key: cord-258583-5qdthy0j
authors: Yan, He; Lu, Shanshan; Chen, Liangpei; Wang, Yufang; Liu, Qiaomei; Li, Dongsheng; Yan, Xisheng; Yan, Jie
title: Multiple organ injury on admission predicts in‐hospital mortality in patients with COVID‐19
date: 2020-09-30
journal: J Med Virol
DOI: 10.1002/jmv.26534
sha: 
doc_id: 258583
cord_uid: 5qdthy0j

Multiorgan injury has been implicated in patients with coronavirus disease 2019 (COVID‐19). We aim to assess the impact of organ injury (OI) on prognosis according to the number of affected organs at admission. This is a retrospective cohort study of patients with confirmed COVID‐19 in Wuhan Third Hospital & Tongren Hospital of Wuhan University from February 17 to March 22, 2020. We classified the patients according to the presence and number of damaged organs (heart, liver, and kidney). The percentage of patients with no, one, two, or three organs affected was 59.75%, 30.46%, 8.07%, and 1.72%, respectively. With the increasing number of OI, there is a tendency of gradual increase regarding the white blood cell counts, neutrophil counts, levels of C‐reactive protein (CRP), lactate dehydrogenase, D‐dimer, and fibrinogen as well as the incidence of most complications. In a Cox regression model, individuals with OI, old age, and an abnormal level of CRP were at a higher risk of death compared with those without. Patients with three organ injuries had the highest mortality rate (57.9%; hazard ratio [HR] with 95% confidence interval [CI] vs. patients without OI: 22.31 [10.42–47.77], those with two [23.6%; HR = 8.68, 95% CI = 4.58–16.48], one [8.6%; HR = 3.1, 95% CI = 1.7–5.7], or no OI [2.6%]; p < .001). The increasing number of OI was associated with a high risk of mortality in COVID‐19 infection.

frequently arise after viral infection and during the exacerbation of COVID-19. [2] [3] [4] Acute respiratory distress syndrome (ARDS), multiple organ dysfunction, and even death are commonly manifested in severe cases. 5 Remarkably, individuals with OI tend to be associated with poorer outcomes. For example, several studies proposed that cardiac injury was significantly associated with fatal outcome of COVID-19 based on the levels of high-sensitivity troponin I (hs-TNI), which supports the notion of the cardiac implications of COVID-19 highlighted by the American College of Cardiology clinical bulletin. 6 Similarly, emerging evidence demonstrates the prevalence of kidney injury among patients with a severe condition, particularly in the intensive care unit (ICU) setting, and suggests the potential of it as an adverse prognostic factor concerning overall survival. However, it remains uncertain whether liver injury affects the mortality of COVID-19 patients, 4, 5 although it occurred more commonly in patients who had severe COVID-19 than mild ones. 7 According to the recent reports, the incidence of liver injury was uncovered as high as 58.06% or 78% in the deceased. 5, 8 Given the multifactorial cascade of events in patients with COVID-19, multiple organ systems are involved and will become prognostic of outcomes related to COVID-19. However, to date, clinical consequences of organ damage were usually studied placing a single organ dysfunction in isolation. 2, 3, 9 No investigation reported whether multiple OI had a relation with the ominous outcomes and to what extent it affects the mortality of COVID-19 patients. In clinical practice, various organs may be affected and can be utilized as a critical prognosticator in the decision-making of therapeutic strategy. We aimed to explore the association between OI and mortality according to the number of affected organs (heart, liver, and kidney) in patients with COVID-19. Cases were excluded if the core data were missing.

We collected data on demographic characteristics (age and sex), clinical data (symptoms and signs, comorbidities, laboratory findings, treatments, and outcomes) by medical records management system on admission. In light of the guidelines for diagnosis and management of COVID-19 released by the National Health Commission of China, 10 patients were divided into four types according to the disease severity, including mild, moderate, severe, and critical conditions. Cardiac biomarkers, liver function, and kidney function indexes measured within 24 h after admission were collected. The major indicators included high-sensitivity cardiac troponin I (hs-cTNI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyl transpeptidase (GGT), and serum creatinine (Scr). The enrolled patients were categorized according to the numbers of damaged organs, including the heart, liver, and kidney. One, two, three, or none of the organic injuries were listed, respectively. The cardiac injury was defined as serum levels of hs-cTNI above the 99th percentile upper limit of the reference range. 11 Patients were considered liver injury as any parameter more than the upper limit of the standard value of ALT, AST, ALP, and GGT. [12] [13] [14] Acute kidney injury was defined as an increase in serum creatinine by 0.3 mg/dl within 48 h according to the kidney disease improving global outcomes (KDIGO) criteria. 15 

The endpoint of this study was the incidence of survival or death in patients with COVID-19. The criterion of successful treatment and hospital discharge was comprised of clinical symptoms and signs resolved, laboratory indexes and chest radiography substantially improved, and two consecutive negative results by reverse transcriptionpolymerase chain reaction assay for COVID-19 at least 24 h apart.

The descriptive data were expressed as mean with standard deviation for continuous variables. Abnormally distributed variables were expressed as median with interquartile range (IQR). The categorical variables are expressed as numbers and proportions. All continuous variables were compared by analysis of variance (Kruskal-Wallis test) or t-test, and categorical variables were analyzed for the study outcome by using the χ2 test or Fisher exact test, as appropriate.

Survival curves were plotted by the Kaplan-Meier method and compared between groups using the log-rank test. The risk for OI and mortality was estimated with the univariable or multivariate Cox regression models and presented as hazard ratios (HRs) with 95% confidence interval (95% CI). A p < .05 was considered a statistically significant difference. All statistical analyses were performed with software SPSS (version 25.0) in this study. No difference was found in the clinical signs and symptoms across groups. Out of the total patients, hypertension (43.7% of patients), diabetes (13.6% of patients), and chronic heart disease (CHD; 11.8% of patients) were among the ranking prevalent comorbidities. Digestive system diseases, chronic obstructive pulmonary diseases (COPD), tumor, liver cirrhosis, hyperlipemia, and cerebrovascular diseases were relatively rare in our investigation. CHD was more common in patients with three, two, or one organ affected compared with those without OI (26.3% vs.

24.7% vs.10.6% vs. 9.8%, p < .001), which is similar to the trend observed in individuals with chronic kidney diseases (CKD; 26.3% vs. 22.5% vs. 8.6% vs. 3.2%, p < .001). The details of patient characteristics are presented in Table 1 .

The laboratory examination and radiologic findings are presented in Notably, our data demonstrated remarkably higher levels of hs-cTNI, creatinine kinase-myocardial band, brain natriuretic peptide, creatine kinase, ALP, total bilirubin, Scr, and blood urea nitrogen in patients with three or two OI than that in other groups. The increased level of procalcitonin (PCT) was more frequent in patients with OI versus those without (p < .001). Patients with three or two OI manifested more obvious abnormal coagulation function than others, including platelet, prothrombin time (PT), activated partial thromboplastin time, international normalized ratio, PT-% activity, FIB, and D-dimer (all p < .001).

No significant difference was found in the proportion of unilateral and bilateral pneumonia, ground-glass opacity, and pleural thickening across groups. However, patients were more likely to have pulmonary consolidation and pleural effusion if they had three or two OI as compared with other groups. Table 3 .

The detailed distribution of the population and type of injured organs in different organs-injured groups are shown in 1, p < .001) compared with patients with no OI as shown in Figure 2 (for three, two, one, and no OI, respectively).

The rate and risk of mortality were of no significant difference among the different types of two OI groups ( Figure 3 ). By contrast, in the context of single OI, patients with cardiac affection had a higher rate (29% vs. 8.51% vs. 6.2%, p = .002) and risk of mortality (HR = 6.01 vs. 1.35 vs. 1, p = .001) compared with those with only liver or kidney affected (Figure 4 ). Table 5 ).

The primary findings of this investigation were the following: Clinical studies suggested SARS-CoV-2 infection was associated with heart, kidney, and liver injury, which could serve as possible risk factors for increased disease severity. 16, 17 However, in previous investigations, OI was usually evaluated in isolation. Various organs might be affected at the same time or one after the other in disease progression, which could identify a specific clinical-pathological profile and maybe an indicator of a more severe course of COVID-19.

Herein, we found a progressive association between the number of injured organs and the mortality rate. COVID-19 patients with one, two, and three organs affected had 3, 8, and 22 times higher risk of mortality than those with none, respectively. This finding indicates the potential clinical utility of comprehensive evaluation of multiple OI (heart, kidney, and liver) for better characterization of those who may poorly respond to conventional therapy.

In our cohort, the overall mortality rate (7.1%) was higher than that reported in other studies, 6 but comparable to the mortality rate in a large cohort study with populations from Europe, Asia, and North America. 18 Through analyzing the potential risk factors for death, we found that older age coupled with CRP and OI served as coeffects on the risk for death. It is important to note that senior age was associated with the progression of ARDS and eventual death among COVID-19 patients. 19 Herein we identified that elderly with chronic comorbidities were more likely to develop multiple OI. However, these patients often presented atypical signs and symptoms, which often led to delayed diagnosis and treatment. patients. 23 In our study, we observed a gradient in the levels of CRP, D-dimer, and PCT with the number increase of OI, leading to a high elevation of these biomarkers in patients with all three organs affected. This further reinforces the view that accumulated systematic inflammation is associated with the end-organ injury. 24 This phenomenon also has therapeutic implications, as anti-inflammatory treatments should be appropriately implemented to prevent subsequent OI with poor prognosis in patients with COVID-19. 25, 26 Second, patients with pre-existing underlying diseases may be more susceptible to OI from SARS-CoV-2 or drugs. [27] [28] [29] The current results showed that patients with three or two OI had a higher percentage of CHD and CKD than those with one or none. This suggested a critical role of CHD and CKD in the development of multiorgan injury and eventual mortality, thus supporting the notion that chronic conditions were strongly associated with an increased risk of developing severe COVID-19. 30 providing a rationale that the liver may not be the primary target of direct infection and cell destruction by SARS-CoV-2.

Patients with elevated liver or kidney enzymes on admission had considerably higher odds of progressing to severe COVID- 19, 34 which was probably due to a history of using antipyretics and multiple antiviral drugs in a subset of patients. 35 In conclusion, we first demonstrated a graded relationship between the number of OI and mortality in SARS-CoV-2 infection.

Clinicians must assess OI as a whole rather than in isolation in hospitalized COVID-19 patients. Abbreviations: CHD, chronic heart diseases; CI, confidence interval; CKD, chronic kidney diseases; CLD, chronic liver diseases; COPD, chronic obstructive pulmonary diseases; COVID-19, coronavirus disease 2019; CVD, cerebrovascular diseases; CRP, C-reactive protein; HR, hazard ratio. a Y intersects the X-axis at X = 1, and the interval between the two points at X-axis is 2.5.

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The authors acknowledge all the patients, doctors, and nurses in- 

The authors declare that there are no conflict of interests. Chen are co-first authors, the order in which they were listed was determined by workload.

This study was performed according to the Declaration of Helsinki principles. The protocol was approved by the National Health Com-

Hospital & Tongren Hospital of Wuhan University (KY2020-047).Written informed consent was exempted owing to the rapid emergence of this infectious disease.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://orcid.org/0000-0001-6110-9630Jie Yan https://orcid.org/0000-0001-6877-5193