Clinical diagnosis, treatment and outcome of critically ill patients with coronavirus disease 2019 infected by SARS-CoV-2 in Wuhan and Shenyang, China: A dual-center, retrospective, observational study

Treatment of critical COVID-19 patients

Authors

  • Jingbo Wang Department of Infectious Disease, The Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
  • Guozhen Li Department of Gastroenterology, Wuhan Red Cross Hospital, Wuhan 430015, Hubei Province, China
  • Haitao Wang Department of General Surgery, The Second Affiliated Hospital of Shenyang Medical College, Shenyang 110001, Liaoning Province, China
  • Liangzhong Ma Department of Internal Medicine, Shenyang 245 Hospital, Shenyang 110046, Liaoning Province, China
  • Wei Wu Department of Intensive Critical Medicine, The Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
  • Yunhai Wu Department of Intensive Critical Medicine, The Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
  • Jinyang Liu Department of Intensive Critical Medicine, The Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
  • Guoliang Pan Department of Psychology, Shenyang Mental Health Center, Shenyang 110168, Liaoning Province, China

DOI:

https://doi.org/10.54844/cai.2022.0081

Keywords:

severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, critically ill cases, acute respiratory distress syndrome, hypoxemia, mechanical ventilation

Abstract

Background and Objective: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is currently circulating worldwide. Our purpose was to describe the clinical diagnosis, treatment and outcome of severe cases of SARS-CoV-2 infection. Methods: In this study, we collected 86 critically ill adult patients with COVID-19 treated in ICU of Wuhan Red Cross Hospital and the Sixth People’s Hospital of Shenyang from December 24, 2019 to February 10, 2021. Patients were divided into death group and survival group. The primary endpoint is the 28-day mortality rate, and the secondary endpoints were the incidence of acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Results: The average age of patients was 67.8 years, of whom 62 patients (72.1%) were male, 58 patients (67.4%) suffered from chronic diseases, and 84 patients (97.7%) had fever. The 28-day mortality rate was 53.5% (46/86 cases), and the average time from admission to ICU to clinical death was 7 days (IQR 3–11). There were 60 patients (69.7%) who occurred ARDS. There were 62 patients (72.1%) who required mechanical ventilation. And 37 patients (43.0%) received convalescent plasma treatment. Moreover, 30 patients (34.9%) were injected with tocilizumab. Conclusions: The mortality rate of critically ill patients with COVID-19 is high. The survival time of death cases is generally 1–2 weeks after entering the ICU. Old age, combined underlying diseases and ARDS are risk factors that increase the risk of death. Most critically ill patients require mechanical ventilation. Convalescent plasma and anti-IL-6 receptor monoclonal antibody may be effective immunotherapy methods.

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2022-08-31

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Wang J, Li G, Wang H, Ma L, Wu W, Wu Y, Liu J, Pan G. Clinical diagnosis, treatment and outcome of critically ill patients with coronavirus disease 2019 infected by SARS-CoV-2 in Wuhan and Shenyang, China: A dual-center, retrospective, observational study: Treatment of critical COVID-19 patients. Community Acquir Infect. 2022;9. doi:10.54844/cai.2022.0081

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Original Article

Clinical diagnosis, treatment and outcome of critically ill patients with coronavirus disease 2019 infected by SARS-CoV-2 in Wuhan and Shenyang, China: A dualcenter, retrospective, observational study


Jingbo Wang1#, Guozhen Li2#, Haitao Wang3, Liangzhong Ma4, Wei Wu5, Yunhai Wu5, Jinyang Liu5, Guoliang Pan6*

1Department of Infectious Disease, The Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China

2Department of Gastroenterology, Wuhan Red Cross Hospital, Wuhan 430015, Hubei Province, China

3Department of General Surgery, The Second Affiliated Hospital of Shenyang Medical College, Shenyang 110001, Liaoning Province, China

4Department of Internal Medicine, Shenyang 245 Hospital, Shenyang 110046, Liaoning Province, China

5Department of Intensive Critical Medicine, The Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China

6Department of Psychology, Shenyang Mental Health Center, Shenyang 110168, Liaoning Province, China


Background and Objective: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is currently circulating worldwide. Our purpose was to describe the clinical diagnosis, treatment and outcome of severe cases of SARS-CoV-2 infection. Methods: In this study, we collected 86 critically ill adult patients with COVID-19 treated in ICU of Wuhan Red Cross Hospital and the Sixth People’s Hospital of Shenyang from December 24, 2019 to February 10, 2021. Patients were divided into death group and survival group. The primary endpoint is the 28-day mortality rate, and the secondary endpoints were the incidence of acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Results: The average age of patients was 67.8 years, of whom 62 patients (72.1%) were male, 58 patients (67.4%) suffered from chronic diseases, and 84 patients (97.7%) had fever. The 28-day mortality rate was 53.5% (46/86 cases), and the average time from admission to ICU to clinical death was 7 days (IQR 3–11). There were 60 patients (69.7%) who occurred ARDS. There were 62 patients (72.1%) who required mechanical ventilation. And 37 patients (43.0%) received convalescent plasma treatment. Moreover, 30 patients (34.9%) were injected with tocilizumab. Conclusions: The mortality rate of critically ill patients with COVID-19 is high. The survival time of death cases is generally 1–2 weeks after entering the ICU. Old age, combined underlying diseases and ARDS are risk factors that increase the risk of death. Most critically ill patients require mechanical ventilation. Convalescent plasma and anti-IL-6 receptor monoclonal antibody may be effective immunotherapy methods.


Key words: severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, critically ill cases, acute respiratory distress syndrome, hypoxemia, mechanical ventilation


Address for correspondence:

Dr. Guoliang Pan, Department of Psychology, Shenyang Mental Health Center, No. 12, Jinfan Middle Road, Hunnan District, Shenyang 110168, Liaoning Province, China. E-mail: pgl0210@126.com

Submitted: 18-03-2022 Revised: 06-07-2022

Accepted: 17-08-2022 Published: 31-08-2022

For reprints contact: reprints@sppub.org



Coronavirus disease 2019 (COVID-19) caused by severe acute respirator y coronavirus 2 (SARS-CoV-2) infection is a new infectious disease which is continuing to erupt globally.[1,2] As of February 10, 2021, 106,125,682 cases had been diagnosed globally and 2,320,497 patients (2.2%) were dead, moreover, fatality rate of critically ill cases is much higher than it.[3,4] Our research on the clinical diagnosis, treatment and outcome of critical COVID-19 cases is of great significance for early identification and treatment in order to reduce mortality of critical cases.


Our dual-center, retrospective study was completed in Wuhan Red Cross Hospital and the Sixth People's Hospital of Shenyang, both of which are designated hospitals for COVID-19 treatment by the government. We retrospectively analyzed the confirmed critically ill cases of COVID-19 from December 24, 2019 to February 10, 2021 according to WHO interim guidelines and China's new coronavirus pneumonia diagnosis and treatment guideline.[5,6] The diagnostic criteria for critical cases are those who meet one of the following conditions: those with respiratory failure and requiring mechanical ventilation, those with shock, and those with other organ failure requiring ICU monitoring and treatment.[7,8] The data was evaluated and collected using the revised version of the International Severe Acute Respiratory and Emerging Infection Consortium medical record report template.[9]


The most important observation indicator was the 28-day mortality after entering the ICU. The secondary observation indicators are the incidence of acute respirator y distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. The diagnosis of ARDS is based on the WHO guidelines for COVID-19.[5] The diagnosis of acute kidney injury is based on the increase of serum creatinine (SCr) by 0.5 mg/dL.[10] The diagnostic criteria for myocardial injury is that the serum troponin I (TNI) exceeds the upper limit of the normal reference value (> 0.5 ng/mL). The diagnosis for liver damage is that serum glutamyl transpeptidase (ALT) exceeds the upper limit of the normal reference value (> 40 U/L). Laboratory tests were carried out in the medical examination centers of Wuhan Red Cross Hospital and the Sixth People's Hospital of Shenyang. For the surviving cases as of February 10, 2021, their survival status were followed up until February 24, 2021.


For descriptive data, the mean ± standard deviation (SD) and median (IQR) were used to represent continuous variables, and the percentage (%) was used to represent categorical variables. When comparing the death group and survival group, two independent sample t-test or Wilcoxon rank sum test was used for parametric data or nonparametric data of continuous variables, and chi-square test was used for categorical variables. SPSS version 26.0 (SPSS Inc., Chicago, USA) was used for analysis, and less than 0.05 is considered statistically different.


The Ethics Committee of Wuhan Red Cross Hospital and the Sixth People's Hospital of Shenyang agreed to this study. (No. KY-LW-2021-04-01) Due to the sudden epidemic of this infectious disease, written informed consent was exempted.


As of February 10, 2021, Wuhan Red Cross Hospital and Sixth People's Hospital of Shenyang have admitted 86 critical cases of COVID-19. The average age of the patients was 67.8 ± 15.3 years, and 70 patients (82.5%) were over 60 years old (Table 1). There were 62 male patients (72.1%). There were 40 patients (46.5%) who had contact history with confirmed or highly suspected patients. And 58 patients (67.4%) had chronic underlying diseases, of which 23 patients (26.7%) suffered from cardiovascular diseases.


Table 1: Demographics and baseline characteristics of critically ill patients with COVID-19
Characteristics Survivors (N = 40) Non-Survivors (N = 46) All patients (N = 86)
Age, years 50.6 ± 12.9* 70.4 ± 11.2 67.8 ± 15.3
Age range, N (%)
  30–39 years 4 (10.0) 2 (4.3) 6 (6.9)
  40–49 years 3 (7.5) 1 (2.2) 4 (4.6)
  50–59 years 3 (7.5) 3 (6.5) 6 (6.9)
  60–69 years 13 (32.5) 13 (28.2) 26 (30.2)
  70–79 years 7 (17.5) 15 (32.6) 22 (25.6)
  ≥80 years 8 (20.0) 14 (16.3) 22 (25.6)
Sex, N (%)
  Female 14 (35.0) 10 (21.7) 24 (27.9)
  Male 30 (75.0) 32 (69.5) 62 (72.1)
Exposure, N (%)
  Exposure to patients# 17 (42.5) 23 (50.0) 40 (46.5)
  Chronic medical illness 18 (45.0)* 40 (86.9) 58 (67.4)
  Chronic cardiac disease 7 (17.5) 16 (34.8) 23 (26.7)
  Chronic pulmonary disease 4 (10.0) 10 (21.7) 14 (16.3)
  Diabetes 5 (12.5) 8 (17.4) 13 (15.1)
  Cerebrovascular disease 2 (5.0) 3 (6.5) 5 (5.8)
  Malignancy 0 3 (6.5) 3 (3.5)
  Aplastic anemia 1 (2.5) 0 1 (1.2)
  Infective endocarditis 1 (2.5) 0 1 (1.2)
  Smoking 15 (37.5) 14 (30.4) 29 (33.7)
#Patients who have confirmed SARS-CoV-2 infection or are highly suspected of being infected. *P < 0.05 vs. non-survivors cases. COVID-19: coronavirus disease 2019.


The most common symptom was fever (97.7%), followed by cough (77.9%), and dyspnea (72.1%) (Table 2). Of the 86 severe cases, 6 (6.9%) developed fever 2–8 days after the onset of other symptoms. In all cases, lung X-ray or CT showed exudates from both lungs and typical ground glass shadows. The median time from onset of clinical symptoms to imaging manifestations of pneumonia, to entering ICU was 4.1 days (IQR 3.0–7.0) and 8.2 days (IQR 6.0–12.0), respectively.


Table 2: Symptoms, comorbidities, and treatments of critically ill patients with COVID-19
Items Survivors (N = 40 ) Non-Survivors (N = 46 ) All patients (N = 86 )
  Symptoms, N (%)
  Fever 39 (97.5) 45 (97.8) 84 (97.7)
  Cough 35 (87.5) 34 (73.9) 67 (77.9)
  Dyspnoea 30 (75.0) 32 (69.5) 62 (72.1)
  Malaise 18 (45.0) 24 (52.2) 42 (48.8)
  Myalgia 14 (35.0) 13 (28.2) 27 (31.4)
  Rhinorrhoea 11 (27.5) 9 (19.6) 20 (23.2)
  Arthralgia 8 (20.0) 7 (15.2) 15 (17.4)
  Chest pain 7 (17.5) 8 (17.4) 15 (17.4)
  Headache 6 (15.0) 8 (17.4) 14 (16.3)
  Vomiting 5 (12.5) 5 (10.8) 10 (11.6)
Comorbidities, N (%)
Acute respiratory distress syndrome 20 (50.0)* 40 (86.9) 60 (69.7)
  Acute kidney injury 19 (47.5) 27 (58.7) 36 (41.9)
  Cardiac injury 18 (45.0) 28 (60.9) 36 (41.9)
  Liver dysfunction 15 (37.5) 15 (32.6) 30 (34.9)
  Hospital-acquired infection 10 (25.0) 17 (36.9) 27 (31.4)
  Pneumothorax 2 (5.0) 1 (2.2) 3 (3.5)
Treatments, N (%)
  Mechanical ventilation 18 (45.0)* 44 (95.6) 62 (72.1)
  Non-invasive 13 (32.5) 21 (45.6) 34 (39.5)
  Invasive 11 (27.5) 17 (36.9) 28 (32.5)
  Prone position ventilation 27 (67.5) 25 (54.3) 52 (60.5)
  High flow nasal cannula 25 (62.5) 21 (45.6) 46 (53.5)
  Extracorporeal membrane oxygenation 3 (7.5) 10 (21.7) 13 (15.1)
  Antibacterial agents 36 (90.0) 44 (95.6) 80 (93.0)
  Glucocorticoids 29 (72.5) 32 (69.5) 61 (70.9)
  Antiviral agents 26 (65.0) 24 (52.2) 50 (58.1)
    lopinavir/ritonavir 15 (37.5) 19 (41.3) 34 (39.5)
    Remdesivir 11 (27.5) 5 (10.9) 16 (18.6)
  Immunoglobulin 17 (42.5) 30 (65.2) 47 (54.6)
  Convalescent plasma 27 (67.5)* 10 (21.7) 37 (43.0)
  Vasoconstrictive agents 12 (30.0) 20 (43.5) 32 (37.2)
  Tocilizumab Injection 23 (57.5)* 7 (15.2) 30 (34.9)
  Blood purification 7 (17.5) 10 (21.7) 27 (31.4)
  Renal replacement therapy 4 (10.0) 13 (28.2) 17 (19.7)
*P < 0.05 vs. non-survivors cases. COVID-19: coronavirus disease 2019.


The median Acute Physiology and Chronic Health Evaluation II (APACHE II) score of all the critical cases enrolled was 24 points (IQR 21–27), and the median SOFA score was 8 points (IQR 6–11). For death group and survival group, the median APACHE II scores were 26 points (IQR 24–29) and 21 points (IQR 19–24), respectively, and the median SOFA scores were 9 points (IQR 7–11) and 5 points (IQR 4–6), there is no significant difference between two groups (Table 3). The lymphocyte counts of 73 patients (84.9%) decreased. The death group and the survival group were 0.53×109/L and 0.7×109/L, respectively, and no statistical difference between them (Table 3).


Table 3: Differences in intensive care measures and vital signs between sur vivors and non-sur vivors of critically ill patients with COVID-19
Items Survivors (N = 40) Non-Survivors (N = 46) All patients (N = 86)
Duration from onset of symptoms to radiological confirmation of pneumonia, days 6.5 (3.0–9.0) 2.9 (2.0–6.0) 4.1 (3.0–7.0)
Duration from onset of symptoms to ICU 12.1 (7.0–14.0) 5.3 (3.0–9.0) 8.2 (6.0–12.0)
admission, days
Heart rate, beat/min 89 (61–101) 95 (59–111) 92 (65–111)
Systolic blood pressure, mmHg 123 (90–149) 139 (88–150) 130 (92–157)
Ratio of PaO2 to FiO2, mmHg 105.2 (66.6–136.7) 57.9 (42.0–74.1) 83.1 (49.9–200.1)
APACHE II score on day 1 21 (19–24) 26 (24–29) 24 (21–27)
SOFA score on day 1 5 (4–6) 9 (7–11) 8 (6–11)
Lymphocyte count, ×109/L 0.7 (0.5–1.3) 0.5 (0.1–1.1) 0.6 (0.1–1.2)
IL-6, pg/mL 29.9 (21.1–42.1) 42.9 (29.9–65.2) 33.7 (26.8–49.6)
CRP, mg/L 99.8 (79.3–149.2) 130.1 (95.3–210.1) 110.3 (87.1–231.9)
D-dimer, mg/L 32.3 (20.9–51.1) 41.8 (30.5–60.1) 35.8 (20.6–49.7)
Prothrombin time, s 11.1 (8.1–14.7) 12.8 (9.7–16.9) 12.1 (9.6–17.3)
Glutamyltranspetidase, U/L 66 (23–109) 76 (30–262) 72 (27–262)
Serum creatinine concentration, μmol/L 77.5 (39.0–117.1) 91.7 (48.6–170.3) 89.8 (56.7–189.5)
Troponin I, ng/mL 2.1 (0.3–3.8) 2.5 (0.3–5.2) 2.6 (0.4–3.9)
Lactate concentration, mmol/L 1.3 (0.9–1.6) 3.0 (1.5–3.5) 2.3 (0.9–5.2)
Data are median (IQR). COVID-19: coronavirus disease 2019, APACHE II: acute physiology and chronic health evaluation II, FiO2: fraction of inspired oxygen, PaO2: partial pressure of oxygen, SARS-CoV-2: severe acute respiratory coronavirus 2, SOFA: sequential organ failure assessment, IL-6: interleukin-6, CRP: C-reactive protein.


Hospital acquired infections occurred in 27 patients (31.4%), which was based on the culture results of blood, sputum, urine, P ICC tip and bronchoalveolar lavage fluid. Nine different microorganisms were detected, including multi-drug-resistant Acinetobacter baumannii (MDR-AB strain and CR-aba strain), extended-spectrum β-Lactamase (ESBL)-positive K pneumonia, carbapenem-resistant Klebsiella oxytoca (CRE strain), ESBL-positive and quinolone-resistant Escherichia coli (ESBL QNR-ECO strain), methicillin-resistant coagulase-negative Staphylococcus hominis, Methicillin-resistant Staphylococcus aureus (MRSA strain), high-levul-aminoglycoside -resistant Enterococcus faecalis (H LAR strain), methicillin-resistant coagulase-negative Staphylococcus capitis (Mrcon strain) and candida albicans.


Organ function damage occurred in most cases, including 60 patients (69.7%) of ARDS, 36 patients (41.9%) of acute kidney injury, 36 patients (41.9%) of myocardial damage, 30 patients (34.9%) of liver damage and 3 patients (3.5%) of pneumothorax (Table 2). The median value of Scr, TNI, ALT, IL-6, CRP and D-dimer was 89.8 μmol/L, 2.6 ng/mL, 72 U/L, 33.7 pg/mL, 110.3 mg/L and 35.8 mg/L, respectively. There was no statistical difference in above six indicators between death group and survival group (Table 3).


Among the patients, 62 patients (72.1%) received mechanical ventilation, 52 patients (60.5%) received prone position ventilation, 46 patients (53.5%) received high-flow nasal cannula oxygen, and 13 patients (15.1%) received extracorporeal membrane oxygenation (ECMO). Antibiotics were given to 80 patients (93.0%). Intravenous glucocorticoids were given to 61 patients (70.9%). There were 50 patients (58.1%) who received antiviral therapy, among which, 34 patients (39.5%) were given lopinavir/ritonavir, and 16 patients (18.6%) were given Remdesivi. Immunoglobulin therapy was given to 47 patients (54.6%). Convalescent plasma was received in 37 patients (43.0%). Vasoconstrictors were given to 32 patients (37.2%). Tocilizumab injection was given to 30 patients (34.9%). Blood purification therapy was given to 27 patients (31.4%). And there were 17 patients (19.7%) who received renal replacement therapy (Table 2). The criteria for these treatment therapies were based on two planes of China.[11,12]


Among 40 surviving cases, 28 patients were discharged from the hospital, and the other 12 patients were still in the hospital on the 28th day of admission to ICU, 3 of whom received invasive ventilator therapy, one case using non-invasive ventilator, 2 cases using high-flow nasal cannula for oxygen inhalation, and 6 cases using ordinary nasal cannula to inhale oxygen.


The most important observation is that critically ill patients died within 28 days after entering the ICU, and the median survival time from entering ICU to clinical death was 7 days (IQR 3–7). Compared with survival cases, death cases are more likely to progress to ARDS (40 [86.9%] vs. 20 [50.0%]) and are more likely to require mechanical ventilation (44 [95.6%] vs. 18 [45.0%]), and there are significant differences between two groups (Table 2). Of the 62 cases receiving mechanical ventilation, 38 patients (61.3%) died within 28 days.


Compared with patients in survival group, patients in death group were older (70.4 ± 11.2 years vs. 50.6 ± 12.9 years), and were more common with chronic diseases (40 [86.9%] vs. 18 [45.0%]), and the difference between two groups was statistically significant (Table 1). Patients in survival group, compared with death group, were more treated with convalescent plasma (27 [67.5%] vs. 10 [21.7%]) and tocilizumab injection (23 [57.5%] vs. 7 [15.2%]), and the difference between two groups was statistically significant (Table 2). In death group, the average time from onset of clinical symptoms to imaging manifestations of pneumonia and to ICU admission was 2.9 days and 5.3 days, respectively, which were significantly shorter than 6.5 days and 12.1 days in survival group (Table 3). The oxygenation index (OI, the ratio of PaO2 to FiO2) of the death group was significantly reduced to 57.9 mmHg. However, OI of sur vival group was 105.2 mmHg (Table 3).


We reported 86 laboratory-confirmed severe cases of COVID-19 caused by SARS-CoV-2 infection. And 58 patients (67.4%) of them suff ered from c hronic diseases. The patients were characterized by severe hypoxemia with significantly reduced oxygenation index. There were 46 patients (53.5%) who died within 28 days after entering ICU. Moreover, 60 patients (69.7%) progressed to ARDS, 62 patients (72.1%) required mechanical ventilation, 37 patients (43.0%) received convalescent plasma, and 30 patients (34.9%) were injected with anti-IL-6 receptor monoclonal antibody.


Since there are no specific antiviral drugs for SARS-CoV-2 infection, the most important measure at present is supportive treatment.[13,14,15] Therefore, critical cases should be transferred to ICU as soon as possible for organ function support. Among the previously published studies, the treatment for severe cases was mainly under extreme epidemic conditions.[16,17] Our study enrolled 86 critically ill cases whose treatment measures have become more perfect due to government's overall arrangement of medical personnel and rescue equipments.


Similar to SARS-CoV and MERS-CoV, SARS-CoV-2 is also a coronavirus that can be transmitted to humans, with a high mortality rate for severely infected patients.[18] Our study found that the mortality rate of severe cases of SARS-CoV-2 infection was 53.5%, which was higher than the previous SARS and lower than MERS. A study of severe SARS cases from Canada showed that the 28-day mortality rate was 43%.[8] In addition, studies from Singapore[19] and Hong Kong, China[20] found that the 28-day mortality rate of severe SARS cases was 38% (17/45 cases) and 26% (14/54 cases), respectively. A study from Saudi Arabia found that the 90-day mortality rate of 12 people infected with MERS was 58%.[21] According to the limited autopsy and puncture histopathological observations, the pathological changes of SARS-CoV-2 infection are mainly lung consolidation. The pathophysiological basis of severe viral pneumonia is ARDS. Therefore, the mortality rate of severe SARS-CoV-2 infection is about 50%, similar to that of severe ARDS.[22]


In SARS and MERS patients, elderly men are more likely to progress to critically ill cases than elderly women and young men.[23] Similar to previous studies, our study observed that 72% of COVID-19 critical cases were male with a median age of 68 years, and the average age of the death group was 19.8-year (70.4–50.6 years) higher than survival group.[24,25] Suffering from chronic diseases is an increased risk factor for death.


In our research, fever is the most common symptom of COVID-19 critically ill patients in the early stage of onset, but not all cases have fever symptoms. We found that 6 patients (6.9%) did not develop fever at the time of onset. The delayed appearance of the obvious clinical symptoms of fever is not conducive to the early recognition of SARS-CoV-2 infection, however, of whom are already infectious at this time. This means that routine SARS-CoV-2 nucleic acid screening for high-risk infectious populations may be identify infected persons early, even in the asymptomatic stage, which is very beneficial for isolating the source of infection and blocking the spread of the virus.


Regarding laborator y tests, in our study, more than 92% of critically ill cases had decreased lymphocyte counts. This is mainly due to the SARS-CoV-2 virus targeting lymphocytes, especially T-lymphocytes.[26] Decrease in lymphocytes in critically ill patients with MERS is also common, nevertheless, the main cause is apoptosis.[27] Therefore, we speculate that cell necrosis or apoptosis is the possible cause of the decrease of lymphocyte counts in severe SARS-CoV-2 cases. Degree of lymphocyte reduction may be an important reason for the deterioration of the patient's condition.[28] In our study, we also observed that the degree and duration of lymphocyte count decrease in the death group were more significant than those in the survival group, and there was no obvious improvement after treatment in dead cases.


In this study, more than 79% of critical cases had abnormally elevated levels of three typical pro-inflammatory cytokines including Interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF), especially IL-6. This indicated that a significant cytokine storm, cytokine release syndrome (CRS), occurred in critical cases.[29] The damage of lung cells caused by SARS-CoV-2 virus particles does not directly lead to death. The main cause leading to death is excessive activation of non-specific immune cells, which release a number of pro-inflammatory factors resulting in the damage of alveolar capillary epithelial cells. Then a large amount of blood flows out of capillary and fills pulmonary alveoli, which affects respiratory function. In addition, the study found that the inflammatory markers CRP in critically ill patients also increased significantly. With dynamically monitoring the changes of IL-6 and CRP, 27 critical cases were exactly identified whose prognosis significantly improved resulting with being treated in time. These results suggest that IL-6 and CRP can be used as early warning indicators of disease deterioration.


Mechanical ventilation is the most important respiratory support method in critical cases. In our study, the proportion of mechanical ventilation was 72.1%, of which invasive mechanical ventilation was 32.5%, and ECMO was 15.1%. The indication for ECMO is when FiO2 > 90%, the oxygenation index is less than 80 mmHg for 3–4 hours, and the airway plateau pressure is ≥ 35 cmH2O. The study found that there is a significant difference of oxygenation index between dead cases and survival ones, suggesting that the oxygenation index is closely related to disease progression and outcome. When entering the ICU, there was no significant difference in APACHEII and SOFA scores between death group and survival group. It indicates that the initial impairment occurred in critical cases is lung injury, and then other organ function impairments will occur one after another with disease progressing. In our study, only 3 patients (3.5%) occurred barotraumas, which was mainly related to 28-day use of ventilator and ECOM. However, approximately 25% of SARS patients suffered barotrauma in 2003.[20] At present, the incidence of barotraumas has been significantly reduced, which is related to the widespread use of protective ventilation when using ventilators,[30] which benefits from standardized training after SARS.


In this study, 37 patients (43%) received convalescent plasma which can provide antibody-secreting cells (ASCs), follicular helper T cells (Tfh), activated CD4+ T and CD8+ T cells.[31] The amount of plasma used to each patient was 1200–2000 mL. Among 37 cases achieving convalescent plasma, 27 patients (72.9%, 27/37 ) were alive, 30 patients (81.1%, 30/37) produced synthetic antibody whose IgG antibody titer increased by more than 300 times. The convalescent plasma may be an effective immunotherapy for COVID-19, however, indications, timing, dosage, evaluation indicators need to be further studied in larger samples. And 34.9% (30/86) of critically ill patients with significantly elevated level of IL-6 and extensive lesions in both lungs were treated with tocilizumab. Tocilizumab is a recombinant humanized monoclonal antibody against IL-6 receptor that can inhibit IL-6 signaling pathway by binding to it, which blocks the excessive pulmonary inflammation driven by IL-6. The dosage was 4–8 mg/kg body weight, and the cumulative administration was up to two times. Among 30 cases injecting tocilizumab, 23 patients (76.7%, 23/30) were alive, 20 patients (66.6%, 20/30) whose IL-6 level decreased more than 30 times. It indicated that IL-6 receptor inhibitors may be an effective therapeutic drug.


In our research, 58.1% (50/86) of patients received antiviral therapy, of which 68.0% (34/50) used Lopinavir/Ritonavir, and 32.0% (16/50) used Remdesivir. Lopinavir/Ritonavir is a protease inhibitor that can inhibit the maturation of virus particles.[32] Its application is based on an ongoing Chinese clinical registration trial study (ChiCTR2000029308). Remdesivir is an adenosine triphosphate analog that inhibits virus-dependent RNA polymerase.[33,34] In Wuhan, recruits for Remdesivir include mild and medium SARS-CoV-2 cases (NCT04252664) and severe cases (NCT04257656). However, Remdesivir was not recommended for use in the guideline on drugs for COVID-19 issued by WHO in November, 2020.[35] More than half of the patients received intravenous glucocorticoids. In these cases, the oxygenation index gradually deteriorated and pneumonia progressed rapidly, accompanied by overactivated inflammatory response. Although intravenous glucocorticoids are commonly used in the treatment of severe SARS and MERS pneumonia, its use in SARS-CoV-2 pneumonia is also controversial.[36] With continuous improvement of the treatment of COVID-19, glucocorticoids was strongly recommended for critically ill patients in the guideline issued by WHO in November, 2020.[35] For 40 patients in survival group, psychological assessment was managed in rehabilitation stage using Posttraumatic Sreess Disorder Check List (PCL), Generalized Anxiexy Disorder-7 (GAD-7) and Insomnia Severity Indexto-7 (ISI-7) to evaluate PTSD symptoms, depression, anxiety and stress. 23 patients (57.5%) displayed different degrees of the aforementioned conditions, which were significantly higher than non-infected population. Until now, there is no report on the psychological treatment of COVID-19. Nevertheless, psychological impact of COVID-19 has been paid much attention, and psychosocial crisis prevention and intervention models should be urgently developed.[37] In Chinese guideline, it has been proposed to evaluate psychological situation of sober patients and do psychological nursing.[11] The relevant implementation details need to be further explored.


First, only 86 cases were included in this study. However, the number of cases is still much larger than the previous studies. We hope that the results of the study can encourage further exploration of the diagnosis and treatment strategies for critical COVID-19 cases. Second, the current treatment measures for critical COVID-19 cases are limited. The methods used in this study, such as convalescent plasma, IL-6 receptor inhibitors, antiviral drugs, and glucocorticoids treatment, still need to explore its safety and effectiveness in depth.


Critical COVID-19 cases infected with SARS-CoV-2 have a higher mortality rate. Old age, chronic diseases and ARDS increase the risk of death. The oxygenation index is closely related to disease severity, progression and clinical outcome. Mechanical ventilation is currently the main rescue measure for critical cases. Convalescent plasma and anti-IL-6 receptor monoclonal antibody may be effective immunotherapy methods.


Ethics approval

This study was approved by the Ethics Committee of The Sixth People’s Hospital of Shenyang. (No. KY-LW-2021-04-01)


Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


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