Clinical features of critically ill patients with COVID-19 infection in China

Importance: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections outbreak in China is now a global issue. There is only a limited understanding of the clinical characteristics of patients with SARS-CoV-2 infections is available. Objective: To describe the characteristics, management strategies, and outcomes of critically ill patients with SARS-CoV-2 infection. Design, Setting, and Patients: This is aretrospective, multi-center case series of 50 critically ill patients with confirmed SARS-CoV-2 infection who were admitted at Zhongnan Hospital of Wuhan University and Wuhan Pulmonary Hospital in Wuhan, China, from January 8 to February 9, 2020. Exposures: Documented Corona Virus Disease, 2019 (COVID-19). Main Outcome Measures: Demographic, clinical, laboratory, imaging data were collected along with management strategies, complications and outcomes of enrolled individuals. Results Fifty critically ill patients with SARS-CoV-2 infections were enrolled. Their median age was 62 (range, 29-92) [IQR,49.5-69.0] years, 68% were male, and 28 (56%) patients had comorbidities, the most common being hypertension. In this cohort, 20(40%) patients survived ,16(32%) patients died, and the rest remained hospitalized. The invasive mechanical ventilator was used in 36(72%) patients with 15(30%) of them requiring prone positioning, and 17(34%) switched to ECMO. The compliance scores of lungs (Cstat)on the day of ICU admission among survivors were higher than those in non-survivors [42.0(18.0-47.0), vs. 19.5(14.0-24.2), p=0.038].The blood IL-6 levels and neutrophils counts at the first day of ICU admission were significantly higher in non-survivors compared to survivors [123.7(85.3-228.8), vs. 20.2(6.8-67.2) ng/ml, p=0.025 for IL-6, and 20.2(6.8-67.2) vs. 4.01(1.99-7.05) injury scale (LIS), and positive end-expiratory pressure levels were constantly higher for 10 days in non-survivors than those who survived (p<0.05). The frequency of vasopressor uses and neuromuscular blockers was higher in non-survivors from day 1 to day 10 compared to survivors (p<0.05). In the whole cohort, the most common complications were ARDS (97%), shock (44%), arrhythmia (38%), acute cardiac injury (26%), and acute kidney injury (22%). A secondary bacterial infection was noted in 17(34%) patients. Univariate analysis indicated that lower lung complianceand higher neutrophil counts at the day of ICU admission were related to higher mortality (p-0.03, and 0.04, respectively) Conclusion We demonstrated that SARS-CoV-2 infection-related critical illness predominantly affected old individuals with comorbidities and characterized by severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation and rescue therapies. Low lung compliance and persistently elevated PaCO2 indicated poor outcomes.


Introduction
In February 2019, a new coronavirus was isolated for the first time from a patient in Wuhan, China, who presented with acute pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ dysfunction syndrome (MODS) [1][2][3]. The virus was identified as a family member of severe acute respiratory syndrome coronaviruses (SARS-CoVs), and it was designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [4]. The clinical disease caused by SARS-CoV-2 was named Corona Virus Disease, 2019, or COVID-19. The main route of human-to-human transmission of SARS-CoV-2 is probably airborne [5][6][7][8]. As of Feb 14, 2020, statistical data show that the outbreak constitutes an epidemic threat in China, where the exponential increase in the number of individuals acquired SARS-CoV-2 has reached 52,526 confirmed cases, with 8,083 (15%) of them being in critical conditions and 1,367 (26%) died. The disease has a high fatality rate and has several clinical features that resemble the infection caused by SARS-CoV and MERS-CoV [9][10][11][12][13]. This viral infection has resulted in a significant concern regarding the global pandemic. While the knowledge about this virus is accumulating, the information regarding critical illness among infected individuals with SARS-CoV-2 remains limited. Therefore, we describe the clinical course and outcomes of 50 critically ill patients with SARS-CoV-2 admitted to 2 intensive care units (ICUs) in tertiary hospitals in Wuhan, China, which is considered the epicenter of this viral outbreak.

Study Design and Participants
This case series was approved by the institutional ethics board of ZhongnanHospital of Wuhan University (No. 2020020) and Wuhan Pulmonary Hospital (No. 2020020). Oral consent was obtained from patients or patients' relatives. All consecutive patients with COVID-19 admitted to ICU of the two hospitals from January 8 to February 9, 2020, were screened. Included patients with COVID-19 had virology confirmation with RT-PCR methods. Patients were admitted to ICU if respiratory or other organ supports were needed. Zhongnan Hospital and Wuhan Pulmonary Hospital located in Wuhan, Hubei Province, the endemic areas of COVID-19, are responsible for the treatments for COVID-19 assigned by the government. All patients with COVID-19 enrolled in this study were diagnosed according to World Health Organization interim guidance [14].

Data Collection
The medical records of patients were analyzed by the research team of the Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University. The electronic medical records was used to abstract the information regarding demographics, medical history, exposure history, underlying comorbidities, symptoms, signs, laboratory findings, chest CT scans, and management or treatment strategies (i.e., antiviral therapy, antibiotics, vasopressor, sedative-analgesic agents, corticosteroid therapy, respiratory support, extracorporeal membrane oxygenation (ECMO), kidney replacement therapy) and patient outcomes. The data were reviewed by a trained team of physicians. Heart rate, mean arterial pressure, arterial blood gas, and ventilation parameters were obtained at 8 a.m. of every day during ICU stay. All patients were followed for the assessment of complications and outcomes until hospital discharge or death. ARDS was defined according to the Berlin definition [15]. Acute kidney injury was identified according to the Kidney Disease: Improving Global Outcomes criteria [16]. The cardiac injury was defined when the serum levels of cardiac biomarkers (e.g., troponin I) were above the 99th percentile upper reference limit or new abnormalities were shown in electrocardiography and echocardiography [13]. The Acute Physiology and Chronic Health Evaluation (APACHE II), Glasgow Coma Score (GCS), Sequential Organ Failure Assessment (SOFA), and Murray scores were followed every 2 days during ICU stay. Also, the information regarding dyspnea, ARDS, use of high-flow nasal cannula oxygen therapy (HFNC), invasive or noninvasive mechanical ventilator,intubation, and ECMO were abstracted.

Statistical Analysis
Categorical variables were described as frequencies and percentages, and continuous variables were summarized using mean and standard deviations or median and interquartile range (IQR) values, as appropriate based on the variable normal distribution.
Means for continuous variables were compared using independent group t-tests when the data were normally distributed; otherwise, the Mann-Whitney test was used. Data (nonnormal distribution) from repeated measures were compared using the generalized linear mixed model. Proportions for categorical variables were compared using the X 2 test, although the Fisher exact test was used when the data were limited. All statistical analyses were performed using SPSS (Statistical Package for the Social Sciences) version 13.0 software (SPSS Inc). For unadjusted comparisons, a 2-sided α of <.05 was considered statistically significant. We did not adjust for multiple comparisons and, given the potential for type I error, the findings should be interpreted as exploratory and descriptive.  As shown in Table 2

Comparisons of survivors and non-survivors
The non-survivors were older than survivors (66. 5 Figure 1). Non-survivors received significantly more vasopressors than survivors (p<0.05; Figure1). Table 3 and Figure 1 show the dynamic changes of vital signs, mechanical ventilation parameters, treatment measures, and scores from day 1 to day 10. During this period, the vital signs were roughly kept within normal range by using various organ support therapy modalities, although non-survivors had higher heart rates. From day 5, the level of PaCO2 in non-survivors began to increase and was continuously higher than that in ICU-survivors.

Dynamic clinical course of Illness
At the same time, the LIS was higher in non-survivors than in the survivors. The median of PEEP was 10mmHg from day 1 to day 10. Vasopressors and neuromuscular blockers were used more frequently in non-survivors from day 5 than those in survivors (p<0.05).
Less common complications included cerebral infarction, cerebral hemorrhage, and hypoxic-ischemic encephalopathy. Among those with AKI, 50% required continuous renal replacement therapy (CRRT). In the 36 enrolled discharged patients, 7(19.4%) patients Univariate analysis and multivariate analysis for mortality-related risk factors

Discussion
Our analysis of critically ill patients with COVID-19 revealed that this disease affected older patients with comorbidities. These patients had severe hypoxia/ ARDS, and the majority of them required mechanical ventilation. Some of these patients needed prone ventilation and ECMO to maintain their gas exchange.The survivors had lower IL-6 and higher Cstat than non-survivors on the first day of ICU admission. The dynamic assessment of variables indicated that the persistent elevation in PaCO2, LIS, HR, and neutrophil counts occurred more often in non-survivors. Also, non-survivors persistently required higher PEEP, more neuromuscular blockers and vasopressor support. Lower Cstat and higher neutrophil counts were risk factors for mortality.
To our knowledge, this is the first report to summarize the clinical features and dynamic pulmonary parameters among critically ill patients with COVID-19. The timeline between the illness onset to ICU admission was about 10 days, which was similar to previous reports [11,13]. This time point may represent the peak viral shedding period.
At ICU admission, we noted some abnormal laboratory findings in critically ill patients with COVID-19, which included neutrophilia, lymphopenia, prolonged prothrombin time, and hypoxemia. An elevated level of lactate dehydrogenase and aspartate aminotransferase was also common. The above abnormal values indicated the presence of MODS in this systemic viral infection. In the early stage of MODS induced by SARS-CoV-2 infection, the common manifestations included ARDS, coagulation dysfunction, and acute liver injury.
Furthermore, the level of white blood cell count, neutrophil count, and IL-6 were higher in non-survivors than those in survivors. Neutrophilia was also a risk factor for death in our There is currently no treatment recommended for coronavirus infections except for supportive care as needed [21]. Several antivirals and other agents have been used during the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak. Herein, most patients were given antiviral and glucocorticoid therapy prior to ICU admission, but the efficacy of these drugs should be assessed in the future. Secondary infection was common in the late stages of the illness and at least partly due to the prolonged ICU length of stay. Thus, controlling the secondary infection is also critical to reduce hospital mortality.
Diffuse alveolar damage with varying degrees of the organization is seen on pathologic examination in patients with SARS who have acute lung injury [22]. For our patents, severe disease with lung injury is believed to reflect an excessive host response with the production of large quantities of proinflammatory cytokines ("cytokine storm").
Angiotensin-converting enzyme 2 (ACE2) and lymphopenia may also be associated with organ injury in SARS-CoV-2 infection, as they were found in other similar viral infection outbreaks [23,24]. Other possible mechanisms include direct viral invasion; the virus was recovered from lung and stool in one report [25]. Additionally, the post-mortem examination may be needed to discover the pathogenesis of the COVID-19. We also identified the Cstat of ICU admission as a clinical risk factor for death by univariate logistic regression analysis. Additionally, increased dead space has been shown in the previous reports. Furthermore, positive pressure ventilation tends to increase alveolar dead space by increasing ventilation in alveoli that do not have a corresponding increase in perfusion, thereby worsening V/Q mismatch and hypercapnia. In fact, hypercapnia was obvious in ICU-non-survivors of our patients. This study has several limitations. Only 36 patients were discharged (including alive and dead) were used to compare between survivors and non-survivors in this study. Due to the limited number of patients, the differences between survivors and non-survivors should be interpreted carefully. The median of ICU length of stay was 10 days, and we tracked some important data during this timeline. Future studies are needed to track temporal changes for longer periods of time to describe the whole clinical progress among critically ill patients with COVID-19. Although we collected cases from two ICU located in Wuhan, multicenter studies are needed to thoroughly describe the comorbidities and clinical features of this illness.
In conclusion, we have demonstrated that SARS-CoV-2 infection-related critical illness predominantly affects older patients with comorbidities and is associated with severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation. The low Cstat at ICU admission and continuous elevated PaCO2 indicated poor outcomes.
Take Home Message 1.
Almost all these patients (94%) developed severe ARDS, and the majority of them (72%) required invasive mechanical ventilation. Some of these patients needed prone ventilation (30%) and ECMO (34%).

2.
64% of these patients were complicated with heart problems, including arrhythmia and acute cardiac injury. 44% of the patients progressed to shock, and 22% to acute kidney injury.

3.
The survivors had lower IL-6 and higher Cstat than non-survivors at the day of ICU admission.

4.
Persistent elevation in PaCO2, lung injury scores, heart rates, and neutrophil counts occurred more often in non-survivors. Also, non-survivors persistently required higher PEEP, more neuromuscular blockers and vasopressor support.

5.
Lower Cstat and higher neutrophil counts were risk factors for mortality.

Declarations
Funding: This work was supported by the National Natural Science Foundation (grants  P values indicate differences between survivors and non-survivors. P < .05 was considered statistically significant.    PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; PEEP, positive end-expiratory pressure; SOFA, Sequential Organ Failure Assessment.
P values indicate differences between survivors and non-survivors. P < .05 was considered statistically significant.