Analysis of Clinical Characteristics of Patients with Critical COVID-19

Background: According to the data from the joint investigative team of the WHO and China, the fatality rate in Wuhan is 5.8%and 0.7% in the rest of China. Most of the patients who have died have had chronic diseases or advanced age, and patients with critical COVID-19 have the highest death rate. Patients with critical COVID-19 are the main focus of research on treatment. However, there are few reports on critical COVID-19 patients in China and worldwide. It will help other researchers and clinicians around the world for similar cases. Purpose: Coronavirus disease 2019 (COVID-19) is highly infectious and has a high fatality rate.This paper summarizes and analyses the clinical characteristics of patients with critical COVID-19 to improve clinicians' understanding of this disease. Methods: We selected 16 patients with critical COVID-19 who were treated in the ICU of a grade A hospital in Wuhan from February to March 2020. Then, we collected the clinical data and analysed their general conditions, clinical symptoms, blood tests, CT scans and treatments. Results: Patients with critical COVID-19 had comorbidities (87.5%), and the main symptoms were low or moderate fever (75%), cough and expectoration (68.75%), and multiple lesions in both lungs (100%). 2. Patients with critical COVID-19 were divided into the non-surviving and surviving groups, and the interleukin-6 (IL-6) level and CD4/CD8 ratio were signicantly different (P<0.05). 3. On chest CT, multiple patchy lesions were observed in both lungs, mainly as patchy infected lesions, partial consolidation, ground-glass opacities, and interstitial changes. 4. There were 10 patients (62.5%) who survived and 6 (37.5%) who died. Conclusion: Critical COVID-19 is mainly characterized by low or moderate fever, cough and sputum and often occurs in people with chronic disease.Chest CT showed multiple patchy ground-glass opacities and consolidation. For critically ill patients, it is important to monitor interleukin-6 (IL-6) and CD4/CD8 ratio. Early treatment involves thymalfasin, . There were 12 patients with fever among the 16 patients with critical COVID-19, including 5 patients with low fevers, 6 patients with moderate fevers, and 1 patient with a high fever. Patients with critical COVID-19 generally had a fever, but it was usually a low- or moderate-grade fever, which may be related to their reduced immunity. 2. The chest CT manifestations of patients with critical COVID-19 are multiple patchy ground-glass opacities; multiple patchy, aky infectious lesions; partial consolidation; merging; and interstitial changes. The results of this study suggest that consolidation indicates a relatively worse prognosis, but this need to be conrmed in a large sample. Patients with critical COVID-19 may exhibit leucopenia, leucocytosis and lymphocytopenia 13 ; a reduced lymphocyte count and elevated levels of inammatory markers are risk factors for a poor prognosis 8 . In the 6 patients who died in this study, the lymphocyte counts were signicantly reduced, the levels of IL-6 reached more than 140 pg/ml, and the CD4/CD8 ratios were signicantly reduced. Even when immunoglobulin, thymalfasin and other treatments that regulate the immune system are adopted, the mortality of the patients is still high, which may be related to the late initiation of immunoregulatory therapy. In addition, large doses of a broad-spectrum protease inhibitor (ulinastatin) have been shown to reduce the plasma levels of the inammatory factor IL-6 and increase the levels of the anti-inammatory factor IL-10 14 ; therefore, large doses can be considered for critical COVID-19 patients.


Background
In December 2019, the rst case of pneumonia of unknown cause was found in the South China Seafood Wholesale Market in Wuhan, which was nally con rmed to be an acute respiratory infectious disease caused by a novel coronavirus named SARS-CoV-2. In February 2020, the WHO named the disease coronavirus disease 2019 (COVID-19) 1,2 . COVID-19 quickly spread throughout the country. Through a series of preventive measures, the outbreak in China has been effectively controlled, but the foreign epidemic is still not under control. As of August 28, 2020, 24664109 patients had been con rmed overseas, including a total of 45,068 deaths, and the number of con rmed patients and deaths is still increasing. According to the data from the joint investigative team of the WHO and China, the fatality rate in Wuhan is 5.8%and 0.7% in the rest of China. Most of the patients who have died have had chronic diseases or advanced age, and patients with critical COVID-19 have the highest death rate 3  published by the Chinese government, a suspected case met one of the following criteria: 1. nasopharyngeal swab, sputum, lower respiratory tract secretion, blood, stool or other specimen tested positive for COVID-19 nucleic acid by realtime uorescence RT-PCR; 2. viral gene sequencing showed a high degree of homology with SARS-CoV-2. Serum samples tested positive for SARS-CoV-2-speci c IgM and IgG antibodies; serum SARS-CoV-2-speci c IgG antibody conversion, or a 4-fold reduction in titres. We collected a total of 16 patients with critical COVID-19 admitted to the intensive care unit of a grade A hospital in Wuhan from 1st February to 25th March 2020. The clinical classi cation of disease severity stipulates that patients with critical COVID-19 meet one of the following conditions: 1. respiratory failure requiring mechanical ventilation; 2. shock; or 3. organ failure requiring ICU care. This study was approved by the Ethics Commission of The Central Hospital of Wuhan. Written informed consent was waived by the Ethics Commission of the designated hospital for emerging infectious diseases.

Detection method
Patients were divided into the non-surviving group and the surviving group, and their general conditions, clinical symptoms, blood tests, CT imaging characteristics, the changes in each indicator and the relationship between the indicators and critical COVID-19 were compared.
Statistical processing SPSS 22.0 software was used, and the measurement data with a normal distribution are expressed as the mean ± SD.
The t-test was used for the comparison of the mean values of the two groups, and the variance test was used for the comparison of the mean values of more than two samples. P < 0.05 was considered statistically signi cant.

Laboratory Tests
The total number of peripheral blood white blood cells was elevated in 5 patients (31.25%) and decreased in 4 patients (25%), while 7 patients had normal white blood cell counts (43.75%). The lymphocyte count was reduced in 14 patients (87.5%) and normal in 2 patients (12.5%). The C-reactive protein level was elevated in 5 patients (31.25%), and the procalcitonin level was elevated in 5 patients (31.25%). The 16 patients were divided into the non-surviving group (6 patients, 37.5%) and the surviving group (10 patients, 62.5%). There were statistically signi cant differences between the non-surviving group and surviving group in the interleukin-6 level and CD4/CD8 ratio (P < 0.05), suggesting that the interleukin-6 level and the CD4/CD8 ratio may affect the prognosis of patients. The results of the statistical analysis suggest that the higher the level of interleukin-6 is, the lower the CD4/CD8 ratio and the worse the prognosis (Table 1).  treated with thymalfasin 1.6 mg twice a week for 1 month. Four patients (25%) were given 5% immunoglobulin injections with 100-ml intravenous infusion for 5-7 days. Five patients (31.25%) were given 5% human albumin by intravenous drip (10 mg) daily for 3-7 days. Four (25%) patients with extensive ground-glass opacities in both lungs and fever received methylprednisolone treatment (20 or 40 mg intravenous drip, 2 times/day for 3-10 days). All 16 (100%) patients were treated with high nasal ow humidi cation due to aggravated shortness of breath and decreased blood oxygen saturation levels. Four patients (25%) were treated with continuous renal replacement therapy (CRRT) due to severe infection and renal dysfunction. Due to poor therapeutic effects, 7 patients were treated with endotracheal intubation and invasive ventilation. One patient was treated with percutaneous tracheotomy due to a long invasive ventilation time. One patient with a concurrent fungal infection was treated with antifungal therapy. There were 10 patients (62.5%) who survived and 6 patients (37.5%) who died. Five of the 6 patients with chronic diseases died of Type I respiratory failure (Table 2). merging; and interstitial changes. The results of this study suggest that consolidation indicates a relatively worse prognosis, but this need to be con rmed in a large sample. Patients with critical COVID-19 may exhibit leucopenia, leucocytosis and lymphocytopenia 13 ; a reduced lymphocyte count and elevated levels of in ammatory markers are risk factors for a poor prognosis 8 . In the 6 patients who died in this study, the lymphocyte counts were signi cantly reduced, the levels of IL-6 reached more than 140 pg/ml, and the CD4/CD8 ratios were signi cantly reduced. Even when immunoglobulin, thymalfasin and other treatments that regulate the immune system are adopted, the mortality of the patients is still high, which may be related to the late initiation of immunoregulatory therapy. In addition, large doses of a broad-spectrum protease inhibitor (ulinastatin) have been shown to reduce the plasma levels of the in ammatory factor IL-6 and increase the levels of the anti-in ammatory factor IL-10 14 ; therefore, large doses can be considered for critical COVID-19 patients.
At present, there are no speci c antiviral drugs for COVID-19, and treatment is mainly nutritional support, immune regulation and other symptomatic support therapies. Previous studies have shown that dot-interferon can be tried (5 million U or the equivalent dose for adults, atomized inhalation twice a day). Chloroquine phosphate (referred to as 'chloroquine') has a wide range of general antiviral and speci c anti-coronavirus effects and can improve the treatment success rate of patients with COVID-19, shorten the length of hospital stay and improve the prognosis 5,15,16 . Remdesivir is a novel nucleotide analogue, and its anti-coronavirus activity has been demonstrated in vitro 17,18 . Lopinavir/ritonavir also has anti-coronavirus activity in vitro 19 . Plasma from recovering patients may contain antibodies that neutralize the virus, and there is evidence of that treating patients with antibodies from recovering patients is effective 20,21 . Tian et al.
found that a speci c human monoclonal antibody against SARS-CoV is a potential candidate for the treatment of COVID-19 22 . Based on the latest clinical standards 5  All 16 patients in this study were routinely treated with Chinese medicine.
Due to the critical condition of patients in the ICU, their ability to cough up phlegm is reduced, resulting in airway obstruction, impaired breathing, aggravation of the pulmonary infection, atelectasis and other complications. In addition, due to the in uence and limitation of various monitoring channels, it is challenging to routinely turn patients over and actively assist the patient to produce phlegm; instead, it is necessary to rely on passive sputum aspiration to remove secretions in a timely manner. On 28th February, Gross Examination Report of a Covid-19 Death Autopsy suggested that a large number of viscous secretions could be seen in the lung tissue, and there were brous cords. COVID-19 mainly causes in ammatory responses characterized by deep airway and alveolar injury 25 . In this study, 6 patients with critical COVID-19 did not survive, and they all had serious Type I respiratory failure. Based on the current pathological and anatomical data and given the possibility of airway obstruction by mucus and the later brotic changes in the lung tissue, the management of airway humidity and sputum drainage should be strengthened. In this study, 6 of the 16 patients with critical COVID-19 died, and 5 of them had chronic diseases, with a mortality rate of 37.5%. In addition to chronic diseases and complications of COVID-19, mortality may be related to the lack of human resources, airway humidi cation and sputum drainage. We modi ed the treatment of our patients based on these clinical observations, and the mortality rate was signi cantly reduced, suggesting that strengthening airway humidi cation and sputum drainage, facilitating expectoration, and reducing the exudation of airway secretions could reduce the mortality rate of COVID-19 patients.

Conclusion
This novel coronavirus is different from HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, MERS-CoV and SARS-CoV, and there are no speci c antiviral treatments. Critical COVID-19 is characterized by low and moderate fever. Chest CT indicated multiple patchy lesions in both lungs, mainly characterized by patchy infectious lesions, partial consolidation, ground-glass opacities and interstitial changes. Consolidation on imaging may indicate a poor prognosis. Currently, treatment involves supportive therapies, antiviral treatments, antibodies from surviving patients, monoclonal antibodies, and traditional Chinese medicine treatment. The routine use of hormone therapy is not recommended. It is important to monitor IL-6 level and CD4/CD8 ratio. Early treatment with thymalfasin, immunomodulatory treatment with immunoglobulin, and treatment with a large dose of ulinastatin to reduce the plasma levels of in ammatory factors should be considered. Attention should be paid to ensuring airway humidi cation and drainage, enhancing expectoration, and reducing airway secretions. Although the sample size is very small for this study, authors explained the clinical symptom in critical patient. It will help other researchers and clinicians around the world for similar cases.
Declarations Figure 1 A-B are the results of chest CT examinations of a nonsurviving patient, which show multiple patchy lung lesions, mainly patchy infectious lesions, consolidation of the bilateral lower lungs, and scattered ground-glass opaci cation indicative of the formation of a hyaline membrane in the bilateral lungs. C-D show the results of a patient who survived. The patient was discharged from the hospital. The CT images were characterized by multiple patchy lesions in both lungs, with the majority being patchy infectious lesions, but consolidation was not obvious.