key: cord-0708098-mz0yvguq
authors: Wang, Peng; Tan, Xiang; Li, Qian; Qian, Min; Cheng, Aiguo; Ma, Baohua; Wan, Peng; Zhang, Xinli; Guo, Changyun; Sheng, Mengting; Yi, Mengqiu; Yu, Min
title: Extra-pulmonary complications of 45 critically ill patients with COVID-19 in Yichang, Hubei province, China: A single-centered, retrospective, observation study
date: 2021-03-05
journal: Medicine (Baltimore)
DOI: 10.1097/md.0000000000024604
sha: 18c1e5184e28bff43aebc792a6bed626f1dc65cb
doc_id: 708098
cord_uid: mz0yvguq

Mortality of critically ill patients with coronavirus disease 2019 (COVID-19) was high. Aims to examine whether time from symptoms onset to intensive care unit (ICU) admission affects incidence of extra-pulmonary complications and prognosis in order to provide a new insight for reducing the mortality. A single-centered, retrospective, observational study investigated 45 critically ill patients with COVID-19 hospitalized in ICU of The Third People's Hospital of Yichang from January 17 to March 29, 2020. Patients were divided into 2 groups according to time from symptoms onset to ICU admission (>7 and ≤7 days) and into 2 groups according to prognosis (survivors and non-survivors). Epidemiological, clinical, laboratory, radiological characteristics and treatment data were studied. Compared with patients who admitted to the ICU since symptoms onset ≤7 days (55.6%), patients who admitted to the ICU since symptoms onset >7 days (44.4%) were more likely to have extra-pulmonary complications (19 [95.0%] vs 16 [64.0%], P = .034), including acute kidney injury, cardiac injury, acute heart failure, liver dysfunction, gastrointestinal hemorrhage, hyperamylasemia, and hypernatremia. The incidence rates of acute respiratory distress syndrome, pneumothorax, and hospital-acquired pneumonia had no difference between the 2 groups. Except activated partial thromboplastin and Na(+) concentration, the laboratory findings were worse in group of time from symptoms onset to ICU admission >7 days. There was no difference in mortality between the 2 groups. Of the 45 cases in the ICU, 19 (42.2%) were non-survivors, and 16 (35.6%) were with hospital-acquired pneumonia. Among these non-survivors, hospital-acquired pneumonia was up to 12 (63.2%) besides higher incidence of extra-pulmonary complications. However, hospital-acquired pneumonia occurred in only 4 (15.4%) survivors. Critically ill patients with COVID-19 who admitted to ICU at once might get benefit from intensive care via lower rate of extra-pulmonary complications.

At the end of December 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, the capital of Central Hubei Province, China. The pneumonia cases were characterized primarily by fever, cough, and bilateral infiltrates on chest imaging. [1] [2] [3] The World Health Organization (WHO) named it coronavirus disease 2019 which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Till now, SARS-CoV-2 has spread rapidly all over the world, but there are few specific tools to control the growing epidemic and treat those who are seriously sick. Previous researches have demonstrated human-to-human transmission of the COVID-19 through droplets or direct contact. [4, 5] The most effective methods are quarantine, isolation, infection-control measures and on supportive care for those who become ill. [6] However, the still insufficient testing capacity for COVID-19 in other countries means that many suspected cases and asymptomatic carrier are not yet counted completely. [7] As of September 15, 2020, there were more than 29 million cases worldwide in total, which threatened global public health. Previous study indicated that the mortality of critically ill patients with COVID-19 was considerable, which was up to 61.5% in Wuhan Jinyin Tan Hospital. [8] Nevertheless, specific data about the clinical characteristics of critically ill patients of COVID-19 is remain unknown, which is paramount importance to reduce mortality. Consequently, it is vital for collection and analysis data about critically patients of COVID- 19. In this study, we investigated critically ill patients with confirmed COVID-19 who were admitted to The Third People's Hospital of Yichang, nearby Wuhan in Hubei province. The baseline COVID-19 associated morbidity and mortality data from this study will be considerable value for who are most likely to intensive care unit (ICU) treatment. By collecting data of the clinical characteristics and laboratory findings of critically ill patients infected with COVID-19, we described the relation of time from symptoms onset to ICU admission and prognosis. Our study provides a new insight into the strategy to reduce the mortality of COVID-19.

This single-centered, retrospective, observational study was conducted in The Third People's Hospital of Yichang. The hospital located in Hubei Province, nearby Wuhan, the epidemic areas of COVID-19. And the hospital is one of the major teaching hospitals and responsible for the treatments for COVID-19 assigned by the government. All consecutive patients with confirmed COVID-19 admitted to The Third People's Hospital of Yichang from January 17 to March 29, 2020, were enrolled. The reporting guidelines for STROBE were used in the design and implementation of our research.

From January 17 to March 29, 2020, there were 398 patients with confirmed SARS-CoV-2 infection hospitalized in The Third People's Hospital of Yichang in total, and of which, 49 cases were critically ill and admission to the ICU. Excluded 1 case who was <18 years old, 2 cases who died soon after ICU admission, and 1 case who refused life support in the ICU. Oral consent was obtained from patients or law of agents. 45 patients with COVID-19 enrolled in this study were diagnosed according to World Health Organization interim guidance. Laboratory confirmation of SARS-CoV-2 infection was performed via real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay (Daan Gene Co., Ltd. Of Sun Yat-sen University) of nasal and pharyngeal swab specimens or lower respiratory tract secretions. Only laboratory-confirmed cases were included in this analysis. Critically ill patients were defined as these admitted to the ICU who required mechanical ventilation or had a fraction of inspired oxygen (FiO 2 ) of at least 60% or more. Identification of critically ill patients was achieved by reviewing and analyzing admission logs and histories from all available electronic medical records and patient care resources. The Ethics Commission of The Third People's Hospital of Yichang approved this study. Written informed consent was waived due to the rapid emergence of this infectious disease and the retrospective nature of the study.

Epidemiological, clinical, laboratory, radiological characteristics, and treatment data were obtained with data collection forms from electronic medical records. The data were reviewed by a trained team of physicians. Information recorded included age, sex, exposure history, chronic medical histories (chronic cardiac disease, chronic pulmonary disease, chronic kidney disease, cerebrovascular disease, diabetes, malnutrition, schizophrenia, malignancy, hemopathy and autoimmune disease), symptoms from onset to ICU admission (fever, cough, dyspnea, myalgia, rhinorrhea, arthralgia, chest pain, headache, coma, vomiting, bellyache and diarrhea), complications (acute respiratory distress syndrome (ARDS), acute kidney injury, cardiac injury, acute heart failure, liver dysfunction, gastrointestinal hemorrhage, pneumothorax, hyperamylasemia, hypernatremia, hospital-acquired pneumonia), laboratory values on ICU admission (arterial blood gas analysis, FiO 2 , partial pressure of oxygen, PaO 2 , white blood cell count, lymphocyte count, platelet count, prothrombin times, activated partial thromboplastin time, D-dimer, lactate concentration, creatine kinase-MB, NT-pro BNP, creatinine, total bilirubin and procalcitonin), treatments (oxygen therapy, prone position ventilation, renal replacement therapy, vasoconstrictive agents, antiviral agents, antibacterial agents, glucocorticoids and immunoglobulin), as well as living status. Any missing or uncertain records were collected and clarified through direct communication with involved health-care providers and their families.

Continuous variables were expressed as mean (standard deviation [SD]) or median (interquartile range [IQR] ) and compared with the Mann-Whitney U test; categorical variables were expressed as number (%) and compared by x 2 test or Fisher's exact test between data of patients who admitted to the ICU since symptoms onset >7 days and those who admitted to the ICU since symptoms onset 7 days. A 2-sided a of less than 0.05 was considered statistically significant. The analyses have not been adjusted for multiple comparisons, and given the potential for type I error, the findings should be interpreted as exploratory and descriptive. Statistical analyses were done using the IBM SPSS (Statistical Package for the Social Sciences), version 23.0 software, unless otherwise indicated. 

Similarities of clinical features between SARS-CoV-2 and previous b-coronavirus infections had been noted. In this cohort, the most common symptoms were fever (40, 88.9%), cough (39, 86.7%), and dyspnea (37, 82.2%). Less common symptoms were vomiting, myalgia, headache, rhinorrhea, diarrhea, chest pain ( and those who admitted to the ICU since symptoms onset 7 days (Table 3) .

Chest computed tomography (CT) findings of critically ill patients with SARS-CoV-2 infection were bilateral ground glass opacity and consolidation (Fig. 1) .

Of the 45 critically ill patients, the mortality rate was 42.2% in total. And the mortality rates of patients who admitted to the ICU since symptoms onset >7 days and those who admitted to the ICU since symptoms onset 7 days were 50.0% and 36.0% respectively. However, there was no difference in prognosis between the 2 groups (P = .345). Furthermore, compared with survivors in this cohort, nonsurvivors had much higher incidence rates of hospital-acquired pneumonia ( (Fig. 2) . Besides, mortality rate was positive associated with incidence rates of extra-pulmonary complications (coefficient of contingency = 0.416, P = .002) and hospital-acquired pneumonia (coefficient of contingency = 0.442, P = .001). The incidence of ARDS had no difference between survivors and non-survivors (16 [61.5%] vs 16 [84.2%], P = .097) (Fig. 2) . 

As of September 15, 2020, nearly 30 million laboratory confirmed cases of infection with the novel coronavirus (SARS-CoV-2) in total were reported all over the world. And about 900,000 patients were killed by the disease. Compared with moderate patients, the incidence of complications was higher in severe and critically ill patients. [9] As of March 29, 2020 we reported on 45 critically ill patients with COVID-19, characterized by severe hypoxemia. Of all included patients, 32 (71.1%) had ARDS and 35 (77.8%) had extra-pulmonary complications (e.g. acute kidney injury, cardiac injury, acute heart failure, liver dysfunction, gastrointestinal haemorrhage, etc). 20 (44.4%) of critically ill patients were admitted to the ICU more than 7 days since symptoms onset, and 25 (55.6%) were on or less than 7 days since symptoms onset. Interestingly, our study showed that fever symptom and history of exposure to Wuhan or close contact with some individuals with confirmed or highly suspected SARS-CoV-2 infection seemed to be dominant reason for promoting patients to see the doctors and caused their attention.

Although the novel coronavirus was quickly isolated and sequenced, [10] there are no proven, effective drugs to treat COVID-19. Until now, the mainstay of treatment has still been isolation and supportive care. All critically ill patients who suffer from severe hypoxemia, unstable hemodynamic and even multiple organ dysfunction caused by COVID-19 should be admitted to ICU. However, a considerable problem is the shortage of sufficient ICU beds to treat these critically ill patients, which leads to delay in ICU admission. It would make the critically ill patients miss the opportune for best treatment, if they are not admitted to ICU or admitted too late. Recently, this report, to our knowledge, is the first case series to investigate time from symptoms onset to ICU admission of critically ill patients with SARS-CoV-2 infection.

Since Chinese government has taken action quickly and effectively, the overall mortality of COVID-19 is about 4.0% in China, and the mortality is about 0.7% except Wuhan. [11] The number of patients with COVID-19 is increasing rapidly in other countries out of China, which might lead to higher mortality rate in the countries which are lack of medical resources, especially.

Despite lower mortality rate than severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), [12, 13] COVID-19 has led to more total deaths due to the large number of cases. For reducing mortality rate, it is important to know the clinical characteristics of critically ill patients.

Previous studies showed that old age, male, and presence of chronic medical illness might be associated with increased mortality. [1, 8, 14] The mortality rate in critically ill patients with SARS-CoV-2 infection in our cohort was 42.2%. Our study showed that non-survivors had higher rates of extra-pulmonary complications and hospital-acquired pneumonia than survivors. The rates of ARDS had no difference between survivors and nonsurvivors. Pathology of critically ill patients who died from COVID-19 manifested that while the SARS-CoV-2 was mainly distributed in lung, the infection also involved in the damages of heart, vessels, liver, kidney and other organs. [15, 16] On the basis of observation from COVID-19 patients, Bin Cao and his fellows hypothesized that in severe or critical COVID-19 cases, in response to the infection of SARS-CoV-2, alveolar macrophages or epithelia cells could produce various proinflammatory cytokines and chemokines, and then monocytes and neutrophils were chemotactic to the infection site to clear these exudates with virus particles and infected cells, resulting in uncontrolled inflammation which led a further worsening of lung injury. [17] Furthermore, extra-pulmonary organs could be attacked directly by disseminated SARS-CoV-2 or injured by the systemic cytokine. [17] Therefore, we supposed that ICU physicians interfered at early phase of SARS-CoV-2 infection, which might get benefit for critically ill patients from prognosis. We analyzed the clinical data of 20 critical COVID-19 cases admitted to the ICU since symptoms onset >7 days, and 25 admitted to the ICU since symptoms onset 7 days as well. Of the 45 cases, 30 (66.7%) were male. There was no difference in gender and age structure, and chronic medical illness between the 2 groups. This might be because all of patients who admitted to the ICU were critically ill, and this had no relationship with the time of ICU admission.

Similarities of clinical features between our cohort and previous reports had been noted. Most patients presented with fever, cough, dyspnea, and bilateral ground-glass opacities on chest CT scans. These features of COVID-19 bear some resemblance to SARS-CoV and MERS-CoV infections. [18, 19] . Critically ill patients with COVID-19 who admitted to the ICU since symptoms onset 7 days had significant lower incidence rates of hypernatremia, acute kidney injury, gastrointestinal hemorrhage, and cardiac injury than those who admitted to the ICU since symptoms onset >7 days. Therefore, we speculated that, for critically patients with COVID-19, time from symptoms onset to ICU was directly associated with the extra-pulmonary complications which responsible for multiple organ dysfunction, or even failure. It is generally known that, for sepsis patients, the mortality rate has positive correlation to the exhaustion of the organic function, and it is in direct proportion to the number of the failure organ. So, we supposed that once patients with SARS-CoV-2 infection had been Medicine classified critical cases, should be admitted to ICU at once, and these patients might get benefit from intensive care via lower rate of extra-pulmonary complications. However, we did not conclude that there was significant difference in prognosis between the 2 groups. Meanwhile, in our cohort, incidence rates of hospitalacquired pneumonia had no difference between the patients who admitted to the ICU since symptoms onset >7 days and those who admitted to the ICU since symptoms onset 7 days as well, which had significant difference between survivors and non-survivors. Incidence rate of hospital-acquired pneumonia in non-survivors was much higher than survivors. So, hospital-acquired pneumonia might be another reason for the mortality. Critical COVID-19 cases had numerous laboratory abnormalities. Firstly, the most common laboratory abnormalities observed in our study were depressed absolute value of lymphocytes. This phenomenon suggests that SARS-CoV-2 might mainly act on lymphocytes, especially T lymphocytes, as does SARS-CoV. Pathology of critically ill patients who died from COVID-19 [16] found decreased numbers of lymphocytes in spleen. Virus particles spread through the respiratory mucosa and infect other cells, induce a cytokine storm in the critically ill patients, generate a series of immune responses with altering in peripheral white blood cells and immune cells such as lymphocytes. Previous researchers had clarified that apoptosis of T and B lymphocytes was in models of sepsis, post-mortem analysis of septic patients, [20] [21] [22] and in the circulation of patients with septic shock. [23] Therefore, we speculated that necrosis or apoptosis of lymphocytes also induced depressed lymphocytes in critically ill patients with COVID-19. It suggested that the level of depressed lymphocytes reflected the severity of COVID-19, which might provide a new index for predicting severity of illness. Furthermore, the other laboratory abnormalities in critically ill patients were prolonged prothrombin time, increased D-dimer, up-regulated creatine kinase-MB and creatinine, elevated lactate dehydrogenase. These laboratory abnormalities were similar to those previously observed in patients with MERS-CoV and SARS-CoV infection, [24] which suggested that COVID-19 might be associated with cellular immune deficiency, coagulation activation, myocardia injury, hepatic injury, and kidney injury.

Denstaedt et al had found that depressed lymphocytes were associated with increased mortality and risk of hospital-acquired infection and occurs commonly in patients with persistent critical illness. [23] The hospital-acquired pneumonia incidence rate in our cohort was about 35.6% what might be attributed to depressed lymphocytes. We found prognosis of the 45 critical COVID-19 cases in our cohort was positive associated with extra-pulmonary complications (coefficient of contingency = 0.416, P = .002) and hospital-acquired pneumonia (coefficient of contingency = 0.442, P = .001). Between critically ill patients who admitted to the ICU since symptoms onset >7 days and those who admitted to the ICU since symptoms onset 7 days, there was significant difference in extra-pulmonary complications, while no difference in the prognosis of the 2 groups. We suspected that it might be caused by hospital-acquired pneumonia due to decreased numbers of lymphocytes.

The limitations of this study include the small number of patients from a single center. Collection of standardized data for a larger cohort would help to further define the clinical presentation, natural history, and risk factors. At the same time, finding of statistical tests and P values should be interpreted with caution, and non-significant P values do not necessarily rule out difference between critically ill patients with COVID-19 who admitted to the ICU since symptoms onset >7 days and those who admitted to the ICU since symptoms onset 7 days.

In this single-center case series of 45 critically ill patients with COVID-19 in Yichang, Hubei, China, the shorter duration from symptom onset to ICU admission, the less extra-pulmonary complications. So critically ill patients with SARS-Cov-2 infection who admitted to ICU at once might get benefit from intensive care via lower rate of extra-pulmonary complications. Our study provides a new insight for fighting COVID-19 globally.

The author(s) read and approved the final manuscript

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We thank all the patients and their families involved in the study. And we would like to thank Editage for help with language editing of the manuscript.