key: cord-302159-exexcag6 authors: Wei, Yanqiu; Lu, Yanjun; Xia, Liming; Yuan, Xianglin; Li, Gang; Li, Xinying; Liu, Li; Liu, Wenhua; Zhou, Peng; Wang, Cong‐Yi; Zhang, Huilan title: Analysis of 2019 novel coronavirus infection and clinical characteristics of outpatients: An epidemiological study from a fever clinic in Wuhan, China date: 2020-06-16 journal: J Med Virol DOI: 10.1002/jmv.26175 sha: doc_id: 302159 cord_uid: exexcag6 BACKGROUND: Since the outbreak of 2019 novel coronavirus (SARS‐CoV‐2) pneumonia, thousands of patients with fever or cough were flocked into fever clinic of designated hospitals in Wuhan, China. To date, no data have ever been reported to reflect the prevalence of Corona Virus Disease 2019 (COVID‐19) among these outpatients. Moreover, it is almost unknown to discriminate COVID‐19 and nucleic acid negative patients based on clinical features in the fever clinics. METHODS: The infectious status of SARS‐CoV‐2 was estimated among the outpatients. The epidemiological and clinical characteristics were compared between COVID‐19 and nucleic acid negative patients. RESULTS: The nucleic acid positive rate for SARS‐CoV‐2 in the outpatients from our fever clinic was 67·1%, while the majority of COVID‐19 patients were mild cases. The predominant initial symptom in those COVID‐19 patients was fever (78.2%), followed by cough (15.6%). Very significantly lower number of eosinophils was characterized in COVID‐19 patients as compared to that of nucleic acid negative patients. More importantly, the proportion of subjects with eosinophil counts lower than normal levels in COVID‐19 patients was much higher than that of nucleic acid negative patients. Fever combined with bilateral ground‐glass opacities in CT imaging and eosinophil count below the normal level are probably a valuable indicator of COVID‐19 infection in those outpatients. CONCLUSIONS: Those findings may provide critical information for the regions such as Europe and United States that are facing the same situation as Wuhan experienced, and could be valuable to prevent those nucleic acid negative patients from misdiagnosis before antibody testing. This article is protected by copyright. All rights reserved. by WHO, 7 and now became a global pandemic along with patients diagnosed in more than 190 additional countries. The first case of COVID-19 was characterized in Wuhan, Hubei Province in December 2019. Its clinical manifestations are very similar to those infected by the severe acute respiratory syndrome coronavirus (SARS-CoV) occurred in 2003. 8, 9 Although the mortality rate of COVID-19 in China is 3%, far lower than that of SARS (10.0%), 10, 11 the mortality rate in Wuhan, unfortunately once reached 9.0% in the early stage of the outbreak, and similarly in Italy now. However, the mortality in Wuhan gradually decreased, suggesting that early diagnosis and treatment could significantly reduce its death rate. Upon the supports from the outsides of Wuhan, increasing cases with respiratory symptoms were accessible to laboratory tests and medical treatments from the fever clinics. Nevertheless, no data have been reported in terms of the proportion of COVID-19 patients among all outpatients in fever clinics, or the proportion of severe cases among all COVID-19 patients. Similarly, no convincing evidence has been suggested to discriminate COVID-19 from nucleic acid negative patients, or mild case from severe case of COVID-19. As a leading hospital in Hubei Province, Tongji Hospital serves as one of the main designated hospitals to carry out fever clinic. This study is designed to analyze the infection rate of SARS-CoV-2 in patients visiting fever clinic in Wuhan, and to compare the clinical features between COVID-19 and nucleic acid negative patients based on the epidemiological, clinical, laboratory and CT scan results. To further provide more information that could be considered as a worthy reference for the frontline clinicians, a "Clinical Rapid and Preliminary Sorting Score System" was proposed in case that the results for nucleic acid assays are not available or negative because of inappropriate sample collection. This system was designed to assess the possibility of COVID-19 positivity based on the clinical characteristics and laboratory results in outpatients. In this retrospective study, we recruited all febrile patients from the fever clinic of Tongji Hospital in Wuhan, China, from January 30 to February 4, 2020, the peak time period of this pandemic in Wuhan. The COVID-19 nucleic acid assays were conducted in Tongji Hospital. Throat-swab specimens from the upper respiratory tract were collected from all outpatients twice with a 24h interval. Fever was defined as axillary temperature reached 37.3 o C or above. Due to the strong transmission potency of those newly infected were plotted as a figure. Proportions for categorical variables were compared using the χ2 test, although the Fisher exact test was used when the data were limited. Means for continuous variables were compared using the Mann-Whitney test. A "Clinical Rapid and Preliminary Sorting Score System" was proposed to assess the possibility of COVID-19 positivity based on the clinical characteristics and laboratory results in outpatients. Specifically, the predictive proportions of COVID-19 positivity were carried out based on the mean positive predictive value in different combinations of clinical charts, CT scan and eosinophil count. All statistical tests were two-sided, and P<0·05 was considered as statistically significant. Since Tongji Hospital is almost located in the center of COVID-19 epidemic, its fever clinic received 936 visitors between January 30 th to February 4 th of 2020, which was the peak period of this outbreak. All of those 936 visitors were undergone at least twice of COVID-19 nucleic acid assays with a 24h of interval, and 628 of whom were positive for the assays, and thus diagnosed as COVID-19 (67·1%), while the rest 308 visitors were negative (32·9%). In terms of age distribution, the average age for the diagnosed COVID-19 patients was 53 years (±14.8 years), while the average age for nucleic acid negative patients was 49 years (±13.0 years), which was significantly younger than that of COVID-19 patients (P < 0.01). Among those COVID-19 patients, 296 are males (47.1%) and 332 are females (52.9%). In those nucleic acid negative patients, 142 are males (46.1%) and 166 are females (53.9%). No significant difference was noted between the COVID-19 patients and nucleic acid negative patients in terms of genders (Table1). It was noted that fever was the predominant initial symptom in COVID-19 patients, which accounted for 78.2%, followed by cough (15.6%). Other symptoms including fatigue (6·7%), chest tightness (2.4%), diarrhea (1.9%), muscle ache (1.3%), and dyspnea (1.0%) were also observed. Only a very small proportion of COVID-19 patients also manifested anorexia (0.5%), rhinobyon (0.3%), vomiting (0.2%), sore throat (0.2%), aversion to cold (0.2%), nausea (0.2%), hypersomnia (0.2%), expectoration (0.2%), dizziness (0.2%) and xerostomia (0.2%). However, fever was also characterized to be the major initial symptom for those nucleic acid negative patients as well, which accounted for 73.1%, and cough accounted for 21.1% (Table 1) . Among all 936 visitors, 460 of them conducted routine blood tests, and 309 were COVID-19 patients, while the rests were nucleic acid negative patients. The average number of lymphocytes in COVID-19 patients was 1·2×10 9 /L, while it was 1·4×10 9 /L for the nucleic acid negative patients, and no significant Accepted Article difference was observed between the two groups (P=0·062). In sharp contrast, COVID-19 patients displayed significantly lower number of platelet counts as compared to that of nucleic acid negative patients (195·30×10 9 /L vs. 216·00×10 9 /L; P=0.026). Remarkably, very significantly lower number of eosinophils was characterized in COVID-19 patients as compared to that of nucleic acid negative patients (0.02×10 9 /L vs. 0.03×10 9 /L; P=0.002). More importantly, the proportion of subjects with eosinophil counts lower than normal levels in COVID-19 patients was much higher than that of nucleic acid negative patients (74·11% vs. 59·60%; P=0·002) ( Table 2) patients, while only 58·0% of nucleic acid negative patients displayed the above manifestation. Characteristically, the COVID-19 patients were more likely to have both lungs involved (90·2% vs. 80·7%; P<0·001). Further analysis of the lesion sites revealed that those nucleic acid negative patients were more likely to exhibit lesions in the right upper lobe (17·8% vs. 11·7%, P=0·019) of right lung (42·8% vs. 34·8%, P=0·030), and lower lobe of left lung (19·7% vs 13·5%, P=0·023) ( Table 3) . As aforementioned (Table 1) , fever and cough were the primary symptoms in both COVID-19 and nucleic acid negative patients. To better discriminate the initial symptoms in those two types of patients to improve diagnostic feasibility, we further analyzed their initial symptoms by classifications. Remarkably, patients manifested muscle ache in the initial symptoms had the highest nucleic acid detection rate (80·0%; 95% CI: 45·9-95·0), followed by the initial symptoms coupled with dyspnea (75·0%; 95% CI: 37·7-93·7), while the detection rate in patients with initial symptoms of fever (68.6%; 95% CI: 65.1-71.9) or diarrhea (66.7%; 95% CI: 42.8-84.2) was relatively lower. However, the number of patients with initial symptoms including muscle ache (10/936) or dyspnea (8/936) was relatively small and, therefore, the above conclusion is worthy of further large-scale clinical observations. To further provide a risk assessing system that could be considered as a worthy reference for the frontline clinicians, a "Clinical Rapid and Preliminary Sorting Score System" was proposed, which was constructed by combination of symptomatic manifestations such as fever, chest CT scan with bilateral ground-glass Accepted Article opacities and eosinophil count. Interestingly, the results indicated that if the patients manifested these four characteristics (fever, bilateral CT imaging, Ground-glass opacity and eosinophil count below the normal level), the possibility for a COVID-19 positivity could reach up to 79·8% (95% CI: 71.97-87.7), and the OR ratio was 2.782 (95% CI: 1.578-4.905). Similarly, once patients only manifest bilateral lung ground-glass changes and eosinophil count below the normal level, the possibility for a positive result in nucleic acid assay could also reach 77.0% (95% CI: 71.0-83.0) ( Table 4) . Among 628 diagnosed COVID-19 patients, 553 cases were mild cases (87·9%), while 75 were severe cases (11.9%). In general, the mild cases (52 years ± 15·1 years) were significantly younger than that of severe cases (57 years ± 11·5 years) (P = 0·004). Among 553 mild cases, 262 of them (47·4%) were males, and 291 (52·6%) were females. Similarly, 34 out of 75 severe cases (45·3%) were males, and the rest 41 (54·7%) were females. No preferential distribution in terms of genders was observed in either mild or severe/critical cases was observed. However, it seemed that more severe cases manifested cough in their initial symptoms as compared to that of mild cases (24% vs. 14·5%; P=0.033) ( Table 5 ). This is the first retrospective study with large sample size of visitors from a single fever clinic in Wuhan, China. Based on the analysis of the initial clinical symptoms of 936 visitors in the fever clinic of Tongji hospital and the estimation of basic reproductive number (R0) in previous studies, 14, 15 person-to-person transmission, particularly in the crowded public places, is likely the major style contributing to the COVID-19 outbreak. This transmission style exacerbated the outbreak in Wuhan significantly from late January to early February of 2020. Given that Tongji Hospital is located in the center of this epidemic, the number of visitors in its fever clinic was far beyond of its capacity. In particular, From January 30 th to February 4 th of 2020, 5,686 COVID-19 cases were confirmed in Wuhan, while 628 of which were diagnosed in Tongji Hospital, which accounted for 11.0% of the total diagnosed cases. 16, 17 Among 936 visitors included in this study, the detection rate for SARS-CoV-2 reached up to 67% (628/936). Interestingly, there is no statistical difference in gender distribution between COVID-19 patients and nucleic acid negative patients, suggesting that SARS-CoV-2 is susceptible to both genders. This finding is different from Chen and his colleagues reported, 18 but consistent with the data published by Wang and his colleagues. 14 This discrepancy is likely caused by the small sample size included by Chen and his colleagues. However, all studies including our own indicated that aged subjects are more susceptible to SARS-CoV-2 infection. The primary symptoms of COVID-19 patients were fever and cough, which were similar to the clinical manifestations of SARS and MERS. [19] [20] [21] In general, COVID patients are difficult to be discriminated from nucleic acid negative patients based on symptoms such as fever, cough and others. Therefore, we first assessed the relationship between the first symptom(s) and the positive rate of SARS-CoV-2 detection. Remarkably, visitors initially complained with muscle ache displayed up to 80% positively of SARS-CoV-2, followed by dyspnea (75%), indicating that initial symptoms manifested by muscle ache or dyspnea could be more critical for a quick assessment for possibility of SARS-CoV-2 infection, as fever and cough are also common in those nucleic acid negative visitors. However, only 8 patients (1.3%) were found with aching muscle in our study, while a study in the hospitalized patients revealed that around 23.1% COVID- In general, antibodies specific for COVID-19 virus could not be detected until day 10 following infection, and track records for all of our outpatients revealed that none of them had more than day 6 of the initial symptoms before visiting the fever clinic (1 to 6 days). Therefore, it seems that nucleic acid assay is the only way to reach a confirmative diagnosis of COVID-19 during the early stage of infection. Unfortunately, false negative result could be produced in certain patients, which would delay the diagnosis and give timely treatment for saving their lives. In order to make a preliminary assessment whether a patient was COVID-19 in case that nucleic acid assays are not available or negative because of inappropriate sample collection, we proposed a system by combining the initial symptoms, laboratory tests, and chest CT scans. Remarkably, fever combined with muscle ache can reach a 75.0% possibility for a positive result in nucleic acid assays, while the possibility of nucleic acid positive could reach up to 79.8% once fever combines with bilateral lung ground glass-like changes in CT scans and eosinophil count below normal level. In particular, by combining bilateral lung ground glass-like changes in CT-scans with eosinophils below normal level only can also reach 77.0% possibility to be positive for nucleic acid assay. Together, this system could be useful for helping those nucleic acid negative patients and regions lack of nucleic acid detection kits from misdiagnosis before antibody testing. One major limitation for our study is that we could not track their records after visiting our fever clinic. Once a confirmative diagnosis reached, only those severe and critical COVID-19 patients were arranged for hospitalized treatment by the Outbreak Control Center under city government based on the available bed units in the designated hospitals in Wuhan, and the purpose of this policy was designed to increase the efficiency for the use of limited bed units at that time. For those patients with mild symptoms or nucleic acid negative patients were advised for home quarantine for 14 days. Therefore, we cannot track those patients for their location of admission and for obtaining additional medical histories. However, the situation was changed later upon the arrival of medical staff from outsides and the establishment of cabin hospitals and two additional infectious hospitals. In summary, this retrospective study included 936 visitors from the fever clinic of Tongji Hospital from January 30th to February 4th of 2020, which was the peak time of this outbreak. The detection rate for COVID-19 was as high as 67.1%. By analysis with different groups, we demonstrated that muscle ache and fever could be two independent markers for early assessing the possibility of COVID-19, while eosinophil counts below normal levels could a viable marker to assess the possibility of a patient being diagnosed as COVID-19 by combining other initial symptoms, laboratory tests and chest CT scan. 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