RESEARCH ARTICLE
Clinical features of 2041 human brucellosis cases in China Yujing Shi1☯, Hui Gao2☯, Georgios Pappas3☯, Qiulan Chen1☯, Mei Li2, Jun Xu2, Shengjie Lai1,4,5, Qiaohong Liao1, Wenwen Yang6, Zhongtao Yi2, Zulaguli Rouzi2, Hongjie Yu ID1,4,5*
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1 Division of Infectious Diseases, Key Laboratory of Surveillance and Early–warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China, 2 The Sixth People’s Hospital of the Xinjiang Uygur Autonomous Region, Urumqi, China, 3 University Hospital of Ioannina, Ioannina, Greece, 4 School of Public Health, Fudan University, Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, China, 5 Hubei Provincial Center for Disease Control and Prevention, Wuhan, China, 6 Hubei Provincial Center for Disease Control and Prevention, Wuhan, China ☯ These authors contributed equally to this work. *
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Abstract OPEN ACCESS Citation: Shi Y, Gao H, Pappas G, Chen Q, Li M, Xu J, et al. (2018) Clinical features of 2041 human brucellosis cases in China. PLoS ONE 13(11): e0205500. https://doi.org/10.1371/journal. pone.0205500 Editor: Rodney D. Adam, Aga Khan University Kenya, KENYA Received: March 12, 2018 Accepted: September 26, 2018 Published: November 26, 2018 Copyright: © 2018 Shi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This study was supported by the grants from: the National Science Fund for Distinguished Young Scholars (grant no. 81525023) (http://www. nsfc.gov.cn/), China CDC’s Key Laboratory of Surveillance and Early-warning on Infectious Disease (http://www.chinacdc.cn/), Emergency Response Mechanism Operation Program, Chinese Center for Disease Control and Prevention (131031001000015001), the United States
Background Human brucellosis has become a major public health problem in China. However, the available clinical data on brucellosis cases are limited.
Methods We retrospectively reviewed medical charts of 2041 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. These patients were admitted to the Sixth People’s Hospital of the Xinjiang Uygur Autonomous region between 1st January and 31st December 2014. Data on these patients were collected from hospital medical records.
Results Many patients presented with fatigue (67%), fever (64%), arthralgia (63%) and sweating (54%). High erythrocyte sedimentation rate (ESR) (69%), high C-reactive protein (CRP) (39%), high alanine aminotransferase (ALT) (33%) and high aspartate aminotransferase (AST) (20%) were the most common laboratory findings, especially in acute patients. There was evidence of focal involvement in 90% of patients. A total of 61.5% of brucellosis patients recovered. Multivariate logistic regression analyses suggested that the risk factors key to unfavorable prognosis were: age�45 years (OR = 1.75, 95% CI 1.36–2.24), back pain (OR = 1.50, 95% CI 1.16–1.94) and joint tenderness (OR = 1.73, 95% CI 1.13–2.65). The increasing duration of the illness increased the risk of poor prognosis.
Conclusion Patients with brucellosis showed different characteristics in different clinical stages. In China, the chronicity rate of human brucellosis is high. The risk of poor prognosis is increased in
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Clinical features of brucellosis
National Institutes of Health (Comprehensive International Program for Research on AIDS grant U19 AI51915) and Shanghai Academic/Technology Research Leader (No. 18XD1400300). H.Y. has received investigator-initiated research funding from Sanofi Pasteur, GlaxoSmithKline, bioMe´rieux Diagnostic Product (Shanghai), and Yichang HEC Changjiang Pharmaceutical Company. S.L. is supported by the grants from the National Natural Science Fund (No. 81773498) and the Ministry of Science and Technology of China (2016ZX10004222-009). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views and opinions expressed in this publication are those of the authors and are not necessarily endorsed by the funding agencies. Competing interests: The authors have read the journal’s policy and have the following conflicts: H. Y. has received investigator-initiated research funding from Sanofi Pasteur, GlaxoSmithKline, bioMe´rieux Diagnostic Product (Shanghai), and Yichang HEC Changjiang Pharmaceutical Company. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
patients aged 45 years or older, patients who have had brucellosis for a substantial period of time, and patients with back pain or joint tenderness. The clinical management of brucellosis should be improved to include sensitive diagnostic methods for subacute and chronic brucellosis.
Introduction Brucellosis, caused by bacteria of the genus Brucella, is a major zoonosis worldwide. Although it has been well controlled in most developed countries, brucellosis is still endemic in Africa, Asia, the Middle East, the Mediterranean and South America [1, 2]. Human brucellosis is a major public health problem that has re-emerged in China since the mid-1990s, with the highest recorded number of cases (56,989 cases) in 2015 [3–5]. This may be due to the dynamic growth of animal husbandry in China, which enhances the chance of human infection. Moreover, the national infectious disease surveillance system has reported an increased rate of human brucellosis [6]. The disease is spread to humans mainly by the ingestion of infected meat or unpasteurized dairy products, by contact with infected animals or inhalation of infectious aerosolized particles [7]. Brucellosis usually leads to protean manifestation and may have polymorphic features affecting any organ system. The diagnosis of brucellosis is challenging because unusual presentations and non-specific symptoms can lead to misdiagnosis and treatment delay. Although the mortality rate is low, brucellosis can be severely debilitating and disabling [8, 9]. A timely and accurate diagnosis is key to the clinical management of brucellosis. There is an urgent need for an increased awareness of the clinical characteristics of brucellosis among physicians. Between 2000 and 2012, research into the clinical characteristics of brucellosis was done in Turkey [10], Iran [11], Greece [12] and Saudi Arabia [13]. But the results differed between studies. This may be due to small sample sizes or different methods for case classification. In order to reliably examine the clinical characteristics of brucellosis, the series used in the present study is larger than that used in previous studies, and a common case classification is used. Reliable data on the clinical characteristics of human brucellosis should improve the identification of relevant prognostic factors and improve the clinical management of this debilitating condition. This study aims to describe the symptoms, signs and laboratory findings of 2041 hospitalized patients with laboratory confirmed brucellosis, and assess the risk factors for their clinical outcomes.
Methods Setting The Sixth People’s Hospital of the Xinjiang Uygur Autonomous Region (hereafter called the Sixth People’s Hospital) is a tertiary infectious disease specialist hospital with 11 clinical departments and 460 beds. As an important referral center, the hospital approximately reported 27% of total reported brucellosis cases in Xinjiang yearly. A total of 2041 patients with laboratory-confirmed brucellosis were admitted to the hospital between January 1st and December 31st of 2014 and were included in this retrospective study. We accessed patient medical records from March 12th to early April 2016 and performed telephone interviews in late April 2016. The patient files were examined using a standardized form, which recorded demographic data, medical history, clinical and laboratory findings, any antibiotic treatment, and any focal involvements.
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Case definition A confirmed case of brucellosis was defined as a patient with compatible clinical symptoms (such as arthralgia, fever, sweating, chills, headache, myalgia, malaise) and laboratory evidence of Brucella infection diagnosed by bacteria culture or SAT (�1:200). Based on the duration of the systemic disease before admission to hospital, patients were divided into three groups: acute brucellosis (12 months). All cases underwent routine laboratory tests.
Treatment and follow-up Patients were treated with various combinations of antibiotics. The antibiotics regimens were given on the basis of China’s Practice Guideline for brucellosis diagnosis and treatment [14]: doxycycline (100mg every 12 h), rifampin (600 -900mg every 24 h), intramuscular streptomycin (15mg/kg every 24 h), levofloxacin (200mg every 12 h), ciprofloxacin (750mg every 12 h), and co-trimoxazole (960mg every 12 h). For children under 8 years of age and pregnant women, only rifampin (600-900mg every 24 h) was provided. Given the effectiveness of previous treatment and patient compliance (Xinjiang’s vast land posed a challenge to subsequent patient visits), the treatment duration was extended to 3–6 months for all patients. The outcome of treatment (including medication compliance and symptom recovery) was investigated by telephone interview. Admittedly telephone interview is not the ideal method of follow-up, but since in chronic/ persisting brucellosis the symptoms are often subjective and telephone interview allowed for a larger enrollment of patients in follow-up, we considered this to be an acceptable follow-up method.
Data analysis Data were entered into Epidata (version 2.0, Odense, Denmark). Medians and interquartile ranges (IQRs) were calculated for continuous variables, and compared between different groups using the Wilcoxon rank sum test. For categorical variables, case frequencies in each category were compared using a Chi-square test or Fisher’s exact test. For multiple comparisons, the Bonferroni correction was applied. To further examine the association between potential risk factors and treatment outcome, we first performed univariate analysis. For multivariable logistic regression, we included variables with p38.3˚C, respectively. ¶Include rash (12), joints deformity (4), meningeal irritation (2) and jaundice (1) in acute brucellosis, rash (2) in subacute brucellosis and cardiac murmur (1) in chronic brucellosis. �
Percentages of cases with each type were compared with a Chi-square test or Fisher’s exact test (where 20% cells have expected count less than 5). n.s: adjusted p�0.05, not significant https://doi.org/10.1371/journal.pone.0205500.t002
and weight loss (19%). In a comparison of different clinical groups, fever, splenomegaly, lack of appetite and cough were more common in acute cases (68%, 45%, 27%, 12%, respectively) than in subacute (56%, 36%, 19%, 5%, respectively, adjusted p42 U/L
355 (23)
56 (12)
3 (4)
414 (20)
Subacute> Chronic
Median AST (IQR)
28 (20–44)
22 (16–30)
18 (14–25)
26 (18–40)
Subacute> Chronic
Bilirubin >18.6 umol /L
225 (15)
48 (11)
6 (8)
279 (14)
0.03
n.s
Median bilirubin (IQR)
10.3 (7.2–15.2) 9.9 (7.0–13.4)
9.5 (6.2–13.0)
10.1 (7.1–14.6) 0.01
n.s
Urea nitrogen >7.14 mmol/L
48 (3)
20 (4)
6 (8)
74 (4)
0.05
n.s
Median urea nitrogen (IQR)
4.1 (3.4–5.0)
4.4 (3.5–5.3)
4.5 (3.7–5.1)
4.2 (3.4–5.1)
0.0002
Acute < Subacute
Creatinine >124 umol/L
8 (0.5)
3 (0.7)
0
11 (0.5)
0.80
n.s
Median creatinine (IQR)
60 (51–68)
58 (50–66)
59 (51–68)
59 (51–68)
0.03
Acute > Subacute
643 /1515(42)
143 (32)
17 (23)
803 (39)
Subacute, Chronic
Serum biochemistry
Inflammatory markers CRP >10 mg/L Median CRP(IQR)
7.6 (3.0–21.9)
4.2 (1.3–14.7)
2.3 (0.9–7.6)
6.6 (2.4–20.0)
Subacute, Chronic
ESR elevation¶
1088 (72)
280 (63)
43 (57)
1411 (69)
0.0002
Acute > Subacute, Chronic
Median ESR (IQR)
29 (16–46)
26 (12–47)
22 (12–40)
28 (15–46)
0.0015
Acute > Subacute, Chronic
Bacterial culture and serum-antibody-test Culture positive
758/1426 (53)
131/424 (31)
14/75 (19)
903/1925(47)
Subacute, Chronic
SAT �200
1394 (92)
419 (94)
69(92)
1882 (92)
0.33
SAT �400
996 (66)
261 (59)
38 (51)
1295 (63)
0.002
Acute > Subacute, Chronic
Median SAT titer(IQR)
400 (200–400)
400 (200–400) 400 (200–400) 400 (200–400)
0.007
Subacute > Chronic
n.s
Data are no. (%) of cases, unless otherwise indicated. Percentages may not total 100 because of rounding. Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; SAT, standard tube agglutination test; † Anemia: female and children 15 mm/h. �
Medians were compared between each group with the Wilcoxon rank sum test. For categorical variables, percentages of cases in each group were compared with Chi-
square test or Fisher’s exact test (where 20% cells have expected count less than 5). n.s: adjusted p�0.05, not significant https://doi.org/10.1371/journal.pone.0205500.t003
findings more frequently occurred in acute cases than in the other two groups, adjusted p
