Clinical Features of Patients Without Fever Infected by SARS-CoV-2: an Observational Study

Objective: A large number of patients had infected by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). We aimed to clarify the clinical features of the patients without fever infected by SARS-CoV-2. Methods: This is a retrospective and single-center study. We collected and analyzed the data of demographic, clinical presentation, laboratory tests, radiological results, treatment, and complications. The patients with fever and without fever were compared. Results: 113 patients were enrolled in the study, 36 (31.9%) patients without fever on admission. Among the patients without fever, the mean age was 41 years (IQR, 30-53; Range, 8-82years) and 18 (50%) were male. The median from the onset of illness to the rst admission was 3.0 days. None of the patients without fever had complications and received high-ow oxygen therapy or invasive ventilation. As of Feb 22, 2020, 8 patients (22.2%) were discharged, and the remaining patients were still hospitalized. Conclusions: Out of 113 patients with SARS-COV-2 infection, patients without fever accounted for 31.9% in total. The clinical prognosis of patients without fever may be better than those of patients with fever on admission.


Introduction
In December 2019, a series of cases of pneumonia with unknown causes were found in Wuhan city, Hubei province, which were identi ed as 2019-nCoV [1][2][3][4] . On February 11, 2020, the International Committee on Taxonomy of Viruses (ICTV) renamed it as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which was a new strain of RNA virus that had not been discovered in animals or humans so far5. Additionally, the SARS-CoV-2 infected disease was named as coronavirus disease 2019 (COVID-19) by WHO. By Jan 10, 2021, con rmed SARS-CoV-2 cases had occurred in 223 countries, areas or territories 5 . Globally, 88,828,387 cases have been diagnosed with COVID-19, while in China, this value was 97,625. Unfortunately, overall, 1,926,625 patients died because of COVID-19 5 .
Therefore, the global cooperation between governments, health workers, and the public are vital to prevent its spread 6 .
Thus far, many published scienti c studies mainly focused on the epidemiology and clinical features of COVID-19 1,2,6−10 . However, the difference in clinical characteristics of cases without fever has not been reported. By Jan 23, 2020, three studies of 99 patients, 41 patients, and 138 patients respectively with laboratory-con rmed in the Wuhan area indicating 3%, 2%, and 1.4 % of patients without fever, respectively 1,6,7 . Xu et al 9 suggested that 23 % (62) of the patients without fever and the atypical symptoms of patients in Zhejiang province were signi cantly larger than the patients in Wuhan. An observation study of 1099 laboratory-con rmed cases including 483 (43.95%) patients of Wuhan from 30 hospitals in China suggested that 12.1% of patients without fever 10 . Meanwhile, due to the precautions taken and management implemented quickly by the Chinese government, more patients without fever have been diagnosed with COVID-19 before their symptoms getting worse or during the incubation period.
In this study, we retrospectively collected and analyzed detailed clinical data of patients with laboratorycon rmed SARS-CoV-2 infection in a hospital of Changsha, Hunan province. We concluded clinical manifestations and prognostic characteristics of COVID-19 patients without fever in order to direct clinical treatment and provide further guidance on patient management.

Study design and participants
This study used a retrospective design. Patients with COVID-19 admitted to the Changsha Public Health Center from Jan 30 to Feb 22, 2020, were included. All the enrolled patients were diagnosed with SARS-CoV-2 infection on the basis of the WHO interim guidance 11 . The clinical outcome was monitored up to Feb 22, 2020, the nal date of follow-up. This study was approved by the institutional ethics board of the Second Xiangya Hospital, Central South University. As an urgent retrospective study, informed consent was waived by the ethics board.

Data collection
The medical information of patients with SARS-CoV-2 infection was collected, including age, gender, history of Hubei exposure in two weeks, days from illness onset, physical examination, comorbidities, signs and symptoms, laboratory ndings, and chest radiography at admission. The treatment, complications, oxygen support, and prognosis were recorded during hospitalization. Laboratory ndings were collected for each patient, including complete blood count, coagulation test, liver and renal function, erythrocyte sedimentation rate, C-reactive protein, procalcitonin, lactate dehydrogenase and creatine kinase. All data were collected by two physicians (ND and FT). Laboratory-con rmation of SARS-CoV-2 was done in the designated hospital. The SARS-CoV-2 RNA extraction procedure was performed with the Viral Nucleic Acid Isolation Kit according to the manufacturer's instructions.

De nitions
Fever was de ned as an elevated body temperature and presence of axillary temperature ≥37.0°C 12 .
Assessment of body temperatures (axillary) with admission was performed by using mercury thermometers. Patients who reported any fever history during the time from the onset symptom to admission were categorized into the fever group. Acute respiratory distress syndrome (ARDS), according to the Berlin de nition, referred to a decrease in the PaO2/FiO2 index below 300 mmHg 13 . Acute kidney injury (AKI) was identi ed and classi ed based on the highest serum creatinine level or urine output criteria according to the kidney disease improving global outcomes classi cation 14 .

Statistical analysis
As the difference onset of illness, we divided the cohort into patients with symptoms of fever and those without fever. Characteristics are expressed as mean ± standard deviation or median (IQR) for continuous variables and a percentage or frequency for categorical variables. Continuous variables were compared using Student's t-test (normal distribution) or Mann-Whitney U-test (Skewed distribution), and categorical variables were compared using Fisher's exact test or Chi-square analysis. All analyses were carried out using R (http://www.R-project.org). Two-sided P values <0.05 were considered statistically signi cant.

Demographics and clinical characteristics
By 22 Feb 2020, 113 patients with SARS-CoV-2 infection were included in the study, including 36 (31.9%) patients without fever and 77 (68.1%) patients with fever on admission. In total, 75 (64%) patients had a history of Hubei exposure and all 113 patients had been exposed to people infected by SARS-CoV-2. There was no difference in the history of Hubei exposure between without fever and fever patients. Of these patients, the median age was 45 years (IQR, 35-60; Range, 8-83years) and 62 (54.9%) were male (Table 1). Compared with fever patients, the patients without fever were younger (median, 41vs 50 years) and were more likely to admission early (median, 3 vs 5 days, P = 0.032). The underlying comorbidities between patients without fever and fever patients were signi cant differences. Only 5 (13.9%) patients without fever had the underlying disease, less than those in fever patients (  ). The symptom of sore throat in patients without fever were more in frequency than the fever group (P = 0.037).

Laboratory testing and vital signs
On admission, there were more cases in fever patients of fast heart rate (> 100 bpm) when compared with this in patients without fever (32% vs 13.9, P = 0.037). There was no difference between fever and patients without fever on respiratory rate, systolic pressure and diastolic pressure (Table 1). Of all patients' admission recordings, 37.2% and 10.6% of patients had leucopenia and thrombocytopenia, respectively. Moreover, the levels of white blood cell count, lymphocyte count, monocyte count, and platelet count in patients without fever were higher than fever patients (P < 0.05). However, the levels of lactate dehydrogenase, C-reactive protein, and erythrocyte sedimentation rate in patients without fever were lower than those in patients with fever (P < 0.05) ( Table 2). All of the 36 patients without fever had received the chest CT scan, 5 (13.9%) of them showed unilateral pneumonia, 29 (80.6%) of them showed Bilateral pneumonia (Fig. 1).  Table 3). For the patients without fever, all of them received the oxygen support of the nasal cannula. In 14 fever patients with ARDS, 10 of them received high ow high-ow nasal cannula oxygen, and 3 of them received invasive ventilation (1patient was given extracorporeal membrane oxygenation). Most of the cases were given antiviral treatment and traditional Chinese medicine treatment in both patients without fever and fever patients. 12 (33.4%) patients without fever received antibiotic treatment which was less than 51(66.2%) of fever patients (P = 0.001). Additionally, systematic corticosteroid and gamma globulin treatment were less used in patients without fever compared with fever patients (P < 0.001). Data are n (%) unless speci ed otherwise. ECMO, extracorporeal membrane oxygenation.

Outcomes
As of Feb 22, 2020, 28 patients have been discharged and two patients died (1.8%). A total of 83 patients are still hospitalized. Although two of the fever patients were dead, the prognosis between without fever and fever patients had no difference follow up to Feb 22, 2020. Discharge health is based on fever reduction for at least three days, and there is better evidence that chest X-rays and the virus clear samples from the lower respiratory tract.

Discussion
To our knowledge, this is the rst study reported the clinical features of patients without fever on admission. Previous studies had reported that fever was the most common symptom of patients with COVID-19, whereas the symptoms without fever were in a minority in Wuhan 6,7 . Recently, several studies suggested that the symptoms of patients without fever were increasing outside Wuhan 9,10 . In this study, the percentage of patients without fever was more than in previous studies. The reason for this may be related to the early screen for SARS-CoV-2 infection in the large scales of individuals during the incubation period and the local government's comprehensive management. Moreover, recent study 7 showed that one reason for the rapid spread may be also associated with the atypical symptoms in the initial stage in cases with SARS-CoV-2 infection, including patients without fever.
In our study, the days of onset illness to admission in patients without fever were shorter than those in fever patients, which suggested that the time of con rmed diagnosis with SARS-CoV-2 infection in patients without fever was earlier than in fever patients. An observation study suggested that days onset of symptoms to hospital admission of COVID-19 were shorter in non-ICU patients than in ICU patients, and the age and complications were the risk factors of worse clinical outcome 7 . Our data demonstrated that the fever patients were more tend to develop into ARDS compared with patients without fever, and the clinical characteristic of patients with fever was more severe than those without fever. That could be explained by that the patients without fever were younger and rarely had underlying disease than fever patients, which was also consistent with the previous studies 7,8 .
Patients with any underlying disease were more likely to have a bacterial infection due to impaired immune function 15 . Evidence illuminated that lymphocytes, especially T lymphocytes, were the main targets by SARS-CoV-2 as well as SARS-CoV 6 . Compared with patients without fever, the percentage of white blood cell count (≤ 4×10 /l) and lymphocyte count(< 1×10 /l) were slightly lower in fever patients.
The decrease of lymphocyte count was related to the progress of the disease 15 . In addition, C-reactive protein and erythrocyte sedimentation rate were associated with in ammation reactions, which were signi cantly higher in severe patients. Therefore, compared with patients without fever, more patients with fever were given antibiotic therapy. To date, no speci c treatment of COVID-19 has been recommended except for symptomatic supportive treatment 7,9 . In our study, some patients were also given corticosteroid or gamma globulin on the basis of the difference in the severity of the disease. However, further research needs to assess whether systemic corticosteroid and gamma globulin therapy are bene cial for patients with COVID-19.
N.D., C.G, and F.T collected epidemiological and clinical data. T. Guo is responsible for summarizing all data related to the virus. N. Ding, Y. Zhou, G. Yang and X. Chai take responsibility for the accuracy of the data analysis. N. Ding, Y. Zhou and G. Yang contributed equally and share the second authorship. Y. Zhou drafted the manuscript. G. Yang revised the nal manuscript. X.C. is responsible for summarizing all epidemiological and clinical data.