key: cord-0758322-w3tcuous
authors: Sun, Liang Liang; Wang, Jian; Wang, Yu Sheng; Hu, Ping Fang; Zhao, Zheng Qing; Chen, Wei; Ning, Bei Fang; Yin, Chuan; Hao, Yu Shi; Wang, Qiong; Wang, Chen; Liu, Ya Long; Chen, Cheng; Yin, Ji Zhong; Huang, Hai; Xie, Wei Fen
title: Symptomatic features and prognosis of 932 hospitalized patients with coronavirus disease 2019 in Wuhan
date: 2021-04-26
journal: J Dig Dis
DOI: 10.1111/1751-2980.12983
sha: 89d14bd80d6c2d7998734ea13f61582cc3327bbf
doc_id: 758322
cord_uid: w3tcuous

OBJECTIVE: To discern the symptomatic features of coronavirus disease 2019 (COVID‐19) and to evaluate the severity and prognosis of the disease. METHODS: In this retrospective cohort study, 932 hospitalized patients with COVID‐19 in Wuhan were enrolled, including 52 severe and 880 non‐severe cases. All patients were followed up for 3 months after discharge. The symptomatic features and follow‐up data of the patients in both groups were analyzed and compared. RESULTS: Of the 932 patients, fever (60.0%), cough (50.8%) and fatigue (36.4%) were the most common symptoms. In total, 32.7% of the severe cases presented with gastrointestinal symptoms at disease onset, including anorexia, nausea, vomiting or diarrhea, which was significantly higher than that of the non‐severe group (P = 0.0015). The incidence of olfactory disturbance and dysgeusia was only 3.1% and 6.2%, respectively. After adjusting for age and sex, multivariate regression analysis showed that fever lasting for over 5 days (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.00‐3.62, P = 0.0498), anorexia at onset (OR 2.61, 95% CI 1.26‐5.40, P = 0.0096), and modified Medical Research Council level above grade 2 when dyspnea occurred (OR 14.19, 95% CI 7.01‐28.71, P < 0.0001) were symptomatic risk factors for severe COVID‐19. During the follow‐up, cough (6.2%), dyspnea (7.2%), fatigue (1.8%), olfactory disturbance and dysgeusia (1.5%) were the significant remaining symptoms. CONCLUSIONS: COVID‐19 causes clusters of symptoms with multiple systems involved. Certain symptomatic characteristics have predictive value for severe COVID‐19. Short‐term follow‐up data reveal that most patients have a good prognosis.

Electronic medical records of the patients hospitalized in the Optical Valley Branch of Maternal and Child Hospital of Hubei Province due to COVID-19 were copied and sent to the data processing center in Shanghai under the coordination of the hospital. Data including patients' demographic characteristics, clinical, laboratory, treatment, and outcome data were collected and extracted. All necessary variables with suitable explanations were first defined by the research team. An experienced respiratory clinician team reviewed the copies of the medical records and collected the data. The collected data were then entered into a computerized database using a self-designed double-entry system. The data-entry team ensured that all data needed were collected. If core data were missing, requests for clarification were immediately sent to the coordinators who subsequently contacted the attending clinicians.

A standardized electronic follow-up questionnaire was designed to supplement detailed symptomatic information and 3-month followup data after discharge, including onset symptoms, their onset time, duration and frequency, symptoms after discharge, and so on (Appendix 1). All patients were followed up by telephone after discharge by 15 clinicians mainly, consisting of respiratory specialists and doctors who have been working at the front line of the epidemic in Wuhan.

To ensure the validity of the collected data, patients who had died after discharge, those who were unable to cooperate or had unreliable narrators (ie, patients with dementia or communication problems) were excluded from the cohort. The time of the final follow-up visit was August 2, 2020. The accuracy and completeness of the data were finally checked by all the co-authors.

Data cleaning, including logical checks, outlier checks, and variable engineering, was performed by experienced programmers; variable engineering was also assisted by an experienced clinician. The original variables were transformed if needed, including but not restricted to converting continuous variables into categorical variables and combining multiple variables into single variables for information integration.

Laboratory-confirmed COVID-19 was defined as a positive result on reverse transcription-polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swab specimens or specific serum antibodies to SARS-CoV-2.

The severity of COVID-19 was evaluated following the protocol issued by the National Health Commission of the People's Republic of China (Trial Version 7.0), as mentioned above. 9 Patients with at least one of the following conditions were defined as severe cases:

(a) dyspnea (respiratory rate ≥30 times/min); (b) finger oxygen saturation ≤93% in the resting state; (c) arterial oxygen partial pressure/fraction of inspiration oxygen ≤300 mmHg; and (d) pulmonary imaging showing that pulmonary infection had progressed by >50% within 24-48 hours.

The time of symptom onset was defined as the earliest day when any symptom was noticed by patients themselves or physicians. Fever was defined as 37.3 C or higher on axillary temperature. Septic shock was defined according to the 2016 international guidelines for management of sepsis and septic shock. 10 Acute kidney injury was defined according to the KDIGO clinical practice guideline. 11 The definition of acute respiratory distress syndrome followed the Berlin diagnostic criteria. 12 Acute myocardial injury was defined as serum levels of ultrasensitive cardiac troponin I above the 99th percentile of the upper limit of normal. 13 The modified Medical Research Council (mMRC) dyspnea scale was defined as follows: level 0, no breathlessness; level 1, breathless when hurrying or walking up a hill; level 2, breathless when walking slower than people of the same age, or who needed to stop when walking; level 3, breathlessness or stop walking after around 100 m or a few minutes; and level 4, breathless when dressing, or unable to leave the house. 14 

Categorical variables were presented as number and percentages or frequencies. Continuous variables were presented as mean ± standard deviation, or median and interquartile range (IQR). Normal distribution of the continuous variables was determined by using the Shapiro-Wilk test and the Anderson-Darlin test. An independent group t-test or Mann-Whitney U-test was used to compare the differences in the continuous variables, depending on the normal distribution of the variables. The χ 2 test or Fisherʼs exact test was used to analyze the difference in categorical variables between the groups.

Univariate and multivariate logistic regression models were used to determine the symptomatic risk factors for severe COVID-19. Variables with a P value of less than 0.05 were included in the multivariate analysis. Based on previous findings and clinical considerations, a total of 11 variables, including significant basic demographic data and symptomatic characteristics in univariate analysis, were included in the multivariate analysis. If the difference between groups was not significant, the number of events was too small, odds ratio (OR) could not be calculated, or were collinear with other variables, the variable was excluded from the univariate analysis.

All the statistical analyses were performed using SAS JMP Pro 15.0 (SAS Institute, Cary, NC). A P value of less than 0.05 were considered statistically significant. 

The most common symptoms were fever (60.0%) and cough (50.8%), followed by fatigue (36.4%), anorexia (21.8%) and dyspnea (19.2%).

Compared with those with non-severe disease, patients with severe disease had a significantly higher incidence of dyspnea (59.6% vs 16.8%) and anorexia (48.1% vs 20.2%) (both P < 0.0001; Table 2 ).

Notably, 11.6% of the cases were asymptomatic, including two severe cases.

Fever was the most common symptom among all patients, which was more commonly seen in patients with severe disease than in the non-severe cases (78.8% vs 58.9%, P = 0.0043). Nevertheless, most of the non-severe patients had a persistent low-grade fever (37.3 C-38 C).

A moderate fever (38.1 C-39 C) was more common in patients with severe disease ( Table 2 ). The median duration of the fever was 7 days (IQR 4-11 days) in the non-severe group and 9 days (IQR 6-12 days) in the severe group ( Figure 2 , Table S1 ).

Most patients complained of dry cough and white sputum was common in patients with production of sputum ( Table 2 ). The median duration of cough was 17 days (IQR 9-35 days) for the whole cohort, while that in the severe group was as long as 30 days Table S1 ).

Dyspnea has been reported to be a characteristic symptom of severe COVID-19. In our cohort, when compared with the non-severe cases, dyspnea in patients with severe disease occurred at a later stage, lasted for a longer time and reached higher mMRC levels ( Figure 3 , Table S1 ). The median time from disease onset to dyspnea was 4 days (IQR 1-7 days) among all patients, with 3 days (IQR 1-7 days) in the non-severe group and 7 days (IQR 1-12 days) in the severe cases (P = 0.0048). The most severe dyspnea was observed on the 8th day from the disease onset in the non-severe group and on the 15th day in patients with severe disease. The median duration of dyspnea in patients with severe disease was 28 days (IQR 14-51 days), which was significantly longer than that in patients with non-severe disease (median 15 days [IQR 8-31 days]). As shown in Table 2 , a higher degree of dyspnea at disease onset, as quantified by mMRC level, was observed in patients with severe disease. At the peak stage, the Even when dyspnea was considerably relieved on the 43rd day from the disease onset, mMRC level in 19.0% of the whole cohort was still at level 2. Table S1 ). Altogether 14.5% of the patients had anorexia at disease onset, with a higher proportion in the severe group than in the non-severe group (30.8% vs 13.5%, P = 0.0006; Table S2 ).

Nausea or vomiting and diarrhea were not common among COVID-19 patients. As shown in Table 2 There were no significant differences in the incidences of these symptoms between the severe and non-severe groups ( Table 2 and Table S1 ).

Unexpectedly, the incidence of dysgeusia and olfactory disturbance in our cohort was only 6.2% and 3.1%, respectively ( than the non-severe group, although there was no statistical significance ( Figure 2 , Table S1 ).

A cluster analysis of symptom correlation showed that specific symptoms were positively related and formed several groups ( Figure 4 ). Anorexia, nausea or vomiting, and diarrhea formed a gastrointestinal symptom cluster. Headache and dizziness formed a neuropsychiatric symptom cluster. Dysgeusia and dysosmia were associated and often co-occurred, which formed an otorhinolaryngological symptom cluster. Fatigue and myalgia or arthralgia were highly correlated. In addition to nausea or vomiting and diarrhea, symptoms associated with anorexia included dysgeusia, fatigue and dyspnea. The only sign highly related to dyspnea was anorexia.

As shown in Table S2 , fever and cough were the two most common symptoms at disease onset. Only 17.3% of the severe group had dyspnea at disease onset, while 30.8% of them had anorexia. As shown in Table S3 , a total of 82.7% of the severe group and 63.3% of the nonsevere group started with systematic symptoms at disease onset, including fever, fatigue, myalgia, or joint pain. In total, 32.7% of the severe group started with gastrointestinal symptoms, including anorexia, nausea, vomiting or diarrhea, which was significantly higher than that of the non-severe group (P = 0.0015).

To explore the predictive effect of clinical symptoms on disease severity we conducted a multivariate regression analysis involving variables with significant statistical differences between the two groups in the univariate analysis ( 

All patients were followed up for 3 months after discharge ( Table 4 ).

The results showed that 6.2% of the patients still had cough, which was mostly a dry cough. A total of 1.8% of patients had fatigue, 0.8% had dysgeusia, and 0.5% had olfactory disturbance. Additionally, a total of 7.2% patients still had dyspnea, most with mMRC level 1. As a remaining symptom, the incidence of dyspnea was higher in the severe group than in the non-severe group (P < 0.0001) and patients with severe disease had a higher level of mMRC levels than the nonsevere group (P < 0.0001).

Though numerous studies have reported the clinical characteristics of patients with COVID-19, the symptomatic features of this disease have still not been thoroughly investigated. In this study we closely investigated the clinical data of patients with COVID-19. We uncovered detailed information on the symptomatic features, which is essential for physicians to grasp the characteristics of COVID-19 and make correct judgments about the disease. We found that the symptoms of COVID-19 are diverse and usually not typical. The most common presenting symptoms were fever (60.0%), cough (50.8%) and fatigue (36.4%), which is consistent with previous reports. 15, 16 However, the prevalence of olfactory and taste disorders (OTD) is much lower in our cohort than in other reports. [17] [18] [19] [20] It should be noted that 11.6% of patients with COVID-19, including two severe cases, were asymptomatic, suggesting that screening for COVID-19 based only on symptoms is not reliable.

Although fever is the most common symptom, most patients present with only persistent low-grade fever. Of note, nearly 40% of patients did not have a fever during the disease course. Additionally, a high fever (>39 C) was rare in these patients. However, it should be mentioned that patients with severe COVID-19 were prone to suffer from fever for a long time. A dry cough, which was also one of the most common symptoms in our cohort, usually lasted for a much longer period than fever. As expected, the duration of cough in the severe disease group was much longer than that in non-severe cases.

Dyspnea is a subjective experience that is common in patients with severe pneumonia. The occurrence of dyspnea appeared late and atypically, did not always follow a decline in blood oxygen saturation. presented at least with OTD, and 18.6% of cases had both disorders. 17 One group found that hospitals reported olfactory and gustatory dysfunctions, respectively. 18 However, OTD reports were much rarer in Asian people with COVID-19, ranging from 5.1% to 15.7%. 26, 27 In this report, the incidence rates of dysgeusia and dysosmia were only 6.2% and 3.1%, respectively, which is markedly lower than those from Western countries. There are some possible reasons for this difference. The clinical spectrum of COVID-19 is broad and varies according to ethnicity, which can be perfectly defined by the remarkable difference in the incidence rate of OTD in different regions. It has been reported that SARS-CoV-2 has two major lineages, designated L and S. The prevalent lineage of SARS-CoV-2 in

China was different from that in Europe. The L lineage was more prevalent than the S lineage in the early outbreak of COVID-19 in Wuhan, China. 28 Various SARS-CoV-2 lineages with large molecular divergence may cause distinct clinical symptoms.

It has been reported that older age, high sequential organ failure assessment (SOFA) score, and D-dimer greater than 1 μg/mL are risk factors for COVID-19 with a poor prognosis at the early stage. 16 In this study, we found that the risk factors for severe disease included being aged over 65 years, male sex, having a fever lasting for more than would help health workers with patient triage and recognize those with COVID-19 who required hospital admission. It will also be useful for doctors to screen the patients who are inclined to develop severe illness at an early stage and to adopt intensive treatment before it is too late.

In this study, we followed up the patients for 3 months after their discharge. Most patients with either non-severe or severe disease showed favorable prognoses. Cough, fatigue and dyspnea were the most common remaining symptoms in patients convalescing after COVID-19. Some patients, however, still did not recover from OTD.

Compared with patients with non-severe disease, those with severe disease were more likely to have remaining symptoms after discharge, especially dyspnea.

Our study had some limitations. As a retrospective study, some cases had incomplete documentation of the medical history and clinical manifestation. We had limited time to extract the prospective data during the outbreak of COVID-19. Furthermore, in our cohort, most cases (94.4%)

were not severe. All confirmed COVID-19 cases were required to be admitted to designated hospitals or temporary cabin hospitals in China.

Thus, the proportion of patients with non-severe COVID-19 in Chinese hospitals was higher than that in other countries.

In conclusion, patients with COVID-19 presented atypical but diverse symptoms including fever, cough and fatigue. It is noted that the Chinese patients suffered a lower incidence of OTD than patients in Western countries. The most common remaining symptoms at the recovery stage were cough and fatigue. The proportion and severity of dyspnea as symptoms remaining after discharge in patients with severe disease were higher than in the non-severe group. These data may help clinicians comprehensively understand the symptomatic features of COVID-19 and make correct judgments about the disease.

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Symptomatic features and prognosis of 932 hospitalized patients with coronavirus disease 2019 in Wuhan

We thank Prof. Xiao Fei Ye from the Department of Health Statistics, Second Military Medical University, for his advice on the clinical study, data analysis, and manuscript preparation. We thank all the patients who consented to donate their data for analysis and all the medical staff on the front line caring for patients. There was no funding source for this study. All data are available from the corresponding authors upon reasonable request.

The authors declare that they have no conflicts of interest.

https://orcid.org/0000-0001-6502-6824Wei Fen Xie https://orcid.org/0000-0002-7137-112X