key: cord-1054661-q6zxlk8z
authors: Liu, Di; Wang, Qiang; Zhang, Huacai; Cui, Li; Shen, Feng; Chen, Yong; Sun, Jiali; Gan, Lebin; Sun, Jianhui; Wang, Jun; Zhang, Jing; Cai, Qingli; Deng, Jin; Jiang, Jianxin; Zeng, Ling
title: Viral sepsis is a complication in patients with Novel Corona Virus Disease (COVID-19)
date: 2020-07-24
journal: Med Drug Discov
DOI: 10.1016/j.medidd.2020.100057
sha: 096de5f38ec665b18c430bd0d10898be394975fb
doc_id: 1054661
cord_uid: q6zxlk8z

BACKGROUND: Until June 23th 2020, 9,195,635 laboratory-confirmed cases of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have been reported worldwide, including 473,127 deaths. Bacterial infection is the main cause of sepsis, however, sepsis caused by virus is often ignored. Increased awareness, early recognition of viral sepsis, rapid administration of appropriate antiviral drugs, and urgent treatment can significantly reduce deaths of viral sepsis. OBJECTIVES: Given the rapid global spread of novel Corona Virus Disease (COVID-19), coupled with the high rate of missed diagnosis of viral sepsis caused by SARS-CoV-2 infection, it is urgent to evaluate the multiple organ failure score and viral sepsis in COVID-19 patients, so as to determine the clinical characteristics of viral sepsis more accurately and reveal the risk factors related to mortality. METHODS: Here we provide a full description of three cases of viral sepsis and subsequent multiple organ dysfunction (MODS) caused by SARS-CoV-2 infection imported to Guiyang from Wuhan. RESULTS: We analyzed complete laboratory examination, imaging data and treatment methods for the patients and assessed Sepsis-related Organ Failure Assessment score (SOFA score) and Multiple organ dysfunction scores (MOD score) daily, aimed to elucidate the clinical feature of viral sepsis and MODS and to attract enough attention by clinicians. CONCLUSIONS: Therefore, we strongly suggest to daily evaluate SOFA score and MOD score in severe and critically-ill COVID-19 patients, so as to early diagnose and prevention of sepsis and MODS. Given the rapid global spread of novel Corona Virus Disease (COVID-19), coupled with the high rate of missed diagnosis of viral sepsis caused by SARS-CoV-2 infection, it is urgent to evaluate the multiple organ failure score and viral sepsis in COVID-19 patients, so as to determine the clinical characteristics of viral sepsis more accurately and reveal the risk factors related to mortality. Here we provide a full description of three cases of viral sepsis and subsequent multiple organ dysfunction (MODS) caused by SARS-CoV-2 infection imported to Guiyang from Wuhan. We analyzed complete laboratory examination, imaging data and treatment methods for the patients and assessed Sepsis-related Organ Failure Assessment score (SOFA score) and Multiple organ dysfunction scores (MOD score) daily, aimed to elucidate the clinical feature of viral sepsis and MODS and to attract enough attention by clinicians. Therefore, we strongly suggest to daily evaluate SOFA score and MOD score in severe and critically-ill COVID-19 patients, so as to early diagnose and prevention of sepsis and MODS.

Syndrome Coronavirus 2 (SARS-CoV-2) has occurred in Wuhan, Hubei, China since December 2019 [1] . SARS-CoV-2 virus is a novel beta coronavirus based on gene sequencing [2] . By June 23th 2020, there are 9,195,635 laboratory or clinical confirmed cases in more than 100 countries, 473,127 people have lost their lives.

Compared with the 10% death rate of SARS-CoV [3] and 37% death rate of MERS-CoV [4] , SARS-CoV-2 has a lower death rate of 2% in China [5] . More and more evidences show that COVID-19 spreads from person to person in hospital and family settings [6] [7] [8] , the WHO had announced that COVID-19 was a global pandemic. The main clinical symptoms of COVID-19 patients are fever, cough, fatigue or myalgia, sputum production, headache, diarrhea and haemoptysis were less common symptoms.

About 50% patients developed dyspnea, among which one third were admitted to ICU [9] , while the severe patients often have dyspnea after one week, which rapidly progress to acute respiratory distress syndrome (ARDS), sepsis and multiple organ dysfunction (MODS) [10] .

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [11] . Sepsis can be caused by a variety of pathogens. Bacterial infection is the main cause of sepsis. However, as high as 42% of sepsis patients showed culture negative, suggesting a non-bacterial cause [12] . Although almost any virus can lead to sepsis in susceptible patients, the clinical diagnosis of viral sepsis is very rare. Increased awareness, early recognition of viral sepsis, rapid administration of appropriate antiviral drugs, and urgent treatment can significantly reduce deaths of viral sepsis [13] .

J o u r n a l P r e -p r o o f 5 Given the rapid global spread of COVID-19, coupled with the high rate of missed diagnosis of viral sepsis caused by SARS-CoV-2, it is urgent to evaluate viral sepsis and multiple organ failure score in COVID-19 patients, so as to determine the clinical characteristics of viral sepsis more accurately and reveal the risk factors related to mortality. In our study, we collected fifteen confirmed cases of COVID-19 caused by SARS-CoV-2 infection imported to Guiyang from Wuhan, among which, three cases (20%) were severe or critically-ill patients with viral sepsis. We provided a full description of laboratory examinations, imaging data and treatment methods of the patients, aim to attract enough attention by clinicians and provide treatment experience of viral sepsis. 

Laboratory test were collected upon hospitalization, including blood gas analysis 

All patients were given mask oxygen inhalation and ventilator to assist breathing immediately after admission to improve the situation of hypoxia. Abidol hydrochloride tablets, interferon alfa-2b, ribavirin, Lianhuaqingwen combined with lopinavir plus ritonavir or chloroquine phosphate were given as antiviral therapy.

Thymalfasin and γ-immunoglobulin were administered to enhance immunity. Thus heparin were stopped and leukocyte-removing red blood cells, fresh frozen plasma, cryoprecipitated coagulation factors, platelets and recombinant activated factor VIIa were given to improve coagulation status.

A SOFA score of 2 or above identified a 2-to 25-fold increased risk of death compared with a SOFA score less than 2 [15] . All the three patients met the criteria of Journal Pre-proof J o u r n a l P r e -p r o o f 10 sepsis with SOFA scores over or equal to 2. Case 01 and Case 02 were two severe cases of COVID-19. The number of days in hospital for Case 01 is 17 days, among which 12 days had a SOFA score greater than or equal to 2 points. The number of days in hospital for Case 02 was 25 days, of which 18 days had a SOFA score greater than or equal to 2 points. Case 03 was a critical-ill case of COVID-19, his daily SOFA score was all above or equal to 5. During the last four days post admission, the SOFA score had increased to 9 and septic shock was diagnosed because of persisting hypotension requiring vasopressors to maintain MAP > 65mmHg and having a serum lactate level > 2 mmol/L despite adequate volume resuscitation. The patient began to use ECMO to provide extracorporeal respiration on the first day of admission. From the 3rd to 5th day post admission, 0.1 ug/kg noradrenaline was given to maintain blood pressure. The concentration of lactate in peripheral blood was 3.0 mmol/L. On the 6th day post admission, the PaO2/FiO2 was lower than 100mmHg even when treated with ventilator. 3.0ug/kg noradrenaline was given while the MAP was still lower than 65mmHg, the patient eventually died of septic shock and MODS.

MOD score above or equal to 4 represented marked functional dysfunction and a mortality rate of more than or equal to 50% [16] . Data were collected daily to calculate three patients' MOD score. Among the 17-admission-days of Case 01, the MOD scores did not exceed 2. On the 5th and 6th days post admission, the MOD score was 2 (1 point for bilirubin and 1 point for creatinine) (Fig. 3) . From the 11th to 19th days post admission, the MOD score of Case 02 was 4 (3 points for PaO 2 /FiO 2 and 1 point for bilirubin). When the patient was discharged on 25th day post admission, the MOD score was reduced to 0 (Fig. 3) . Case 03 was a critical-ill case J o u r n a l P r e -p r o o f 11 of COVID-19, the MOD score of the first two days post admission was 5 (3 points for PaO 2 /FiO 2 and 1 point for creatinine). From the 3rd to 5th days post admission, the MOD point increased to 7 (3 points for PaO 2 /FiO 2 , 1 point for creatinine and 2 points for CNS Glasgow Coma Scale). At 12:40pm on 5th day post admission of Case 03, the patient had a sudden increase of heart rate, decrease of blood pressure, progressive decrease of hemoglobin. After dilatation and transfusion, 0.3ug/kg noradrenaline was given. Bedside ultrasound indicated that there was a large amount of blood in the left thorax. Non-coagulated blood was drawn out by thoracic puncture, so heparinization treatment of ECMO and pressurized blood transfusion were stopped immediately.

Coagulation test showed that thrombin time (TT) and activated partial thromboplastin time (APTT) were significantly prolonged (TT: 240s, APTT: 206.3s). At 1:30am on the 6th day post admission, the blood pressure and heart rate decreased gradually.

After rescue, chest compression and intravenous injection of noradrenaline, unfortunately, the patient died on the 6th day post admission (16 days after initial symptoms) with coagulation, respiratory, circulatory and renal dysfunction.

Patients who died of COVID-19 had significantly reduced lung immune cells and reduced peripheral blood lymphocytes. Meanwhile, lymphocytes are over-activated because of the increase in highly pro-inflammatory CCR4 + CCR6 + Th17 cells [5] . The number of peripheral blood lymphocytes was significantly lower in severe patients when admitted to the hospital than mild patients. The T cells and CD4 + T cell subsets of severe patients continued to decrease compared to mild patients [17] . Consistent with these studies, the percentage of peripheral blood T lymphocytes all decreased in the three patients post admission. Respectively for cases 01 and 02, the percentage of Journal Pre-proof CD3 + T lymphocyte was 64.24% and 55.8% for the 7th day post admission, a slightly lower than normal reference range (65%-75% 

Although there have been big progress in the research of sepsis recent years, sepsis is still one of the leading cause of death in intensive care units (ICU) [18] [19] . Bacterial infections represent the majority of sepsis cases. Sepsis caused by virus is often ignored [20] . At present, the viral sepsis caused by SARS-CoV-2 virus has a relatively high risk of sepsis and multiple organ failure [21] . Moreover, research data showed that, severe COVID-19 patients often combined with bacterial or fungal infection. Many patients have organ dysfunction, 4% of them have septic shock [10] . Case 03: Chest x-rays was obtained on the first day post admission. The brightness of both lungs was diffusely decreased and extensive patchy shadows were observed, edges were blurred and the heart shadow enlarged slightly. Right diaphragmatic surface was light and smooth, costal diaphragmatic angle was sharp, while left diaphragmatic surface and costal diaphragmatic angle blunted (1E and 1F). 

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A novel human mAb (MERS-GD27) provides prophylactic and postexposure efficacy in MERS-CoV susceptible mice

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We greatly appreciate all the people, particularly thousands of clinicians, nurses and scientists who are heroically battling to eradicate the epidemic of COVID-19 for days and nights.