family of viruses that are known to cause diseases ranging from common colds to Middle East respiratory syndrome and severe acute respiratory syndrome [6, 7] . The current 2019-nCoV emerged in December 2019, with a cluster of patients identified with connections to Huanan Seafood Market in Wuhan, China.

People infected with 2019-nCoV exhibited symptoms of viral pneumonia, such as fever, difficulty in breathing, and bilateral lung infiltration in the most severe cases.

We found no significant differences in age, sex, and overall comorbidities between severe and critical patients; however, the number of patients in the critical group was significantly higher than that in the severe group for >3 comorbidities. This indicated that the higher the number of complications, the higher the risk of patients developing critical disease.

In blood routine characteristics, the white blood cell count of patients with 2019-nCoV infections should be normal or reduced [4, 8] ; however, we found that the white blood cell count of critical patients was significantly higher than that of severe patients, even by >20 × 10 9 /L in some critical patients. With significantly elevated hypersensitive C-reactive protein, procalcitonin, and IL-6 levels in critical patients, we considered that higher white blood cell counts were associated with mixed viral infections and even leukemia-like responses in some patients. The difference between neutrophil and lymphocyte percentages was significant between the two groups, which is consistent with the results of a previous study [9] . Patients with low lymphocyte percentage seemed to have severe disease; the reason may be related to the decreased immunity caused by the decreased lymphocyte percentage. Unlike the observations of a previous study [10] , the incidence of anemia was higher in critical patients than in severe patients, particularly the incidences of moderate and severe anemia in the present study. Some patients even need blood transfusion, suggesting an association with systemic depletion due to severe infections in critical patients. No difference was observed in the platelet count between the two groups. Even in critical patients, the increase or decrease in platelet counts was only slightly significant, indicating that the effect of 2019-nCoV pneumonia on platelets was not significant.

To our surprise, our conclusions were different from some previous studies [11, 12] .

Through the two meta-analyses of the influence on platelet counts in COVID-19 patients, we found that different studies had different responses to COVID-19 platelets. Remarkably, not all the patients were detected with thrombocytopenia, but many studies were still on platelet normality and advancement. Platelet decline could occur during severe infection, and COVID-19 was no exception. The mechanism might be related to the microcirculation disturbance caused by severe pneumonia, especially the appearance of disseminated intravascular coagulation and extensive pulmonary coagulation. We found that the platelet counts in critically ill patients were decreased than in patients with overall severe decreased platelet counts, which was still within the normal range. However, critically ill patients of coagulant function were obviously abnormal with an increase of most apparent D-dimer. Therefore, we hypothesized that systemic inflammatory response syndrome in critically ill patients seriously affected the coagulation function and various vital organs' functions in the early stage. The platelets didn't have enough time to show a decline before the death of patients.

In terms of blood biochemistry characteristics, serum alanine aminotransferase, aspartate aminotransferase, and albumin levels were used to evaluate liver function in our study. Mild liver function injury was found in both the groups, but no significant difference was noted. Most of the changes in liver function characteristics were temporary and reversible, indicating that liver function injury might be caused by several factors such as immunity, inflammation, and drugs [13] . In this study, the patients' albumin levels often decreased as the disease progressed and even reached a level below the lower limit of the reference range, which is inconsistent with the results of another study [14] ; the albumin levels of the two groups decreased at varying degrees, especially in critical patients, indicating that the consumption of the body due to viral pneumonia was significant. Severe hypoproteinemia can also lead to a series of secondary changes, such as systemic swelling, multiple serosal effusion, and cachexia.

In terms of renal function analysis, blood urea nitrogen and creatinine levels were significantly increased in critical patients, illustrating that renal function damage was prevalent in these patients. However, a recent study indicated that COVID-19

does not result in acute kidney injury [15] , possibly due to the following reasons: (1) 2019-nCoV pneumonia with hypotension can lead to insufficient renal perfusion and cause prerenal kidney injury; (2) the highly expressed angiotensin-converting enzyme 2 in the kidney tissues had a strong affinity for 2019-nCoV, which may directly mediate virus-induced kidney injury [16] and (3) In an early study on COVID-19, some evidence has suggested the presence of electrolyte disorders upon patient's presentation, including sodium, potassium, chloride, and calcium abnormalities [17] . In the present study, the two groups had different electrolyte disorders, with no difference noted in blood potassium and chlorine levels and significant difference noted in blood sodium and calcium levels.

Among these electrolyte disorders, in terms of blood sodium levels, hyponatremia was prevalent in the severe group, whereas the critical group was characterized by hypernatremia. Therefore, the incidence of hypernatremia in critical patients was obviously increased in our study. However, compared with hyponatremia, hypernatremia was more harmful and difficult to manage because it can easily cause hyperosmotic state, cell dehydration, organ function damage, and even death. In terms of blood calcium levels, the two groups showed varying degrees of decreases, with the critical group showing a more obvious decrease. Accompanied by tissue and organ ischemia and hypoxia, severe infection in critical patients could result in changes in cell membrane permeability and a decrease in the activity depending on the adenosine triphosphate function of calcium pumps, eventually leading to accumulation of intracellular calcium and a decrease in blood calcium levels [18] . The reduced blood calcium levels indicated a severe disease and poor prognosis.

The blood glucose levels of severe and critical patients were significantly increased, but not significantly different between the two groups. There was also no significant difference in blood glucose levels between the patients with and without diabetes, which indicated that the patients in both groups were severely stressed. This finding showed that we can control blood glucose within a controllable range through active hypoglycemic treatment, which has great clinical implications for both the control of pulmonary infections and protection of visceral function.

In terms of coagulation function analysis in the two groups, we found that prothrombin time, activated partial thromboplastin time, and D-dimer level were significantly increased in critical patients, whereas fibrinogen level was not different between the two groups. This suggested that conventional coagulation parameters evaluated during the course of 2019-nCoV pneumonia were significantly associated with disease severity. Our conclusions are slightly different from those reported by other scholars [19, 20] , showing a significantly increased D-dimer level in severe patients. Hence, we reinforce the suggestion that routine monitoring of hematological characteristics is useful in establishing an accurate therapeutic strategy and preventing disease progression and even death.

We found that the levels of the six myocardial injury markers were increased in critical patients, with the most significant difference noted in myoglobin level. Our current data demonstrated that patients in the critical group were more susceptible to heart failure. Hypersensitive troponin I is reported to be one of the best laboratory parameters inflecting cardiac injury for predicting the severity of 2019-nCoV pneumonia [21] . It should be noted that the elevated hypersensitive troponin I levels in patients with 2019-nCoV infection are only indicative of myocardial injury that was probably secondary to severe hypoxemia. Another important laboratory parameter is myoglobin [22] . At the time of myocardial injury, myoglobin is the first biomarker to enter the blood, with diffusion rates higher than those of hypersensitive troponin I. Therefore, the degree of myocardial injury can be considered as an important predictor of the severity and prognosis of severe infection. For patients with positive hypersensitive troponin I and myoglobin results, we must select the appropriate respiratory support strategy to improve oxygenation and wait for the recovery of myocardial injury.

Similar to that reported by other studies in terms of inflammatory markers [5, 23] , abnormal laboratory findings include elevated hypersensitive C-reactive protein, procalcitonin, and IL-6 levels, indicating sustained inflammatory responses after 2019-nCoV infection. These inflammatory responses can induce mitochondrial damage and glucose utilization disorders and promote functional damage in vital organs such as the lungs, heart, liver, and kidney. In addition, hypersensitive C-reactive protein, procalcitonin, and D-dimer levels and neutrophil percentage were significantly higher in the critical group than in the severe group, which may represent more prominent inflammation in critical patients.

We also screened high-risk hematological indicators, including lymphocyte percentage, blood urea nitrogen, calcium, D-dimer, myohemoglobin, procalcitonin, and IL-6 levels, for critical patients using multivariate logistic regression analysis.

However, lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels were closely related to the prognosis of all patients, as revealed by analysis of these high-risk factors mentioned above.

A review of different studies showed that the use of specific hematological markers in ICU patients with severe diseases may lead to different results. Atieh et al. In summary, this study established the laboratory characteristics of 51 patients with 2019-nCoV pneumonia who were admitted to the ICU. We conclude that 2019-nCoV pneumonia involves multiple systems, in addition to the respiratory system. 2019-nCoV pneumonia had influence on blood routine characteristics, blood biochemistry characteristics, coagulation function, myocardial markers, and inflammatory markers to some extent. In critical patients, the abnormal increase in several hematological characteristics indicates serious damage; some of these characteristics were closely related to disease prognosis. Therefore, further study is warranted to gain better understanding of these risk factors, which may ultimately help guide efforts aimed at reducing the fatality rate.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. 

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Drafting of the manuscript: Du, Shi, Feng. Critical revision of the manuscript for important intellectual content

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