Clinical characteristics of 199 discharged patients with COVID-19 in Fujian Province: A multicenter retrospective study between January 22nd and February 27th, 2020.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has quickly spread throughout the country and the world since first broke out in Wuhan, China. The outbreak that started from January 22, 2020, in Fujian Province has been controlled as the number of indigenous cases has not increased since March. We aimed to describe the clinical characteristics of patients with COVID-19 in Fujian Province, China.
METHODS: In this retrospective, multicenter study, we collected and analyzed the epidemiological, clinical, and laboratory data of all cases confirmed by nucleic acid tests in five designated hospitals in Fujian Province between January 22 and February 27, 2020. All patients were followed up until discharge. COVID-19 severity was classified as mild, moderate, severe, or critical.
RESULTS: Of 199 discharged patients with COVID-19, 105 patients were male, with a median age of 46.3 years, and 17 patients were severe, and 5 patients were critical on admission. Hypertension and diabetes were the most common comorbidities. The symptoms at illness onset were mainly fever (76.4%), cough (60.8%), and myalgia or fatigue (27.6%). A total of 96.5% of patients had abnormal imaging findings on chest computed tomography. Lymphopenia (37.2%) and hypoxemia (13.6%) were observed. Acute respiratory distress syndrome and respiratory failure occurred in 9 patients (4.5%) and 8 patients (4.0%) respectively. One patient died and the others were cured and discharged with the median hospital stay of 19 days. Old age was negatively correlated with lymphocyte count (r = - 0.296, p < 0.001) and oxygenation index (r = - 0.263, p = 0.001). Bivariate regression analysis revealed that old age (≥ 75 years), hypertension, diabetes, and lymphopenia were correlated with the severity of COVID-19.
CONCLUSIONS: Patients in Fujian Province were mostly nonsevere cases with mild or moderate symptoms, and had a lower mortality than patients in Wuhan (4.3%-15%). Older age, hypertension, diabetes, and lymphopenia were risk factors for severity of COVID-19.

Introduction

Coronavirus disease 2019 (COVID-19) has spread throughout China and worldwide, since the first case was confirmed in Wuhan, China in December, 2019 [1-3]. The causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became the third coronavirus after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) that had caused deadly and disruptive epidemic of acute respiratory disease [4, 5]. Next-generation sequencing and phylogenetic analysis suggested that SARS-CoV-2 is a novel beta coronavirus whose original hosts might be bats [6]. SARS-CoV-2 can be transmitted from person to person through respiratory droplets and close contact [7, 8] and has been found in the saliva, feces, and semen of infected patients [9, 10]. As of July 31, 2020, the number of COVID-19 cases had surpassed 17 million globally with 668,910 deaths, and both the Americas and Europe had been the epicenter since the beginning of March [11]. Moreover, more than half of the cases in a skilled nursing facility were asymptomatic or presymptomatic, leading to rapid and widespread transmission which proved that only symptom-oriented strategies were not sufficient to contain the epidemic [12].

Early studies of COVID-19 described that the clinical characteristics were mainly fever, cough, shortness of breath, myalgia or fatigue, and normal or decreased leukocyte counts, and the mortality rate was as high as 15% [13, 14]. Because of old age and underlying comorbidities, older adults were susceptible to severe COVID-19 outcomes such as acute respiratory distress syndrome (ARDS) and death [15-17]. Nevertheless, studies have shown that the symptoms of patients with COVID-19 in Zhejiang Province, Jiangsu Province, Beijing, and Chongqing City were all milder than those of the initially infected patients in Wuhan and other cities of Hubei Province [18-20]. Located in southeastern China, Fujian Province is not adjacent to Hubei Province and has a population of 39.73 million. Since the first patient infected with COVID-19 was confirmed on January 22 in Quanzhou, Fujian, a total of 296 indigenous cases were confirmed in Fujian Province, and the local outbreak was completely controlled due to the number of infected cases kept no increasing since March. At present no study has revealed the comprehensive situation of COVID-19 in Fujian Province.

The purpose of this study was to describe the epidemiological and clinical characteristics of 199 discharged patients diagnosed with COVID-19 during late-January to late-February 2020 in Fujian Province, China. We further explored the potential risk factors associated with disease severity and hope our findings will provide some details contributing to the understanding of the new highly infectious disease.

Materials and methods

Study design and participants

A retrospective, multicenter study enrolled discharged patients who were confirmed and hospitalized in five designated hospitals that responsible for treating patients with COVID-19 in five cities of Fujian Province from January 22 to February 27, 2020, including Fuzhou, Zhangzhou, Xiamen, Putian, and Quanzhou. All confirmed patients were followed-up until they were either discharged or died, thus the follow-up period was exactly the hospital days of the patients. The last patient in this cohort was discharged on March 3.

Data collection

Nasopharyngeal swab specimens from the upper respiratory tract were obtained from all patients on admission and send to the local Centers for Disease Control to test for SARS-CoV-2 RNA by real time reverse transcription polymerase chain reaction (RT-PCR). Information on demographics (age, sex, body mass index), exposure history (Wuhan exposure history, contact history), clinical characteristics, laboratory results, radiological findings, treatments, and outcomes were collected from electronic medical records. If data were conflicting or missing from records, we contacted directly with patients or their families to ascertain the information. The data were checked by a team of professional physicians.

Definitions

The patients were clinically classified into four types: mild, moderate, severe, and critical as previously described [20, 21]. Specifically, each type was defined as follows: (a) mild type: patients whose clinical symptoms were mild with no abnormal radiological findings; (b) moderate type: patients who had both pneumonia manifestation on chest computed tomography and clinical symptoms such as fever and cough; (c) severe type: patients who had respiratory rate ≥ 30 per min, oxygen saturation without inhaling oxygen at rest ≤ 93%, or oxygenation index ≤ 300 mmHg (hypoxemia); and (d) critical type: patients who developed respiratory failure requiring mechanical ventilation, shock or organ dysfunction and needed intensive care. If the temperature exceeded 37.3°C, it was defined as fever. The oxygenation index was defined as arterial oxygen pressure (PaO2) over inspired oxygen fraction (FiO2). The date of illness onset was defined as the day when the first symptom was noticed, and the incubation period was defined as the time from exposure to the illness onset [22]. Familial clusters were identified as the situation in which two or more patients in the same family were infected within two weeks. Once disease progressed into a more serious type, it was recorded as deterioration of the clinical condition. The discharge standards were as follows: temperature kept below 37.3°C for more than 3 days, respiratory symptoms improved significantly, and nucleic acid test for SARS-CoV-2 was negative for two consecutive times with at least one day interval.

Statistical analysis

Continuous variables with a normal distribution were presented as the mean (SD) and those with a nonnormal distribution were presented as the median (IQR). Categorical variables were expressed as frequency rates and percentages. All patients were divided into two groups: nonsevere (mild and moderate type) cases and severe (severe and critical type) cases, and then bivariate regression analysis of disease severity was performed based on age, sex, comorbidities, and laboratory parameters. SPSS (version 22.0) was used for the above analyses. Spearman's correlation test was used for analyzing the correlations between age and lymphocyte count as well as oxygenation index with GraphPad Prism version 8.0 software. A P value < 0.05 was considered statistically significant.

Ethics statement

This study was approved by the ethical committee in Zhongshan Hospital, Xiamen Branch, Fudan University (B2020-003). The requirement for informed consent was waived because the data were urgently collected and analyzed anonymously.

Results

Epidemiological and clinical characteristics

There were 199 patients infected with SARS-CoV-2 in five hospitals from January 22 to February 27. Of the 199 patients, the median age was 46.3 (SD 16.4, range 16–93; Table 1) years and 105 patients (52.8%) were men. A total of 114 patients had a residing or short traveling history in Wuhan, and one of them had direct exposure to the Huanan seafood market. Twenty-eight patients had close contact with people from Wuhan. Sixty-eight patients were involved in family clusters, with the largest one including six COVID-19 cases. Over one-third of patients had underlying diseases including hypertension (15.6%), diabetes (7.5%), cardiovascular disease (5.5%), and respiratory disease (5.5%) such as tuberculosis, pulmonary bulla, asthma, and chronic obstructive lung disease. Eleven patients (5.5%) complicated with chronic liver disease had a history of hepatitis B infection. The median incubation period was 6 (IQR 3–10) days among 115 patients offering the exact contact date.

Table 1

Demographic, epidemiological and clinical features of patients with COVID-19 in Fujian Province.

Variables	Patients (n = 199)
Age, years
Mean (SD)	46.3 (16.4)
Range	16–93
16–24	12 (6.0)
25–39	72 (36.2)
40–54	59 (29.6)
55–69	35 (19.6)
≥70	21 (10.6)
BMI	23.8 (21.2–26.0) (n = 173)
Low weight (<18.5)	7 (3.5)
Normal weight (18.5–24.9)	106 (53.3)
Overweight (25–29.9)	53 (26.6)
Obese (>30)	7 (3.5)
Sex
Male	105 (52.8)
Current smoking	13 (6.5)
History of exposure
Having been to Wuhan in last 2 weeks	114 (57.3)
Contact with people from Wuhan	28 (14.1)
No relation with Wuhan	53 (26.6)
Family clusters	68 (34.2)
Days of incubation period	6 (3–10) (n = 115)
Any Comorbidities	73 (36.7)
Hypertension	31 (15.6)
Diabetes	15 (7.5)
Respiratory disease	11 (5.5)
Chronic liver disease	11 (5.5)
Cardiovascular disease	8 (4.0)
Malignant tumor	8 (4.0)
Chronic kidney disease	4 (2.0)
Nervous system diseases	3 (1.5)
Signs and symptoms
Heart rate, bpm	86 (78–94)
Mean arterial pressure	96 (89–104)
Fever	152 (76.4)
Highest temperature, °C
<37.3	13 (6.5)
37.3–38.0	77 (38.7)
38.1–39.0	61 (30.7)
>39.0	7 (3.5)
Cough	121.0 (60.8)
Myalgia or fatigue	55 (27.6)
Chest distress	18 (9.0)
Chills	18 (9.0)
Panting	17 (8.5)
Diarrhea	17 (8.5)
Rhinorrhea	15 (7.5)
Dizziness	13 (6.5)
Sore throat	13 (6.5)
Dyspnoea	2 (1.0)
Hyposmia	1 (0.5)
Clinical classifications
Mild type	7 (3.5)
Moderate type	170 (85.4)
Severe type	17 (8.5)
Critical type	5 (2.5)
Chest CT findings at illness onset
Pneumonia	192 (96.5)
Bilateral distribution	162 (81.4)
Ground-glass opacity	135 (67.8)

The data are mean (SD) or n (%). COVID-19 = coronavirus disease 2019, CT = computed tomography.

Except for common symptoms like fever, cough and myalgia/fatigue, gastrointestinal symptom such as diarrhea occurred in 17 patients (8.5%), and the typical upper respiratory tract symptoms such as rhinorrhea and nasal congestion were present in 15 patients (7.5%). Moreover, one patient developed hyposmia at illness onset, and eight presymptomatic patients were admitted to the hospital due to the contact with confirmed cases and had symptoms during hospitalization. The severity classification of different age groups was shown in Fig 1A. Older patients occupied a higher proportion of severe/critical type than younger patients. Furthermore, all patients had a chest CT examination, 81.4% of whom showed bilateral abnormalities and 67.8% of whom presented ground-glass opacities as shown in Fig 2.

Fig 1

Age distributions, clinical classifications and correlations of age, lymphocyte count, and oxygenation index in patients with COVID-19.

In different age groups, (A) number of confirmed patients and the distribution of four clinical classifications, and (B) correlations between age and blood lymphocyte number and (C) oxygenation index on admission in all patients.

Fig 2

Representative thoracic CT images.

(A) CT images from a 71-year-old woman showing bilateral focal ground-glass opacities (GGOs) close to subpleural at day 3 after illness onset and (B) multiple patchy shadows with increasing GGOs at day 10 after illness onset. (C) CT images of a 48-year-old man showing bilateral patchy shadows and multiple GGOs at day 9 after illness onset; (D) the GGOs were absorbed mostly leaving linear opacities or fibrous stripes at day 18 after illness onset.

Laboratory and radiological characteristics

Routine blood tests on admission showed that white blood cell count lower than the normal range was present in 40 patients (20.1%) and lymphopenia was found in 74 patients (37.2%) (Table 2). Seventeen patients (8.5%) had decreased platelets (less than 125 ×109/L) and 14 patients (7.0%) had hemoglobin levels lower than normal range (150 g/L). There were 27 patients (13.6%) with high levels of procalcitonin (more than 0.1 ng/mL) and 82 patients (41.2%) with high level of C- reactive protein (over 10 mg/L).

Table 2

Laboratory findings of patients with COVID-19 on admission in Fujian Province.

	Normal range	All patients (n = 199)
		Median (IQR)	Increased No (%)	Decreased No (%)
Blood routine
White blood cell count, ×109/L	3.5–9.5	5.03 (3.79–6.45)	10 (5.0)	40 (20.1)
Neutrophil count, × 109/L	1.8–6.3	3.24 (2.21–4.39)	18 (9.0)	-
Lymphocyte count, × 109/L	1.1–3.2	1.28 (0.89–1.78)	-	74 (37.2)
Platelet count, × 109/L	125.0–350.0	191 (156–238)	9 (4.5)	17 (8.5)
Hemoglobin, g/L	115–150	137 (126–149)	-	14 (7.0)
Blood biochemistry
Albumin g/L	35.0–50.0	.40.3 (36.8–44.3)	-	26 (13.1)
Total bilirubin, μmol/L	3.0–22.0	12.9 (8.2–18.4)	34 (17.1)	-
Alanine aminotransferase, U/L	9.0–52.0	24 (17–34)	22 (11.1)	-
Aspartate aminotransferase, U/L	14.0–36.0	25 (20–32)	47 (23.6)	-
Lactate dehydrogenase, U/L	140–350	225 (169–407)	65 (32.7)	-
Blood urea nitrogen, mmol/L	2.5–6.1	3.7 (3.0–4.6)	14 (7.0)	-
Serum creatinine, μmol/L	53.0–97.0	67 (55–79)	16 (8.0)	-
Creatine kinase, U/L	38.0–174.0	65 (43–107)	22 (11.1)	-
Potassium, mmol/L	3.5–5.1	3.9 (3.6–4.2)	3 (1.5)	33 (16.6)
Sodium, mmol/L	137.0–147.0	139 (136–140)	2 (1.0)	52 (26.1)
Coagulation function (n = 170)
Prothrombin time	10.5–13.5	11.8 (11.2–12.5)	10 (5.0)	13 (6.5)
Activated partial thromboplastin time	22.0–38.0	29.9 (27.3–33.7)	17 (8.5)	3 (1.5)
Fibrinogen	2.0–4.0	3.5 (3.0–4.3)	53 (26.6)	3 (1.5)
D-dimer	0–0.5	0.23 (0.05–0.38)	29 (14.6)	-
Blood gas analysis (n = 153)
pH	7.35–7.45	7.42 (7.39–7.44)	24 (12.1)	4 (2.0)
PaO2, mmHg	83.0–108.0	95.6 (80.5–111.0)	-	40 (20.1)
SaO2, mmHg	95.5–98	97.7 (96.1–98.2)	-	27 (13.6)
PaO2:FiO2, mmHg	>300	438 (342–512)	-	27 (13.6)
Infection-related biomarkers
Procalcitonin, ng/mL	0–0.1	0.04 (0.03–0.06)	27/187	-
C-reactive protein, mg/L	<10	6.74 (4.68–21.6)	82/181	-
Nucleic acid positive for influenza B	-	2 (0.02)	-	-
IgM positive for influenza B	-	3 (0.02)	-	-
IgM positive for mycoplasma	-	7 (0.04)	-	-

The data are the median (IQR), n% or n/N. IQR = interquartile range, PaO2 = arterial oxygen pressure, SaO2 = arterial oxygen saturation, FiO2 = inspired oxygen fraction.

Regarding hepatic and renal function, 26 patients (13.1%) showed lower level of albumin than normal range (Table 2). The alanine transaminase (ALT) level of 22 patients (11.1%) and aspartate aminotransferase (AST) levels of 47 patients (23.6%) were above the normal range. Sixty-five patients (32.7%) had increased levels of lactate dehydrogenase (LDH). Only 14 patients (7.0%) and 16 patients (8.0%) had increased blood urea nitrogen and serum creatinine respectively, and 22 patients (11.1%) had increased creatine kinase. There were 10 patients with the prolonged prothrombin time and 29 patients with increased D-dimer levels. In terms of blood gas analysis, 27 patients with decreased arterial oxygen saturation (SaO2) and oxygenation index had significant hypoxemia. In addition, older age was correlated with the lower lymphocytes count (r = -0.296, p < 0.001, Fig 1B) and was also associated with lower oxygenation index (r = -0.263, p = 0.001, Fig 1C).

One patient did not display positive nucleic acid results for SARS-CoV-2 until the fifth detection. In addition to the test for SARS-CoV-2, all patients were tested for the nucleic acid, IgM or IgA of nine kinds of respiratory pathogens, including influenza A and B. Culture of bacteria and fungi were conducted in patients with fever. The results showed that two patients were positive for the nucleic acid of influenza B, three were positive for influenza B IgM, and another seven patients were positive for mycoplasma IgM (Table 2).

Treatments and prognosis

During hospitalization, patients had received antiviral treatment, interferon inhalation, empirical antibiotics, and Chinese medicine, accounting for 100%, 52.8%, 48.2%, and 40.2%, respectively (Table 3). Thirty- four patients were administered corticosteroids and 29 patients received intravenous immunoglobulin. Oxygen therapy was given to 83 patients, and only one patient who had ever received a left kidney transplantation underwent extracorporeal membrane oxygenation (ECMO).

Table 3

Treatments and outcomes of patients with COVID-19 during hospitalization.

	All patients (n = 199)	Non-severe (n = 166)	Severe (n = 33)
Treatments
Antiviral therapy	199 (100)	166 (100)	33 (100)
Lopinavir/ritonavir	192 (96.5)	163 (98.2)	31 (93.9)
Arbidol	72 (36.2)	54 (32.5)	18 (54.4)
Ribavirin	36 (18.1)	33 (19.9)	3 (9.1)
Oseltamivir	11 (5.5)	7 (4.22)	4(12.1)
Interferon inhalation	105 (52.8)	87 (52.4)	18 (54.5)
Antibiotics therapy	96 (48.2)	68 (41)	28 (84.8)
Chinese medicine	80 (40.2)	66 (39.8)	14 (42.4)
Corticosteroid	34 (17.1)	17 (10.2)	17 (51.5)
Intravenous immunoglobulin	29 (14.6)	13 (7.8)	16 (48.5)
Oxygen therapy	83 (41.7)	56 (33.7)	27 (81.8)
Nasal cannula	70 (35.2)	55 (33.1)	15 (45.5)
Non-invasive mechanical ventilation (high-flow nasal cannula or face mask)	8 (4.0)	1 (0.6)	7 (21.2)
Invasive mechanical ventilation	4 (2.0)	-	4 (12.1)
ECMO	1 (0.5)	-	1 (3.0)
Complications	15 (7.5)	0	15 (45.5)
ARDS	9 (4.5)	0	9 (27.3)
Respiratory failure	8 (4.0)	0	8 (24.2)
Multiple systemic organ failure	3 (1.5)	0	3 (9.1)
Shock	2 (1.0)	0	2 (6.1)
Admission to intensive care unit	14 (7.0)	0	14 (42.4)
Complicated with bacterial infection	38 (19.1)	16 (9.6)	22 (66.7)
Deterioration	16 (8.0)	0	16 (48.5)
Prognosis
Survival and discharge	198 (99.5)	166	32 (97)
Death	1 (0.5)	0	1 (3.0)
Days from first positive to last negative RT-PCR	15 (11–21)	15 (11–20)	18 (14–23)
Days from admission to discharge	19 (14–25)	19 (15–24)	24 (20.5–28)

The Data are n (%) or median (IQR). ECMO = extracorporeal membrane oxygenation.

The patients were divided into two groups: the non-severe group including mild and moderate type cases, and the severe group including severe and critical type cases (Table 3). Sixteen patients developed deterioration during hospitalization, and the final classification was 166 moderate type, 24 severe type and 9 critical type patients. Of 33 patients in the severe group, 15 patients developed complications including ARDS, respiratory failure, multiple systemic organ failure, and shock, and 14 patients were admitted to intensive care unit (ICU). Moreover, two thirds of severe group had evidence of bacterial infections. By the end of the follow-up, only an 84-year-old man complicated with hypertension and cerebral infraction died on the ninth day of hospitalization, and the remaining patients were cured and discharged. The median period from admission to discharge was 19 (IQR 14–25) days and the duration from the first positive to the last negative RT-PCR for SARS-CoV-2 was 15 (IQR 11–21) days.

Additionally, binary logistic regression analysis was conducted in two groups (Table 4), and found that age ≥ 75 years (odds ratio, 5.61; 95% CI, 1.16–27.11; p = 0.032), hypertension (3.44; 1.06–11.16; p = 0.040), diabetes (6.94; 1.65–29.22; p = 0.008), and lymphocyte count (0.27; 0.091–0.782; p = 0.016) were associated with a high risk of developing severe COVID-19, while total bilirubin (0.993; 0.919–1.073; p = 0.863) and serum creatinine (1.019; 0.982–1.056; p = 0.323) were not risk factors of COVID-19.

Table 4

Binary logistic regression analysis of risk factors of severe COVID-19.

Characteristics and findings	OR (95%CI)	p value
Age (≥ 75 years vs. < 75)	5.608 (1.160–27.109)	0.032
Sex (female vs. male)	0.449 (0.114–1.774)	0.254
Hypertension (Yes vs. No)	3.436 (1.058–11.162)	0.040
Diabetes (Yes vs. No)	6.936 (1.646–29.220)	0.008
Cardiovascular disease (Yes vs. No)	2.509 (0.454–13.851)	0.291
Lymphocyte count (×109 /L)	0.267 (0.091–0.782)	0.016
Serum creatinine (U/L)	1.019 (0.982–1.056)	0323
Total bilirubin (μmol/L)	0.993 (0.919–1.073)	0.863

Discussion

In this multicenter case series study, we reported 199 patients who were diagnosed with COVID-19 and treated in a timely manner in Fujian Province, depicting the status of early SARS-CoV-2 outbreaks in five cities of Fujian Province. The proportion of critical patients was 17% - 32%, and the mortality ranged from 4.3% to 15% in early reports from Wuhan [13–15, 17]. In our study, only 33 patients (16.6%) exhibited severe illness and one died, suggesting that the early outbreak in Fujian Province may have been milder than that in Wuhan. Moreover, as of February 27, based on the data published by the CDC, 296 indigenous cases of SARS-CoV-2 infection and one death were reported in Fujian Province, which were far fewer than the 48 137 cases and 2132 deaths reported in Wuhan. Consistent with the findings of previous studies, our results also showed that hypertension and diabetes were risk factors for COVID-19 [15, 23].

One third of the infected patients were related to family clusters in this study, suggesting that avoiding intrafamilial transmission is urgent to control the pandemic. In addition, the transmission of SARS-CoV-2 through asymptomatic carriers via person-to-person contact had been observed in many reports [7, 8, 12, 24]. Asymptomatic carriers were often diagnosed by screening after other family members or close contacts developed symptoms, and they were an important cause of the COVID-19 pandemic [25, 26]. Moreover, presymptomatic transmission and asymptomatic infection displayed a strong ability to spread the virus [12, 24], exerting great difficulty in restraining the pandemic, so strategies focused solely on clinical symptoms may be not sufficient to prevent the transmission and avoid resurgence of SARS-CoV-2.

Early studies of COVID-19 in Wuhan showed that female patients accounted for 32% - 45.7% [14, 15, 21, 27], but no obvious difference in gender proportion was found in our study. Old age was associated with higher risk of developing ARDS and a lower survival rate than the young, and hypertension was associated with a high risk of mortality from COVID-19 [17, 21, 23]. Consistently, our bivariate logistic regression analysis also revealed that age over 75 years and underlying disease (hypertension and diabetes) were the risk factors for COVID-19 severity. Furthermore, we found that old age was negatively associated with lymphocyte count and oxygenation index, implying that old age may be a dependent risk factor for progression.

Pathological findings had revealed that counts of peripheral CD4+ T and CD8+ T cells were substantially decreased in COVID-19 patients with ARDS [28], suggesting that SARS-CoV-2 may exert major impact on lymphocytes, especially T lymphocytes. Another study showed that critical patients had the lowest percentage of CD8+ T cells among four types of patients with COVID-19 [29]. In addition, laboratory parameters such as lymphocytes could predict the progression of COVID-19 [30]. Here, the binary logistic regression model revealed that low lymphocyte count was an important risk factor for progressing into a severe/critical type of COVID-19.

In this cohort, 5.5% of cases were complicated with chronic hepatitis B, and both ALT and AST levels were increased in some patients. It was suggested that liver damage was often transient in mild cases but prevalent in severe cases of COVID-19 [31]. Moreover, SARS-CoV-2 infected the host via the angiotensin-converting enzyme 2 (ACE2) receptor, which was enriched in cholangiocytes except for lungs, heart, kidney, and intestines [20]. However, the mechanisms of liver damage caused by SARS-CoV-2 require further study.

Approximately half of the severe patients developed complications such as ARDS, respiratory failure, and shock, and were always administered corticosteroids and intravenous immunoglobulins. According to the WHO recommendations published on May 27th, 2020, systemic corticosteroid treatment was not routinely recommended for COVID-19 patients unless they had indications of exacerbation of asthma or chronic obstructive pulmonary disease, septic shock or ARDS [32]. However, studies of corticosteroids for the novel coronavirus pneumonia have yielded various findings. One case-control study showed that methylprednisolone treatment could effectively improve symptoms but prolong the negative conversion of nucleic acids [33]. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial found that dexamethasone reduced the 28-day all-cause mortality and was especially beneficial to patients who had symptoms for more than 7 days or required mechanical ventilation [34]. Moreover, a prospective meta-analysis of seven randomized clinical trials of critically ill patients with COVID-19 also showed that the administration of corticosteroids was associated with lower 28-day all-cause mortality [35]. However, considering that high dose corticosteroid use was closely associated with adverse events [36], the benefits and risks must be carefully weighed before commencing corticosteroid therapy, and the dosage and duration should be evaluated prudently.

All patients received the antiviral drug lopinavir/ritonavir in the cohort, nevertheless, the first trial of lopinavir/ritonavir in adults with severe COVID-19 showed no benefit in contrast with patients receiving standard care [37]. Remdesivir, a promising antiviral drug for SARS-CoV-2, was reported that could shorten the recovery time from 15 days to 11 days in a double-blind, randomized, placebo-controlled trial involving 1063 adults [38]. Moreover, more than 150 candidates are under development since human vaccines for SARS-CoV-2 are not currently available.

The study naturally has several limitations. First, since the data were collected from different hospitals, the reference values of partial laboratory parameters varied greatly. Second, a total of 296 indigenous patients were confirmed and hospitalized in nineteen designated hospitals for SARS-CoV-2 in Fujian Province during the epidemic. Herein, 199 patients with COVID-19 from five hospitals were enrolled, so our conclusions may only represent the epidemic situation in Fujian Province to some extent. Last, the relatively short period of follow-up was limited to the hospital stay, which prevented us from further assessing the readmission, deterioration and sequela in those discharged patients as continuous follow-up of discharged patients is necessary and indispensable to study the long-term effects of COVID-19 on human health.

In summary, our study firstly suggested that compared with the COVID-19 patients in Wuhan during the early outbreak, most COVID-19 patients in Fujian Province were nonsevere cases with a relatively lower mortality rate. In addition, old age, comorbidities such as hypertension and diabetes, and lymphopenia were potential risk factors for patients with COVID-19 to progress into a severe/critical type.

14 Jul 2020

PONE-D-20-18174

Clinical characteristics of 199 discharged patients with COVID-19 in Fujian province: a multicenter retrospective study

PLOS ONE

Dear Dr. shao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript describes important findings from hospitalized cases of COVID-19 in Fujian province at the beginning of the COVID-19 outbreak there. The manuscript could benefit from review by review for grammar and flow in English. In general, in additional to the minor comments below, the discussion section should be modified so that the conclusions more accurately reflect the results and the relativelhy small sample size.

Please completely address the comments below and the comments by the reviewer before submitting the revised manuscript, and please ensure that the update manuscript has been reviewed for grammar and flow in English before submission.

Abstract:

Intro: The authors should add some background information on the COVID-19 outbreak in China and when the outbreak started in Fujian, and what is known until now about the outbreak in Fujian.

Methods: The authors should describe what was done in the methods but the number of patients should be first introduced in the results section. In the methods section please include the dates of the study and explain during what part of the outbreak the data were collected. Were these the first hospitalized cases in the province or was this a convenience sample from the middle of the outbreak?

Results: Please define severe and critical in the methods section. Line 35 please describe more clearly the relationship between age and lymphopenia and oxygen. The older the person the lower the lymphocyte count and the lower the oxygen level? Please describe this in the text.

Conclusions: Mention the findings about severity in Wuhan so that the reader can understand what was different here.

 

Manuscript:

 

Title: Add dates of the study

 

Intro:

Please briefly the history of the COVID-19 epidemic of Fujian province and also the characteristics of the provine. When was the first case identified. How many cases have been identified until now? Where is Fujian province in China in relation to Wujan and what is the population?

 

Methods:

 

Line 78. The ethics statement should be placed at the end of the methods section.

 

Definitions.

Please provide the definition for moderate patients.

 

Please explain how fever was defined? (What temperature cutoff?)

 

Please explain what the follow-up period was. Did everyone get follow-up until they were either discharged from the hospital or died?

 

Results.

Please explain whether the 199 patients included all of the patients who were hospitalized at these five hospitals or whether this was a convenience sample.

 

Line 124. Please provide a breakdown of BMI by normal weight, overweight, and obese

 

Table 1.

Mild/common/severe/critical: Do the authors mean moderate rather than common?

 

Did all 199 patients get a CT? Please add this information.

 

Line 138 and line 144. Please add a percentage to all numbers.

 

Line 151. Please phrase this association more clearly – was older age associated with lower lymphocyte counts?

 

Line 161. Chinese medicine like Lianhuaqingwen accounted for 100%, 52.8%, 48.2%, and 40.2%, respectively. This sentence is not clear. Please rephrase.

 

Line 167. Aggravation – this term should be “deterioration in their clinical condition.” Aggravation does not seem like the appropriate word in English.

 

Did any patients die? Please add this information to the results section.

 

Table 4. Please describe the comparison for lymphocyte count, bilirubin and creatinine.

 

Discussion

 

Line 183

Please provide a specific comparison with numbers and percentages to support the claim that there were less severe patients and less deaths in the Fujian cohort compared to Wuhan.

 

Also, I am not convinced that a cohort of 199 patients is large enough to draw comparisons to the Wuhan about disease severity.

 

In addition, the authors’ conclusions about early detection and quarantine measures being responsible for less severity are not supported by this article. The authors do not discuss incidence in this paper, and the authors also do not at all discuss quarantine measures that were implemented in Fujian province and how those compare to Wuhan. Finally, the cohort of 200 patients is quite small.

 

I suggest removing these broad conclusions and remaining with more modest conclusions.

 

Line 192.

What is the connection of intestinal spread to family clusters? This is not logical. I suggest refocusing this paragraph on transmission and perhaps asymptomatic and presymptomatic transmission. The authors could cite other articles that described that most transmission occur in families.

 

Line 197.

The English needs to be reworked here

 

Line 214.

The authors should present data about Hepatitis B prevalence among cases in the results section if they intend to reference these data in the discussion section.

 

Line 220.

Please update this paragraph to reflect the more recent findings that dexamethasone reduced mortality in severe COVID-19 patients and the changes in recommendations.

 

Line 228.

There has been evidence of effectiveness of an antiviral drug, remdesivir, in reducing time to hospital discharge. The authors should update this paragraph to reflect these findings.

 

Line 234.

The authors should not introduce new information in the discussion section. Information about course of virus positivity should be introduced in the results section and commented on in the discussion section.

 

Limitations

The authors should speak about how representative these hospitals are of hospitals in Fujian province. How many hospitals are there in Fujian? How many hospitalized cases of COVID-19 were there during the same period in other hospitals in Fujian?

 

Conclusions paragraph

The authors should be cautious about drawing conclusions relative to Wuhan because of the small sample size.

 

Please submit your revised manuscript by Aug 28 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Academic Editor

PLOS ONE

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2. Thank you for stating the following in the Acknowledgments Section of your manuscript:

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Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

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Reviewer #1: Yes

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Reviewer #1: This manuscript is a descriptive retrospective analysis of 199 COVID-19 patients admitted to one of five tertiary care centers in Fujian province, China between January 22 and February 27, 2020. A secondary aim of the study was to identify factors associated with disease severity. Study inclusion criteria and statistical analyses are appropriate. The data collection represents a relatively short period of observation, which may influence some of the study findings. Authors state that all data are available in the manuscript and additional files.

Methods:

Additional description of how severity categories were collapsed for multivariable logistic regression is warranted in the methods section. It appears that severe/critical cases were combined and compared to mild/moderate severity illnesses. But this should be explicitly stated.

Results:

In the description of treatment (text and table) it might be of interest to report which antivirals were used for treatment I see this is mentioned in the discussion, but could be noted in the results as well.

Discussion:

On page 17 line 244-245 the authors state "compared with patients infected with COVID-19 in Wuhan, our study suggested most patients in Fujian province were mild and moderate with a minority of severe cases". I think this overstates the results. In this relatively small study of hospitalized patients for a short period (4 weeks) there were 33/199 (16.6%) that were severe, which is in line with estimates from other locations. Case fatality was lower for the observation period in this study compared to others. I'm not convinced the follow-up was long enough to accurately determine the true extent of severe illness and mortality (as data collection ended on March 3, 2020). Readmission and deterioration have been issues in other places. Other the conclusions follow from the results. Some discussion of the implications of the short follow-up time is warranted.

**********

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3 Sep 2020

Dear Editors and Reviewers,

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Clinical characteristics of 199 discharged patients with COVID-19 in Fujian province: a multicenter retrospective study” (ID: PONE-D-20-18174). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope would meet with approval. Revised portion are marked in yellow in the paper. The main corrections in the paper and responds to reviewer’s comments are as following:

Abstract:

Intro: The authors should add some background information on the COVID-19 outbreak in China and when the outbreak started in Fujian, and what is known until now about the outbreak in Fujian.

Methods: The authors should describe what was done in the methods but the number of patients should be first introduced in the results section. In the methods section please include the dates of the study and explain during what part of the outbreak the data were collected. Were these the first hospitalized cases in the province or was this a convenience sample from the middle of the outbreak?

Results: Please define severe and critical in the methods section. Line 35 please describe more clearly the relationship between age and lymphopenia and oxygen. The older the person the lower the lymphocyte count and the lower the oxygen level? Please describe this in the text.

Conclusions: Mention the findings about severity in Wuhan so that the reader can understand what was different here.

Reply: Thank you for your kind comments. We have added the background information of COVID-19 outbreak in China and Fujian province (Page 2, line 24-26). The dates of the study was added and the number of patients was deleted in Methods section (Page 2, line 30-31), and all cases were the first hospitalized cases in these cities (Page 2, line 29). The definition of four types of COVID-19 was introduced in Methods section in manuscript (Page 6, line 96-102), and the description of relationship between age and lymphopenia and oxygen was rephrased clearly (Page 2, line 39-40). The findings about mortality in Wuhan was mentioned in the Conclusions (Page 3, line 43).

Manuscript:

Title: Add dates of the study

Reply: Thanks for your serious comments. We have added dates of the study into the title. (Page 1, line 2-3)

Intro:

Please briefly the history of the COVID-19 epidemic of Fujian province and also the characteristics of the provine. When was the first case identified. How many cases have been identified until now? Where is Fujian province in China in relation to Wuhan and what is the population?

Reply: Thanks for your comments. According to data published by the Centers for Disease Control of Fujian province, we introduced briefly when and where the first COVID-19 case was confirmed in Fujian, and the total number of indigenous cases (Page 4, line 67-69). We also described the geographical location and population of Fujian province (Page 5, line 69-71)

Methods:

Line 78. The ethics statement should be placed at the end of the methods section.

Reply: Thanks for your suggestion. We have placed the ethics statement at the end of methods section behind the Statistical Analysis. (Page 7, line 118-121)

Definitions.

Please provide the definition for moderate patients.

Reply: Thanks for your reminding. We apologize for our negligence regarding confusing the moderate patients with common type. We have corrected “common type” as “moderate type” and reintroduce the definition of four types of COVID-19 patients respectively. In addition, we also revised that in Fig 1A (Page 6, line 96-101; Fig 1A)

Please explain how fever was defined? (What temperature cutoff?)

Reply: Thanks for your comments. The definition of fever was added in the methods section. (Page 6, line 101-102)

Please explain what the follow-up period was. Did everyone get follow-up until they were either discharged from the hospital or died?

Reply: Thanks for your comments, which we think is very valuable for the study. All patients enrolled in the study were followed-up until they were discharged or died, thus the follow-up period was the hospital days of everyone. The last patients in this cohort was discharged on March 3. (Page 5, line 82-84)

Results.

Please explain whether the 199 patients included all of the patients who were hospitalized at these five hospitals or whether this was a convenience sample.

Reply: Thanks for your serious comments. We feel sorry that we did not provide enough information about whether the cohort was a convenience sample or not. The 199 patients included all the patients hospitalized at these five hospitals from Jan 22 to Feb 27, so this cohort was not a convenience sample. (Page 8, line 124-125). As there are eight SARS-CoV-2 designed hospitals in these five cities, not all patients with COVID-19 in above cities were included.

Line 124. Please provide a breakdown of BMI by normal weight, overweight, and obese

Reply: Thanks for your kind suggestion. We’ve provide the detailed number of patients stratified by BMI according to the WHO recommendations for Body Mass Index (Page 8-9, Table 1)

Table 1.

Mild/common/severe/critical: Do the authors mean moderate rather than common?

Reply: Thanks for your correction. We have revised it in the table, presenting the distribution of four clinical types of COVID-19. (Page 10, Table 1).

Did all 199 patients get a CT? Please add this information.

Reply: Thanks for your comments. We have added the information that all 199 patients got a chest CT. (Page 10, line 143).

Line 138 and line 144. Please add a percentage to all numbers.

Reply: Thanks for your reminding. The percentage of all numbers in both lines was added. (Page10, line 150 and line 156-157).

Line 151. Please phrase this association more clearly – was older age associated with lower lymphocyte counts?

Reply: Thanks for your serious comments. We have clearly revised this description about the correlation between age and lymphocyte counts in our manuscript. (Page 12, line 162-165)

Line 161. Chinese medicine like Lianhuaqingwen accounted for 100%, 52.8%, 48.2%, and 40.2%, respectively. This sentence is not clear. Please rephrase.

Reply: Thanks for your careful checks. We are sorry for our carelessness. We have revised the whole sentence as “patients receiving antiviral treatment, interferon inhalation, empirical antibiotics, and Chinese medicine, accounted for 100%, 52.8%, 48.2%, and 40.2%, respectively (Table 3)”. (Page 13, line 172-174)

Line 167. Aggravation – this term should be “deterioration in their clinical condition.” Aggravation does not seem like the appropriate word in English.

Reply: Thanks for your correction. Based on your comments, we have corrected the “aggravation” as “deterioration” in the text. (Page 13, Table3; page 14, line 181)

Did any patients die? Please add this information to the results section.

Reply: Thanks for your comments. This information has been added in the section of results that only an 84-year-old man was died. (Page 14, line 185-186)

Table 4. Please describe the comparison for lymphocyte count, bilirubin and creatinine.

Reply: Thanks for your comments. We’ve described the comparison for lymphocyte count, bilirubin and creatinine on their relationship with clinical severity of COVID-19 in our study (Page 14, line 193-195).

Discussion

Line 183

Please provide a specific comparison with numbers and percentages to support the claim that there were less severe patients and less deaths in the Fujian cohort compared to Wuhan.

Also, I am not convinced that a cohort of 199 patients is large enough to draw comparisons to the Wuhan about disease severity.

Reply: Your suggestion really means a lot to us. According to your comments, we added a specific comparison with numbers and percentages to make our conclusion convincing (Page 15, line 200-203). In terms of mortality, only one death were reported in Fujian, far less than that of Wuhan where 48,137 cases were confirmed with 2132 (4.42%) deaths. (Page 15, line 204-206). Although the sample size of our cohort was not large enough to make comparison with cases in Wuhan, it enrolled more than 60% of the 296 infected patients confirmed in Fujian during the period, representing the situation of COVID-19 in Fujian to some extent.

In addition, the authors’ conclusions about early detection and quarantine measures being responsible for less severity are not supported by this article. The authors do not discuss incidence in this paper, and the authors also do not at all discuss quarantine measures that were implemented in Fujian province and how those compare to Wuhan. Finally, the cohort of 200 patients is quite small.

I suggest removing these broad conclusions and remaining with more modest conclusions.

Reply: Thanks for your suggestions. We feel sorry for our overstatement of the conclusion. We agree with your view that the article could not reflect the relationship between disease severity and early detection or quarantine measures, so we have removed the related sentence in this Discussion section.

Line 192.

What is the connection of intestinal spread to family clusters? This is not logical. I suggest refocusing this paragraph on transmission and perhaps asymptomatic and presymptomatic transmission. The authors could cite other articles that described that most transmission occur in families.

Reply: Thanks for your nice comments, which could make our manuscript more rigorous. We removed the description of intestinal transmission and refocused the asymptomatic and presymptomatic transmission of SRARS-CoV-2 by updating references, which have been revised in the manuscript. (Page 15, line 208-212)

Line 197.

The English needs to be reworked here

Reply: Thanks for your suggestions. The sentence has been corrected as “Early studies of Wuhan showed that female patients accounted for 32% - 45.7% [14, 15, 21, 27], but no obvious gender proportion difference was found in our study”. (Page 16, line 216-217)

Line 214.

The authors should present data about Hepatitis B prevalence among cases in the results section if they intend to reference these data in the discussion section.

Reply: Thanks for your kind reminding. We have added the description of the prevalence of Hepatitis B in the Results section. (Page 8, line 131-132)

Line 220.

Please update this paragraph to reflect the more recent findings that dexamethasone reduced mortality in severe COVID-19 patients and the changes in recommendations.

Reply: Thanks for your suggestions, which is so helpful for the study. We provided the latest WHO recommendations on corticosteroid therapy for COVID-19 (Page 17, line 240-244), and added the latest findings about the effects of corticosteroid in COVID-19 by searching articles about the topic published recently in the Discussion section as follows: Another observational study enrolled 31 patients with COVID-19 found no association between corticosteroid use and virus shedding time, hospital length of stay, or duration of symptoms [35]. Moreover, corticosteroids treatment might be associated with increase mortality of critically ill patients [36]. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial found that dexamethasone (6 mg/d, 10 days) reduced the 28-day all-cause mortality, especially most beneficial in patients who had symptoms for more than 7 days or required mechanical ventilation [37, 38]. In addition, considering high dose corticosteroid use closely associated with adverse events may be a risk factor of death [39], benefits and risks must be carefully weighed before commencing corticosteroid therapy, and the dosage and duration should be evaluated prudently. (Page 17, line 246-254).

There has been evidence of effectiveness of an antiviral drug, remdesivir, in reducing time to hospital discharge. The authors should update this paragraph to reflect these findings.

Reply: Thanks for your comments. We have added the preliminary results of a clinical trial on remdesivir (Page 18, line 257-259). We also revised briefly the description about current development of vaccines for SARS-CoV-2. (Page 18, line 261-263)

Line 234.

The authors should not introduce new information in the discussion section. Information about course of virus positivity should be introduced in the results section and commented on in the discussion section.

Reply: Thanks for your serious comments. The information about the one death in the study has been introduced in Results section and the nucleic acid results had been added in Results section, so we removed the related sentence in Page 17, line 234-238 of the original text. (Page 14, line185-186；Page 12, line 166),

Limitations

The authors should speak about how representative these hospitals are of hospitals in Fujian province. How many hospitals are there in Fujian? How many hospitalized cases of COVID-19 were there during the same period in other hospitals in Fujian?

Reply: Thanks for your serious comments. We added information about the representativeness of our cohort in the manuscript as follows: 296 indigenous cases were confirmed and hospitalized in nineteen designed hospitals for SARS-CoV-2 in Fujian province during the epidemic. Herein only 199 cases with COVID-19 in five hospitals were enrolled, so our conclusions maybe not represent the true situation of the outbreak in entire Fujian Province. (Page 18, line 265-269)

Conclusions paragraph

The authors should be cautious about drawing conclusions relative to Wuhan because of the small sample size.

Reply: We sincerely appreciate the valuable comments. Although the sample size is not large enough to be compared with that of Wuhan, 199 of 296 patients (67.2%) were enrolled in the study during the same period in Fujian province, so we could make prudent conclusions that compared with the COVID-19 in Wuhan during the early outbreak, most COVID-19 patients in Fujian Province were non-severe cases and had a lower mortality rate to some extent. (Page 18, line 271-273)

We have refer to Table 3 in the text. (Page 13, line 176; page 14, line 183)

In addition, the funding information has been removed from the manuscript.

Here we must express our gratitude to you and the reviewers once again, for giving us this chance to revise. All of these comments have contributed a lot to improve the quality of our article. After this revision, we have written a point-by-point response letter to you as you can see above. We feel sorry for our poor writings and tried our best to improve the manuscript and made some changes in the manuscript. These changes will not influence the content and framework of the paper. We hope the correction will meet with approval. We really appreciate for your warm work earnestly, and would be glad to respond to any further questions and comments that you may have.

Thank you once again!.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

14 Sep 2020

PONE-D-20-18174R1

Clinical characteristics of 199 discharged patients with COVID-19 in Fujian province: a multicenter retrospective study between January 22nd and February 27th, 2020

PLOS ONE

Dear Dr. shao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

The authors do not appear to have addressed any of Reviewer 1's comments. The authors should revise the manuscript and include point-by-point responses to Reviewer 1's comments, which they can add to the "response to reviewers" document.

==============================

Please submit your revised manuscript by Oct 29 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Mark Katz

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Oct 2020

Dear Editors and Reviewers,

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Clinical characteristics of 199 discharged patients with COVID-19 in Fujian province: a multicenter retrospective study” (ID: PONE-D-20-18174). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope would meet with approval. Revised portion are marked in yellow in the paper. The main corrections in the paper and responds to reviewer’s comments are as following:

Abstract:

Intro: The authors should add some background information on the COVID-19 outbreak in China and when the outbreak started in Fujian, and what is known until now about the outbreak in Fujian.

Methods: The authors should describe what was done in the methods but the number of patients should be first introduced in the results section. In the methods section please include the dates of the study and explain during what part of the outbreak the data were collected. Were these the first hospitalized cases in the province or was this a convenience sample from the middle of the outbreak?

Results: Please define severe and critical in the methods section. Line 35 please describe more clearly the relationship between age and lymphopenia and oxygen. The older the person the lower the lymphocyte count and the lower the oxygen level? Please describe this in the text.

Conclusions: Mention the findings about severity in Wuhan so that the reader can understand what was different here.

Reply: Thank you for your kind comments. We have added the background information of COVID-19 outbreak in China and Fujian province (Page 2, line 24-26). The dates of the study was added and the number of patients was deleted in Methods section (Page 2, line 30-31), and all cases were the first hospitalized cases in these cities (Page 2, line 29). The definition of four types of COVID-19 was introduced in Methods section in manuscript (Page 6, line 96-102), and the description of relationship between age and lymphopenia and oxygen was rephrased clearly (Page 2, line 39-40). The early COVID-19 mortality in Wuhan was mentioned in the Conclusions section (Page 3, line 43).

Manuscript:

Title: Add dates of the study

Reply: Thanks for your serious comments. We have added dates of the study into the title. (Page 1, line 2-3)

Intro:

Please briefly the history of the COVID-19 epidemic of Fujian province and also the characteristics of the provine. When was the first case identified. How many cases have been identified until now? Where is Fujian province in China in relation to Wuhan and what is the population?

Reply: Thanks for your comments. According to data published by the Centers for Disease Control of Fujian province, we introduced briefly when and where the first COVID-19 case was confirmed in Fujian, and the total number of indigenous cases (Page 5, line 68-71). We also described the geographical location and population of Fujian province (Page 4, line 67-68)

Methods:

Line 78. The ethics statement should be placed at the end of the methods section.

Reply: Thanks for your suggestion. We have placed the ethics statement at the end of methods section behind the Statistical Analysis. (Page 7, line 119-122)

Definitions.

Please provide the definition for moderate patients.

Reply: Thanks for your reminding. We apologize for our negligence regarding confusing the moderate type and common type. We have corrected “common type” as “moderate type” and reintroduce the definition of four types of COVID-19 patients respectively. In addition, we also revised that in Fig 1A (Page 6, line 96-101; Fig 1A)

Please explain how fever was defined? (What temperature cutoff?)

Reply: Thanks for your comments. The definition of fever was added in the methods section. (Page 6, line 101-102)

Please explain what the follow-up period was. Did everyone get follow-up until they were either discharged from the hospital or died?

Reply: Thanks for your comments, which we think is very valuable for the study. All patients confirmed were followed-up until they were either discharged or died, thus the follow-up period was exactly the hospital days of everyone. The last patients in this cohort was discharged on March 3. (Page 5, line 82-84)

Results.

Please explain whether the 199 patients included all of the patients who were hospitalized at these five hospitals or whether this was a convenience sample.

Reply: Thanks for your serious comments. We feel sorry that we did not provide enough information about whether the cohort was a convenience sample or not. The 199 patients included all the patients hospitalized at these five hospitals from Jan 22 to Feb 27, so this cohort was not a convenience sample. (Page 8, line 125-126). As there are eight SARS-CoV-2 designed hospitals in these five cities, not all patients with COVID-19 in above cities were included.

Line 124. Please provide a breakdown of BMI by normal weight, overweight, and obese

Reply: Thanks for your kind suggestion. We’ve provide the detailed number of patients stratified by BMI according to the WHO recommendations for Body Mass Index (Page 8-9, Table 1)

Table 1.

Mild/common/severe/critical: Do the authors mean moderate rather than common?

Reply: Thanks for your correction. We have revised it in the table, presenting the distribution of four clinical types of COVID-19. (Page 10, Table 1).

Did all 199 patients get a CT? Please add this information.

Reply: Thanks for your comments. We have added the information that all 199 patients got a chest CT. (Page 10, line 144).

Line 138 and line 144. Please add a percentage to all numbers.

Reply: Thanks for your reminding. The percentage of all numbers in both lines was added. (Page 10, line 151; page 12 line 157-158).

Line 151. Please phrase this association more clearly – was older age associated with lower lymphocyte counts?

Reply: Thanks for your serious comments. We have clearly revised this description about the correlation between age and lymphocyte counts in our manuscript. (Page 12, line 164-165)

Line 161. Chinese medicine like Lianhuaqingwen accounted for 100%, 52.8%, 48.2%, and 40.2%, respectively. This sentence is not clear. Please rephrase.

Reply: Thanks for your careful checks. We are sorry for our carelessness. We have revised the whole sentence as “patients receiving antiviral treatment, interferon inhalation, empirical antibiotics, and Chinese medicine, accounted for 100%, 52.8%, 48.2%, and 40.2%, respectively (Table 3)”. (Page 13, line 172-174)

Line 167. Aggravation – this term should be “deterioration in their clinical condition.” Aggravation does not seem like the appropriate word in English.

Reply: Thanks for your correction. Based on your comments, we have corrected the “aggravation” as “deterioration” in the text. (Page 13, Table3; page 14, line 182; page 7, line 106-107)

Did any patients die? Please add this information to the results section.

Reply: Thanks for your comments. This information has been added in the section of results that only an 84-year-old man was died. (Page 14, line 186-187)

Table 4. Please describe the comparison for lymphocyte count, bilirubin and creatinine.

Reply: Thanks for your comments. We’ve described the comparison for lymphocyte count, bilirubin and creatinine on their relationship with clinical severity of COVID-19 in our study (Page 15, line 195-196).

Discussion

Line 183

Please provide a specific comparison with numbers and percentages to support the claim that there were less severe patients and less deaths in the Fujian cohort compared to Wuhan.

Also, I am not convinced that a cohort of 199 patients is large enough to draw comparisons to the Wuhan about disease severity.

Reply: Your suggestion really means a lot to us. According to your comments, we added a specific comparison with numbers and percentages to make our conclusion convincing (Page 15, line 201-204). In terms of mortality, only one death were reported in Fujian, far less than that of Wuhan where 48,137 cases were confirmed and 2132 (4.42%) deaths. (Page 15, line 204-206).

Although the sample size of our cohort was not large enough to make comparison with cases in Wuhan, it enrolled 199 cases (＞60%) of the 296 infected patients confirmed in Fujian during the period, representing the situation of COVID-19 in Fujian to some extent.

In addition, the authors’ conclusions about early detection and quarantine measures being responsible for less severity are not supported by this article. The authors do not discuss incidence in this paper, and the authors also do not at all discuss quarantine measures that were implemented in Fujian province and how those compare to Wuhan. Finally, the cohort of 200 patients is quite small.

I suggest removing these broad conclusions and remaining with more modest conclusions.

Reply: Thanks for your suggestions. We feel sorry for our overstatement of the conclusion. We agree with your view that the article could not reflect the relationship between disease severity and early detection or quarantine measures, so we have removed the related sentence in this Discussion section.

Line 192.

What is the connection of intestinal spread to family clusters? This is not logical. I suggest refocusing this paragraph on transmission and perhaps asymptomatic and presymptomatic transmission. The authors could cite other articles that described that most transmission occur in families.

Reply: Thanks for your nice comments, which could make our manuscript more rigorous. We removed the description of intestinal transmission and refocused the asymptomatic and presymptomatic transmission of SRARS-CoV-2 by updating references, which have been revised in the manuscript. (Page 15, line 208-213)

Line 197.

The English needs to be reworked here

Reply: Thanks for your suggestions. The sentence has been corrected as “Early studies of Wuhan showed that female patients accounted for 32% - 45.7% [14, 15, 21, 27], but no obvious gender proportion difference was found in our study”. (Page 16, line 217-218)

Line 214.

The authors should present data about Hepatitis B prevalence among cases in the results section if they intend to reference these data in the discussion section.

Reply: Thanks for your kind reminding. We have added the description of the prevalence of Hepatitis B in the Results section. (Page 8, line 132-133)

Line 220.

Please update this paragraph to reflect the more recent findings that dexamethasone reduced mortality in severe COVID-19 patients and the changes in recommendations.

Reply: Thanks for your suggestions, which is so helpful for the study. We provided the latest WHO recommendations on corticosteroid therapy for COVID-19 (Page 17, line 241-245), and added the latest findings about the effects of corticosteroid in COVID-19 by searching articles about the topic published recently. (Page 17, line 247-255).

There has been evidence of effectiveness of an antiviral drug, remdesivir, in reducing time to hospital discharge. The authors should update this paragraph to reflect these findings.

Reply: Thanks for your comments. We have added the preliminary results of a clinical trial on remdesivir (Page 18, line 258-260). We also revised the description about current development of vaccines for SARS-CoV-2. (Page 18, line 2612-264)

Line 234.

The authors should not introduce new information in the discussion section. Information about course of virus positivity should be introduced in the results section and commented on in the discussion section.

Reply: Thanks for your serious comments. The information about the one death in the study has been introduced in Results section and the nucleic acid results had been added in Results section, so we removed the related sentence in Page 17, line 234-238 of the original text. (Page 14, line185-186; page 12, line 166),

Limitations

The authors should speak about how representative these hospitals are of hospitals in Fujian province. How many hospitals are there in Fujian? How many hospitalized cases of COVID-19 were there during the same period in other hospitals in Fujian?

Reply: Thanks for your serious comments. We added information about the representativeness of our cohort in the manuscript as follows: 296 indigenous cases were confirmed and hospitalized in nineteen designed hospitals for SARS-CoV-2 in Fujian province during the epidemic. Herein only 199 cases with COVID-19 in five hospitals were enrolled, so our conclusions maybe not represent the true situation of the outbreak in entire Fujian Province. (Page 18, line 266-272)

Conclusions paragraph

The authors should be cautious about drawing conclusions relative to Wuhan because of the small sample size.

Reply: We sincerely appreciate the valuable comments. Although the sample size is not large enough to be compared with that of Wuhan, 199 of 296 patients (67.2%) were enrolled in the study during the same period in Fujian province, so we could make prudent conclusions that compared with the COVID-19 in Wuhan during the early outbreak, most COVID-19 patients in Fujian Province were non-severe cases and had a lower mortality rate to some extent. (Page 18, line 273-275)

We have refer to Table 3 in the text. (Page 13, line 173; page 14, line 181)

In addition, the funding information has been removed from the manuscript.

Response to Review 1’ comments

Reviewer #1: This manuscript is a descriptive retrospective analysis of 199 COVID-19 patients admitted to one of five tertiary care centers in Fujian province, China between January 22 and February 27, 2020. A secondary aim of the study was to identify factors associated with disease severity. Study inclusion criteria and statistical analyses are appropriate. The data collection represents a relatively short period of observation, which may influence some of the study findings. Authors state that all data are available in the manuscript and additional files.

Reply: Thanks for your serious comments. Since we only collected data of these patients during hospitalization, the period of observation was dependent of the length of hospital stay (Page 5, line 82-84). In this study, we mainly described the early outbreak condition of COVID-19 in Fujian province, China, so the period of observation may not influence the findings in study to a large degree.

Methods:

Additional description of how severity categories were collapsed for multivariable logistic regression is warranted in the methods section. It appears that severe/critical cases were combined and compared to mild/moderate severity illnesses. But this should be explicitly stated.

Reply: Thanks for your serious comments, which was very valuable for our study. We have added the severity categories in the Statistical Analysis. According to the highest type during hospitalization, patients were divided into two groups: non-severe (mild and moderated type) cases and severe (severe and critical type) cases. (Page 7, line 112-114; page 14, line 180-181).

Results:

In the description of treatment (text and table) it might be of interest to report which antivirals were used for treatment I see this is mentioned in the discussion, but could be noted in the results as well.

Reply: Thanks for your suggestions. For all patients, we recounted and presented the main antiviral drugs used in the cohort in the text: The antiviral drugs were mainly lopinavir/ritonavir, arbidol, ribavirin and oseltamivir. (Page7, line 174) and their exact usage percentage in Table 3.

Discussion:

On page 17 line 244-245 the authors state "compared with patients infected with COVID-19 in Wuhan, our study suggested most patients in Fujian province were mild and moderate with a minority of severe cases". I think this overstates the results. In this relatively small study of hospitalized patients for a short period (4 weeks) there were 33/199 (16.6%) that were severe, which is in line with estimates from other locations. Case fatality was lower for the observation period in this study compared to others. I'm not convinced the follow-up was long enough to accurately determine the true extent of severe illness and mortality (as data collection ended on March 3, 2020). Readmission and deterioration have been issues in other places. Other the conclusions follow from the results. Some discussion of the implications of the short follow-up time is warranted.

Reply: Your suggestion really means a lot to us. The conclusion on comparison between early outbreak in Wuhan and Fujian province was indeed hasty and a bit overstated, so we referred to detailed numbers and percentages in published articles and official data to make the conclusion convincing (Page 15, line 201-206). In this study, we tracked closely the dynamic change of each patient during hospitalization until they were died or cured and discharged, so the true extent of severe illness could be assessed accurately (Page 5, line 82-84). Although the follow-up time limited to length of hospital stay was only five weeks (Jan 22- March 3), it didn’t influence our main findings in the study. Of course, changes in these cured patients’ condition after discharge, such as relapse and deterioration, need longer follow-up to assess. As for the mortality, except one death, all the other patients infected with COVID-19 were cured and met the discharge standard before March 3 (Page 7, line 107-109), so the follow-up was enough to help us obtain the real mortality of COVID-19 in these hospitals. Considering that the readmission and deterioration have been reported in other places, we will next follow up these discharged patients to determine their readmission, deterioration and even sequela. Discussion of the implications of the short follow-up time is implicated in the manuscript. (Page 18, line 270-272).

Here we must express our sincere gratitude to you and the reviewers once again, for giving us chances to revise. All of these comments have contributed a lot to improve the quality of our article. After this revision, we have written a point-by-point response letter to you as you can see above. We feel sorry for our poor writings and tried our best to improve the manuscript and made some changes in the manuscript. These changes will not influence the content and framework of the paper. We hope the correction will meet with approval. We really appreciate for your warm work earnestly, and would be glad to respond to any further questions and comments that you may have.

Thank you once again!.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

8 Oct 2020

PONE-D-20-18174R2

Clinical characteristics of 199 discharged patients with COVID-19 in Fujian province: a multicenter retrospective study between January 22nd and February 27th, 2020

PLOS ONE

Dear Dr. shao,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

The authors have adequately addressed nearly all of the comments from the reviewers.

The manuscript is still suffering from many writing errors. If the authors could have a native English speaker and writer to review the manuscript for flow, subject-noun agreement, and to ensure that everything is written in the past tense, the manuscript would then be more suitable for publication.

In addition, the authors should make the following changes:

Because you did not do a statistical comparison, please change line 203 to “suggesting that the early outbreak in Fuian may have been milder than that in Wuhan.” (instead of the current wording "indicating..")

Please update the section on corticosteroids in the discusson section to include recently published data in JAMA supporting the use of corticosteroids in severe and critical COVID-19 patients and removing less relevant publications on corticosteroids.

==============================

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20 Oct 2020

The manuscript is still suffering from many writing errors. If the authors could have a native English speaker and writer to review the manuscript for flow, subject-noun agreement, and to ensure that everything is written in the past tense, the manuscript would then be more suitable for publication.

Reply: Your suggestions really means a lot to us. We feel sorry for our poor writings, and we have invited a native English speaker and writer from USA to help correct and polish our article carefully.

In addition, the authors should make the following changes:

Because you did not do a statistical comparison, please change line 203 to “suggesting that the early outbreak in Fujian may have been milder than that in Wuhan.” (instead of the current wording "indicating..")

Reply: Thanks for your kind suggestion. We have changed the sentence in line 203 to “suggesting that the early outbreak in Fujian may have been milder than that in Wuhan.” (Page 16, line 206-207).

Please update the section on corticosteroids in the discusson section to include recently published data in JAMA supporting the use of corticosteroids in severe and critical COVID-19 patients and removing less relevant publications on corticosteroids.

Reply: Thanks for your serious suggestion. We have added the newly results published in JAMA on the administration of corticosteroids in critical ill patients with COVID-19 (Page 18, line 252-254) and less relevant publications was removed in the manuscript.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

2 Nov 2020

Clinical characteristics of 199 discharged patients with COVID-19 in Fujian province: a multicenter retrospective study between January 22nd and February 27th, 2020

PONE-D-20-18174R3

Dear Dr. shao,

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PLOS ONE

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Reviewers' comments:

5 Nov 2020

PONE-D-20-18174R3

Clinical characteristics of 199 discharged patients with COVID-19 in Fujian Province: a multicenter retrospective study between January 22nd and February 27th, 2020

Dear Dr. shao:

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