key: cord-346459-tkt5ldyo
authors: Jie, Li Shao; Yu, Yuan; Ping, Zeng Jian; Dong, Xiang Xu; Ping, Chai Xiang; Chao, Hu; Li, Yang; Jing, Yang; Ling, Tan Yan; Yan, Jiang Ming; Peng, Ling
title: Risk factors for Coronavirus disease 2019 pneumonia after admission outside Wuhan, China
date: 2020-11-06
journal: Medicine (Baltimore)
DOI: 10.1097/md.0000000000022980
sha: 
doc_id: 346459
cord_uid: tkt5ldyo

Coronavirus disease 2019 (COVID-19) has spread worldwide, causing significant stress on the medical system. We explored the risk factors for condition changes in COVID-19 pneumonia patients after admission. The patients diagnosed with COVID-19 pneumonia at 2 medical centers in Hunan Province were studied, and those whose conditions changed after admission were compared. Their clinical characteristics and experimental indicators were compared using SPSS software and R language to build a disease risk prediction model. Patients with condition changes after admission were older and had more blood cell abnormalities and impaired organ function (decreased albumin, elevated D-dimer) than normal patients. We found that age, neutrophil ratio, D-dimer, chest Computed tomograpgy (CT) changes, and glucocorticoid use were risk factors for COVID-19 pneumonia after admission. Elderly patients are more susceptible to disease changes after COVID-19 pneumonia; COVID-19 pneumonia patients who develop disease changes after admission have higher neutrophil ratios, increased D-dimer levels, chest imaging changes, and glucocorticoid usage. Additional research is needed.

Coronavirus disease 2019 (COVID-19) is caused by SARS-COV-2, which invades host cells through human angiotensinconverting enzyme 2 (ACE2) and through the human CD147 pathway, causing pneumonia, acute respiratory distress syndrome (ARDS), coagulopathy and even death. [1, 2] COVID-19 was first reported in Wuhan in December 2019 and has caused a pandemic in 187 countries and regions. As of 04:00 on March 23, 2020, 294,110 cases of COVID-19 pneumonia have been diagnosed worldwide, and a total of 12,944 deaths have been reported. [3] In the treatment of COVID-19 pneumonia, how to predict changes in a patients condition is extremely important. Current research has shown that patients requiring intensive care unit (ICU) care have increased inflammation levels. [4] Studies of critically ill patients have shown that patients older than 65 years of age with underlying disease have an increased risk of death. [5] An analysis of patients who progressed to ARDS and died after admission revealed that age, neutrophil count, organ dysfunction and coagulopathy were risk factors for disease progression. [6] However, most of these studies are single-center studies and concentrated in Wuhan, a city where only severe patients are hospitalized when medical resources are overwhelmed, resulting in possible be selection bias. This study analyzed the clinical characteristics of patients with COVID-19 pneumonia who underwent changes after admission at 2 medical centers in Hunan Province to investigate the risk factors for the changes in the condition of patients and construct a risk prediction model to Editor: Gunjan Arora.

Sl and YY should be considered joint first author. This work was supported by the COVID-19 emergency in Xiangtan City (grant number SFYB20201006) Ethics approval and consent to participate: This study was a retrospective database analysis approved by the research ethics committee of Xiangtan central Hospital. Requirement for written informed patient content was waived.

Retrospective anonymous studies do not require consent to participate.

The authors declare that they have no competing interests and agree on the order in which their names listed in the manuscript.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. predict the risk of condition changes of patients with pneumonia after admission to better help and guide clinical treatment.

This study was a retrospective database analysis approved by the research ethics committee of Xiangtan Central Hospital. Requirement for written informed patient consent was waived because all data were anonymous.

We retrospectively collected the medical data of 109 patients diagnosed with COVID-19 in Xiangtan city and Shaoyang city from January 2020 to March 2020, including their general condition, epidemiological history, signs and symptoms, laboratory examination and imaging findings, treatment and prognosis. According to the patients condition change, we divided the patients into normal patients and severe patients. Normal patients were those with fever, cough, and other clinical sysptoms accompanied by imaging showed pneumonia: 1. shortness of breath (respiratory rate (RR)≥30bpm); 2. oxygen saturation 93% in the resting state; 3. arterial partial pressure of oxygen(PaO2)/oxygen absorption concentration (FIO2)300 mm Hg(1 mm Hg= 0.133KPa)[in highaltitude areas (over 1000_m above sea level), correction of PaO2/ FIO2 should be made according to the following formula: PaO2/ FIO2

[atmospheric pressure (mm Hg)/760];4. lung imaging showed significant progression in 50% of lesions within 24 to 48 hours; 5. respiratory failure requiring mechanical ventilation; 6. shock; 7. patients with other failure requiring monitoring and treatment in the ICU. "Severe" patients refer to those who are admitted to the hospital as "normal" and have an aggravated condition during treatment with any of the following manifestations or with any of the following conditions upon admission: The included children met the following criteria:

1. Shortness of breath (<2 months old, RR≥60 times/minutes; 2-12 months old, RR≥50 times/minutes; 1-5 years old, RR≥40 times/min; 0-5 years old, RR≥30 times/minutes), excluding the effects of fever and crying; 2. at rest, oxygen saturation 92%; 3. Assisted breathing (moaning, nasal wing agitation, 3 concave signs), cyanosis, or intermittent apnea; and 4. Lethargy and convulsion, with the condition gradually improving during hospitalization without aggravation.

COVID-19 patients from Xiangtan city and Shaoyang city were admitted to Xiangtan Central Hospital and Shaoyang Central Hospital, respectively, which were designated COVID-19 hospitals. Both hospitals, as grade 3A hospitals, were approved by the National Centers for Disease Control and Prevention for reverse transcription-polymerase chain reaction (RT-PCR) detection. We performed RT-PCR tests on the body fluid samples of all patients, such as nasopharyngeal secretion, sputum, blood, and stool samples, to confirm that the patients were infected. The patients symptoms, signs and medical history were collected. Laboratory tests, such as routine blood, liver and kidney function, myocardial enzymology, coagulation function, D-dimer (DDI), C-reactive protein (CRP), procalcitonin (PCT), and lung computed tomography (CT) tests after admission were also performed. Hormone use history was also included in the collection.

SPSS software and R language were used for statistical analysis. The continuous and categorical variables are described by the mean and standard deviation and by quantity and percentage, respectively. Univariate analysis of continuous variables was compared in patients with mild disease by the t-test, and categorical variables were compared by the Chi-Squared test. P < .05 was considered statistically significant. Independent predictors were selected by the absolute contraction selection operator (LASSO) regression model, and a prognostic nomogram was established to generate a comprehensive index to evaluate the aggravation of the condition of COVID-19 patients. A prediction curve was generated, and the discriminant of the nomogram was quantified by measuring the area under the receiver operating characteristic curve (AUC), sensitivity, specificity and accuracy.

As of March 18, 2020, a total of 109 patients with COVID-19 pneumonia were diagnosed in Xiangtan and Shaoyang, 68 and 41 of who were designated normal and severe, respectively ( 

The laboratory specifications are described in Table 2 . Compared with that in normal patients, the neutrophil ratio was higher in severe patients, and the absolute count of lymphocytes was lower (74.98 vs 62.87, 0.87 vs 1.35, P < .001); the platelet count level in severe patients was also relatively lower (183.54 vs 230.19, P < .001). In the detection of liver function, no significant difference was found in transaminase levels between severe patients and normal patients, but the severe patients showed lower albumin levels and higher globulin levels (38.86 vs 42.59, 29.45 vs 27.17, P < .05). There was no significant difference in renal function and PCT content between normal and severe patients. Regarding the detection of blood coagulation indicators, we found that the severe patients had higher DDI values, which indicated that the severe patients had a tendency toward hypercoagulability, while activated partial thromboplastin time (APTT) and prothrombin time (PT) did not show abnormalities. CRP levels were significantly higher in the severe patients (40.42 vs 11.55, P < .001).

As shown in Figure 1 , we applied the LASSO Logit model to assess the exacerbation of COVID-19 disease. The penalty coefficient in the LASSO model was adjusted by 10-fold cross-validation and the minimum criterion, and 5 predictive factors related to the aggravation of COVID-19 were screened out of 41 related factors. These factors were age, neutrophil ratio, DDI content, imaging changes, and hormone use. For synthesizing the 5 main predictors in the above screening, we used R language to establish a COVID-19 exacerbation risk prediction model to predict a patient's exacerbation risk (Fig. 2) . As shown in Figure 3 , the AUC of the predictor nomogram is 0.94 (0.94-0.99), the sensitivity is 0.82, the specificity is 0.889, and the accuracy is 0.862.

We analyzed the clinical characteristics of 109 patients with COVID-19 pneumonia at 2 medical centers in Hunan Province (Xiangtan city and Shaoyang city) and analyzed the cases with changes in condition after admission. According to the results, elderly patients and patients with chest CT changes after admission were more likely to experience changes in condition, which suggests that we need to pay additional attention to elderly patients and imaging changes because they indicate increased risk of exacerbation. In addition, compared with normal patients, severe patients after admission were older, had potential health problems in the past (such as hypertension, diabetes, and other underlying complications) and had more organ functional impairment, which is consistent with previous studies. [6, 8] However, due to possible bias, additional research is needed. Patients with progression of COVID-19 pneumonia often showed an increase in neutrophil levels and a decrease in lymphocyte levels, which is consistent with the results observed in most current studies. [9] [10] As an inflammatory activating factor, neutrophils are likely to cause overactivation of the bodys immune response and cytokine storms. Elevated neutrophil levels may herald an enhanced immune response. What is confusing is that monocyte and macrophage infiltration are more common under pathological microscopy in patients with fatal COVID-19 pneumonia than granulocyte infiltration. [11] Therefore, we hypothesize that neutrophils activate the immune response to fight against virus invasion, and this effect is one of the possible mechanisms by which SARS-CoV-2 causes damage to the body.

This study showed that patients with changes in COVID-19 pneumonia are more likely than stable patients to develop hypercoagulability, which is manifested by an increase in DDI content. Previous studies have found that SARS-CoV-2 infects humans and causes disease through human ACE2 in the same way as SARS. As ACE2 is an important participating member of the renin-angiotensin system (RAS), SARS-CoV-2 infection may also cause damage to vascular endothelial cells and trigger a medium-to-high coagulation state in the blood. [1] In addition, fever, being bedridden, and bacterial and fungal infections in patients with COVID-19 pneumonia all increase the risks of a hypercoagulable state. [12] Furthermore, the findings of vascular micro-thrombosis confirmed by pathological studies have confirmed our hypothesis. [13] Therefore, anticoagulation therapy for patients with high coagulation risk, such as patients with elevated DDI levels, may be more beneficial to patient prognosis and reduce patient complications. Additional research is needed to confirm this hypothesis.

The use of glucocorticoids in patients with COVID-19 pneumonia is controversial. Currently, the pathophysiological mechanism of SARS-CoV-2 infection in humans is not very clear. Glucocorticoids have led to mixed outcomes in previous viral pneumonia cases, and there have been conflicting results, such as with the use of glucocorticoids in H1N1. [14, 15] In the treatment of SARS patients, glucocorticoids played a substantial role, but some studies have found that the use of glucocorticoids prolonged virus clearance. [16, 17] With the presence of a cytokine storm in COVID-19 pneumonia, studies have found that the use of glucocorticoids in patients who progress to ARDS is beneficial to their prognosis. [6] [7] [8] However, due to the difference in the condition of critically ill patients, research on hormone use is currently mainly retrospective, which may itself be biased. Additional research is still needed.

This study has some limitations. First, the study had a small sample size. Second, our data are not externally validated. The statistical results of possible bias and survivor bias need to be interpreted with caution. Therefore, more research is needed in the future to confirm the findings.

Elderly patients and those with hypertension and diabetes are more likely to develop condition changes after SARS-CoV-2 infection. During the treatment of COVID-19 pneumonia, changes in imaging findings suggest further condition changes. We constructed a disease prediction model for age, neutrophil ratio, imaging finding changes, glucocorticoid use, and DDI levels to predict changes in the disease course. Additional research is needed to combat the COVID-19 pneumonia epidemic.

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SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study

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Figure 3. The ROC curve of the predictor normogram

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Case Report Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

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We thank all medical workers, the patients and their families who participated in the fight against COVID-19 in Xiangtan and Shaoyang city. They have provided great help for the treatment of COVID-19 infection in Shaoyang area and Xiangtan city.

LSJ, YY, JMY, ZJP, XXD and LP conceived and designed the study; LSJ and YY contributed major in writing original manuscript. ZJP, XXD, CXP and HC contributed to the statistical analysis; all authors contributed to data collection, data analysis and read and approved the final manuscript.