key: cord-0943082-ysbopqqq
authors: Jiang, Xiufeng; Tao, Jianxin; Wu, Hui; Wang, Yixin; Zhao, Wei; Zhou, Min; Huang, Jiehui; You, Qian; Meng, Hua; Zhu, Feng; Zhang, Xiaoqing; Qian, Meifang; Qiu, Yuanwang
title: Clinical features and management of severe COVID-19: A retrospective study in Wuxi, Jiangsu Province, China
date: 2020-04-14
journal: nan
DOI: 10.1101/2020.04.10.20060335
sha: ebe6b213518c752d5fbb9fe1777b1b6ba7b2ab5a
doc_id: 943082
cord_uid: ysbopqqq

Objective: We aimed to investigate clinical features and management of 55 COVID-19 patients in Wuxi, especially severe COVID-19. Methods: Epidemiological, demographic, clinical, laboratory, imaging, treatment, and outcome data of patients were collected. Follow-up lasted until April 6, 2020. Results: All 55 patients included 47 (85.5%) non-severe patients and 8 (14.5%) severe patients. Common comorbidities were hypertension and diabetes. Common symptoms were fever, cough and sputum. Lymphopenia was a common laboratory finding, and ground-glass opacity was a common chest CT feature. All patients received antiviral therapy of α-interferon inhalation and lopinavir-ritonavir tablets. Common complications included acute liver injury and respiratory failure. All patients were discharged. No death was occurred and no medical staff got infected. Patients with severe COVID-19 showed significantly older age, decreased lymphocytes, increased C reactive protein, and higher frequency of bilateral lung infiltration compared to non-severe patients. Significantly more treatments including antibiotic therapy and mechanical ventilation, longer hospitalization stay and higher cost were shown on severe patients. Conclusions: Our study suggested that patients with severe COVID-19 may be more likely to have an older age, present with lymphopenia and bilateral lung infiltration, receive multiple treatments and stay longer in hospital.

with health care peers and other people who are interested.

In this retrospective study, we investigated 55 COVID-19 patients in Wuxi, Jiangsu Province, China. All the patients were diagnosed with COVID-19 according to WHO interim guidance and Chinese management guidelines [8, 9] . This study was approved by the Ethics Commission of Wuxi Fifth People's Hospital (2020-007-1), a designated infectious diseases hospital of COVID-19 and informed consent from participants was also waived by the Ethics Commission.

Epidemiological, demographic, clinical, laboratory, imaging, treatment, and outcome data were retrieved from electronic medical records of patients. Follow-up for this study lasted until April 6, 2020. If data were missing or vague, we confirmed by direct communication with health care providers. All data were collected by two independent doctors (JXF & WH) and checked by another doctor (TJX).

To identify COVID-19, laboratory confirmation of SARS-CoV-2 was performed in our hospital and Wuxi Center for Disease Control and Prevention (CDC) by testing throat swab specimens from upper respiratory tract using the standard protocol of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assays [10] . All patients received routine blood examinations including complete blood count, liver and renal function test, coagulation test, cardiac enzyme, electrolytes, C reactive protein, procalcitonin and arterial blood gas analysis. Chest X-ray or CT scan were also done for every patient. The criteria for discharge were body temperature back to normal level for more than 3 days, significant amelioration of respiratory symptoms, obvious improvement of acute lung infiltration in chest radiographs, and two consecutive throat swab or sputum specimens tested negative for SARS-CoV-2 at least 24 hours apart [9] .

The severity of COVID-19 was defined according to the Chinese management guideline (7th edition). The severe-type patients were characterized by dyspnea, respiratory frequency ≥ 30/minute, blood oxygen saturation ≤ 93%, PaO 2 /FiO 2 ratio <300, and/or lung infiltrates >50% within 24-48 hours [9, 11] . Clustered epidemic was defined as at least two confirmed cases or asymptomatic infections were found within a small area (e.g. a family, a construction site, a work unit, etc.) within 14 days, and there existed the possibility of person-to-person transmission due to close contact, or the possibility of infection due to co-exposure [12] . Fever was defined as axillary temperature >37.2°C. Diarrhea was diagnosed as the passing of loose stools >3 times per day. isolated from lower respiratory tract specimens or blood samples [10] . Shock was defined according to the 2016 Third International Consensus Definition[6].

Continuous variables were described using median (interquartile range, IQR) and comparisons between groups were performed using Mann-Whitney U test. Categorical variables were presented as number (%) and compared by χ 2 test or Fisher's exact test between groups as appropriate.

Clinical curves were developed using the Kaplan-Meier method with log-rank test. A two-sided α of less than 0.05 was considered statistically significant. Statistical analyses were done using SPSS (version 26.0) or Graphpad Prism (version 8.0). As shown in Table 1 , 22 (40.0%) cases were imported from Hubei, most of which were from Wuhan due to long-term living in or short-term traveling to Wuhan. There existed 43 (78.2%) cases in 11 epidemic clusters among patients, averaging approximately 4 cases per cluster, mainly through familial clusters and dining clusters. The median incubation period was 7.0 days (IQR 3.5-10.0). The exposure history and incubation period were similar between patients with non-severe and severe illness.

Here, we described two epidemic clusters -one was an imported familial cluster and the other one was a combination of familial, transportation and dining clusters ( Figure 1 ). Patient 1-6 lived together in Wuhan. Patient 1-4 and patient 5-6 returned to Wuxi on January 22 and January 19, 2020, respectively. They got diagnosed and admitted to hospital since January 24, and Patient 6 got severe disease ( Figure 1A ). Any of these six patients could be the first one to get infected and in turn transmitted the virus to the other family members. Patient 7-10 took the same fight back to Wuxi from Japan on January 24 and patient 7-9 were from the same family. On the next day, patient 7-8 had dinner with patient 11-15. They got diagnosis and admission since January 30 and patient 7&11 got severe disease ( Figure 1B Table 1 ). Patients with severe disease had significantly higher frequency of cough (100.0% vs 55.3%, p=0.018), sputum production (87.5% vs 42.6%, p=0.049) and dyspnea (100.0% vs 6.4%, p<0.001) than those with non-severe disease. On admission, patients with severe disease significantly lower lymphocytes (0.83×10 9 /L vs 1.40×10 9 /L, p=0.010), higher C reactive protein (70.27mg/L vs 4.50mg/L, p=0.001) and procalcitonin (0.2ng/mL vs 0.2ng/mL, p=0.039) than those with non-severe disease ( Concurrently, ground-glass opacity was presented on 42 (76.4%) patients. The chest CT features of patients with non-severe and severe disease were shown in Figure 2 .

All patients received antiviral therapy of α -interferon inhalation and lopinavir-ritonavir tablets ( Table 3 ). Significantly more patients with severe disease had respiratory failure than those with non-severe disease (100.0% vs 4.3%, p<0.001).

All patients were discharged from hospital and no death occurred. The median duration of hospitalization among all patients was 16.0 days (IQR 5.0-10.0; Table 3 ) and patients with severe disease had longer hospitalization compared with those with non-severe disease (23.0 days vs 16.0 days, p=0.003; HR=0.37 [95% CI 0.21-0.65], p=0.0012; Figure 3A ). Patients with severe disease also stayed significantly longer in hospital after negative PCR test (14.0 days vs 6.0 days, p=0.002; HR=0.38 [95% CI 0.21-0.66], p=0.0010; Figure 3C ). The median hospitalization cost was 11472.67 yuan (IQR 8220.14-17509.40), in which patients with severe disease spent significantly more money than those with non-severe disease (71902.29 yuan vs 10589.70 yuan, p<0.001).

. CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04. 10.20060335 doi: medRxiv preprint

To our knowledge, this report is the first retrospective study of all 55 COVID-19 patients in Wuxi, Jiangsu Province, China. We described epidemiological, demographic, clinical, imaging features as well as treatment and outcomes of all patients. All patients got recovery and discharged from hospital. No death was occurred and no medical staff got infected.

In our study, the median age of patients with severe disease were significantly higher compared to patients with non-severe disease, suggesting that older patients may be more susceptible of getting severe disease than younger patients. However, no significant sex difference was found between patients with non-severe and severe illness. A majority (78.2%) of patients got infected due to epidemic clusters, mostly via familial and dining clusters, which provided the evidence of person-to-person transmission of SARS-CoV-2. According to cluster investigation technical guidelines from the Chinese Epidemiology Working Group, epidemic clusters are divided into several subtypes, which refer to the cluster of family, dining, work unit, transportation and public place [12] .

Over half (52.7%) of patients had comorbidities, most of which were hypertension (30.9%) and diabetes (16.4%), whereas we didn't discover a significant difference of all comorbidities between patients with non-severe and severe disease other than diabetes. Similarly, recent studies showed that the prevalence of diabetes was averagely about two folds higher in severe cases [15] . Common symptoms found in our study were fever, cough, sputum production, dyspnea, fatigue, chest distress and headache. Interestingly, we found 18 (32.7%) patients had diarrhea, with a higher incidence than that in previous studies [11, 16] . Four (7.3%) patients had no signs and symptoms during the onset and they only got the non-severe disease (data not shown). The existence of asymptomatic infected individuals has been reported and they also had the ability of virus transmission to others [17] . Particularly, patients with asymptomatic infection may not realize their illness and they could be important hidden sources of infection, which may bring potential danger to public health. Therefore, it is of great significance for suspected patients to fully cooperate with self-isolation, supervision and screenings.

In laboratory findings, patients with severe disease had significantly lower levels of lymphocytes and decreased serum sodium concentration as well as higher levels of C reactive protein and procalcitonin than those with non-severe disease, implying these abnormalities could be a potential indicator for severe-type COVID-19. However, unlike some other studies, we didn't find any major differences of leukocytes, neutrophils, D-dimer and liver enzymes between two groups [16, 18] . Our findings also suggested patients with severe disease were more likely to present with increased neutrophils and D-dimer. The results of Chest CT showed a majority of patients had bilateral infiltration and ground-glass opacity, and both of them were presented in all patients with severe disease. Moreover, a small portion of patients showed no obvious abnormalities on CT. Currently, most of the treatments for COVID-19 are supportive therapy. Till now, no specific drugs or vaccinations have been approved for treatment or prevention from infection with SARS-CoV-2. In our study, all patients received the combination therapy of α -interferon and lopinavir-ritonavir. α -interferon is responsible for broad antiviral effect and enhancement of immune response [19] . Lopinavir, a human immunodeficiency virus type 1 aspartate protease inhibitor, was previously approved for treating SARS-CoV infection in 2003, and ritonavir is . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04. 10.20060335 doi: medRxiv preprint combined with lopinavir to increase its plasma half-life through the inhibition of cytochrome P450 [20] . Surprisingly, a recent small-scale clinical trial showed no clinical improvement was observed with lopinavir-ritonavir treatment beyond standard care for treating patients with severe disease [20] . However, Deng et al. found that lopinavir-ritonavir combined with arbidol, another drug against SARS-CoV, might show benefit in delaying clinical progression of COVID-19 and attenuating viral transmissibility [21] . Chloroquine is newly recognized as potential effect against SARS-CoV. In our study, chloroquine was used to treat four (7.3%) patients, mostly used on Overall, it needs to take a long time to identify or invent effective medicine for COVID-19. From our data, patients with severe disease were more likely to be treated by antibiotic therapy, intravenous systemic corticosteroid, intravenous immune globulin, thymosin injection, probiotics tablets, LMWH injection, high-flow oxygen nasal cannula support and mechanical ventilation, which, to some extent, may explain the longer duration and higher cost of hospitalization in severe patients. Our team also used new techniques to treat the critically severe patient, such as transfusion of convalescent plasma, ECMO, and even lung transplant. No significant difference was found in the duration of conversion from the positive PCR test to the negative one after admission (Table 3 & Figure 3B ), however, patients with severe disease had the tendency to stay longer in hospital after the negative PCR test. SARS-CoV-2, the coronavirus causing COVID-19, has been proved to bind the entry receptor of host cells called angiotensin-converting enzyme II (ACE2), the same as previous SARS-CoV and MERS-CoV[25]. ACE2 is a protein with 805 amino acids and diffusely expressed in heart, vessels, lung, kidney and gut. It functions as the conversion of angiotensin I to angiotensin II, playing a pivotal role in renin-angiotensin-aldosterone system (RAAS) [26] . When infected with SARS-CoV-2, the virus predominantly targeted ACE2 in human alveolar type 2cells, resulting in pulmonary symptoms [27] . It has been reported that ACE2 was associated with comorbidities, symptoms and complications in COVID-19 patients, such as hypertension, diabetes, cardiovascular disease and gastrointestinal abnormalities [28] . However, the mechanism still remains unclear. Chen et al. found that SARS-CoV-2 might attack pericytes of human heart, thus causing capillary endothelial cell dysfunction, leading to cardiovascular disease and cardiac injury[29]. Jin et al. suggested that gastrointestinal epithelial cells had a high affinity to ACE2, indicating the potential of fecal-oral transmission and the tendency of gastrointestinal symptoms in dissemination [3] . Despite SARS-CoV-2 had a huge relationship with ACE2, whether ACE2 could be a therapeutic target still remains controversial and needs further research. In Wuxi, potent and strict measures have been taken since the outbreak of COVID-19. People need to wear face masks and use Wuxi Health Code when going out. People who have been to Wuhan recently or have had close contact with them would be advised to quarantine at home for at . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . least 14 days. Suspected patients would receive the nucleic acid PCR test and those who got a positive result would be admitted to hospital immediately. Every confirmed patient with COVID-19 would be arranged in the negative pressure ward of a designated infectious hospital for treatment. Those who got discharged still need the PCR test again two and four weeks after discharge, respectively. Of all patients, one patient retested positive of stool samples. Several limitations do exist in our study. First, this study included only 55 cases thanks to good monitoring and screening in Wuxi, which may cause some statistical and selective bias of our results. Second, no immune function test like serum T cells or cytokines and some other tests like serum lactate dehydrogenase were involved in the laboratory test. As such their role might be underestimated in causing severe disease. Third, this study was limited to the local investigation, and the findings may be inconsistent with nationwide or worldwide studies, which may decrease its credibility.

In summary, our retrospective study established the epidemiological and clinical features of all 55 COVID-19 patients in Wuxi, Jiangsu Province, China, and shared some successful experience of treatment, especially patients with severe disease. Our results supported person-to-person transmission of SARS-CoV-2 and suggested that patients with severe COVID-19 may be more likely to have an older age, present with lymphopenia and bilateral lung infiltration, receive multiple treatments and stay longer in hospital. Further large-sized and randomized clinical trials are urgently needed to identify the effective treatments for COVID-19.

The authors declare that they have no competing interests. Chen, L., et al., The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res, 2020.

. CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04.10.20060335 doi: medRxiv preprint 8.0 (7.0-11.0) 8.0 (7.0-11.0) 9.5 (5.8-18. <0.00 1 . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04. 10.20060335 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04. 10.20060335 doi: medRxiv preprint 

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

Clinical Characteristics of Coronavirus Disease 2019 in China

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Analysis of Epidemiological and Clinical features in older patients with

Epidemiology Working Group, S., C.C.f.D.C. Policy Working Group for Ncip Epidemic Response, and Prevention, Cluster investigation Technical Guidelines for the 2019 Novel Coronavirus Pneumonia (COVID-19), China (1st Trial Version)

Acute respiratory distress syndrome: the Berlin Definition

Kidney disease: Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Asymptomatic cases in a family cluster with SARS-CoV-2 infection

Epidemiologic and Clinical Characteristics of 91 Hospitalized Patients with COVID-19 in Zhejiang, China: A retrospective, multi-centre case series

Interferons alpha and beta in cancer: therapeutic opportunities from new insights

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

This study was supported by Wuxi Municipal Health Commission Major Project (Z201811); Wuxi

Science and Technology Bureau COVID-19 special project (N2020X009); Wuxi Science and Technology Bureau guiding plan (201812). We would like to thank all medical staff with fighting COVID-19 in Wuxi for their huge contributions.