# A Systematic Review and Meta-Analysis of Epidemiology and Clinical Manifestations of Human Brucellosis in China

Authors: Rongjiong Zheng; Songsong Xie; Xiaobo Lu; Lihua Sun; Yan Zhou; Yuexin Zhang; Kai Wang
Journal: BioMed Research International
 (2018)

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## Abstract

Background. Brucellosis has a wide spectrum of clinical manifestations and it may last several days or even several years; however, it is often misdiagnosed and therefore may cause inadequate therapy and prolonged illness. Previous studies about meta-analysis of manifestations of brucellosis reported in English lacked the data published in Chinese, which did not provide details about the contact history, laboratory tests, and misdiagnosis. We undertake a meta-analysis of clinical manifestations of human brucellosis in China to identify those gaps in the literature. We have searched published articles in electronic databases up to December 2016 identified as relating to clinical features of human brucellosis in China. 68 studies were included in the analysis. The main clinical manifestations were fever, fatigue, arthralgia, and muscle pain (87%, 63%, 62%, and 56%, resp.). There are significant differences between adults and children. Rash, respiratory and cardiac complications, and orchitis/epididymitis were more prevalent in children patients. The common complications of brucellosis were hepatitis, followed by osteoarthritis, respiratory diseases, cardiovascular diseases, central nervous system dysfunction, hemophagocytic syndrome, and orchitis/epididymitis in male. In the nonpastoral areas, brucellosis has a high ratio of misdiagnosis. Our analysis provides further evidence for the accurate diagnosis, particularly in assessing severe, debilitating sequelae of this infection.


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## Body

## 1. Introduction

Brucellosis is one of the most common zoonotic infections globally [1, 2]. The disease is transmitted to humans by direct/indirect contact with infected animals or through the consumption of raw meat and dairy products [3, 4]. The main transmission routes are digestive tract, skin, and mucosal and respiratory tract contact with blood body fluids and aerosols.Brucellosis has a wide spectrum of clinical manifestations, often lacks specificity, may last from several days to more than a year, is often misdiagnosed, and therefore causes inadequate therapy and prolonged illness can cause a severely debilitating and disabling illness. Patients may show fever, sweating, fatigue, and osteoarthritis [5] and even more serious conditions in different organ systems [6]. Brucellosis not only causes huge economic loss to the society by influencing the production of animal husbandry, but also threatens the human’s physical and mental health [7].Brucellosis was first reported in China in 1905 [8]. In recent years, human brucellosis incidence has increased sharply [9, 10]. Nationwide surveillance data indicated that the total incidence rate of human brucellosis in mainland China increased from 0.92 cases/100,000 people in 2004 to 4.2 cases/100,000 people in 2014 [11–13]. Currently, human brucellosis remains one of major public health issues in China.This study presents a systematic review of scientific literature published before December 2016 identified as relating to clinical features of brucellosis in China. The objectives of this review were to identify those gaps in the literature of epidemiology, clinical manifestations, contact history, laboratory tests, and misdiagnosis of human brucellosis in China and provide further evidence for the accurate diagnosis, particularly in assessing severe, debilitating sequelae of human brucellosis.


## 2. Methods

### 2.1. Search Strategy

We performed a systematic review of the literature to identify articles relating to clinical features of human brucellosis in China. With assistance of a professional medical librarian we electronically searched the literature in Wan Fang Data, Wei Pu Data, CNKI, Medline, Cochrane Library, and PubMed with MESH and keyword subject headings “brucellosis,” “malta fever,” “brucella melitensis,” or “brucella abortus,” AND “symptom,” “sequelae,” “morbidity,” “mortality,” “transmission mode,” “foodborne,” and “China,” for entries published from databases’ inception before December 2016. We did not restrict the types of studies and publication languages. Duplicate entries were identified by two investigators screening the titles and abstracts of the article, the author, the year of publication, and the volume, issue, and page numbers of the source, and reviewing potentially relevant articles in full.


### 2.2. Selection Criteria

We systematically and inclusively reviewed articles by two investigators. The reviewers selected articles first by title and abstract, next by full text, and last by analyzing eligible studies in detail until demonstrating 100% agreement in articles included and excluded by two investigators.Studies with the following criteria were excluded: (A) articles related to non-human brucellosis; (B) reported data that overlapped with already included articles; (C) articles that could not provide original data of the patients; (D) articles addressing topics that were not related to the clinical features of human brucellosis, such as treatment intervention and experimental laboratory studies.Studies with the following criteria were included: (A) the literatures that described the clinical symptoms/syndromes of human brucellosis and the number of study subjects must more than 10 in each document; (B) the subjects reported in the literature who must be in China; (C) studies that provided data from general brucellosis cases and presented relevant laboratory results.


### 2.3. Data Extraction

Data was extracted by two reviewers independently including data collection, study design, study location, patient characteristics, the number of male and female patients, clinical manifestations, numbers of subjects with each symptom and complication which were recorded for each study, methods of diagnosis, and laboratory parameters. For the sex-related outcomes of epididymo/orchitis, the study population was considered to be only the male subgroups of the study population. Children patients must be of the age of 0–15 years. We also recorded the information relating to duration of illness prior to treatment, diagnostic delay, and exposure to potential risk factors. The results of data extraction must reach an agreement and consensus between the reviewers.


### 2.4. Statistical Analyses

We defined an event rate as the ratio of number of reported cases with a specific clinical manifestation to the total number of reported cases in each study. R statistical software (version 3.4.2, meta package) will be used for creating Forest plots to summarize composite data, generating proportions and corresponding 95% confidence intervals for each manifestation. Two-sidedP values < 0.05 will be considered statistically significant during hypothesis testing.


## 2.1. Search Strategy

We performed a systematic review of the literature to identify articles relating to clinical features of human brucellosis in China. With assistance of a professional medical librarian we electronically searched the literature in Wan Fang Data, Wei Pu Data, CNKI, Medline, Cochrane Library, and PubMed with MESH and keyword subject headings “brucellosis,” “malta fever,” “brucella melitensis,” or “brucella abortus,” AND “symptom,” “sequelae,” “morbidity,” “mortality,” “transmission mode,” “foodborne,” and “China,” for entries published from databases’ inception before December 2016. We did not restrict the types of studies and publication languages. Duplicate entries were identified by two investigators screening the titles and abstracts of the article, the author, the year of publication, and the volume, issue, and page numbers of the source, and reviewing potentially relevant articles in full.


## 2.2. Selection Criteria

We systematically and inclusively reviewed articles by two investigators. The reviewers selected articles first by title and abstract, next by full text, and last by analyzing eligible studies in detail until demonstrating 100% agreement in articles included and excluded by two investigators.Studies with the following criteria were excluded: (A) articles related to non-human brucellosis; (B) reported data that overlapped with already included articles; (C) articles that could not provide original data of the patients; (D) articles addressing topics that were not related to the clinical features of human brucellosis, such as treatment intervention and experimental laboratory studies.Studies with the following criteria were included: (A) the literatures that described the clinical symptoms/syndromes of human brucellosis and the number of study subjects must more than 10 in each document; (B) the subjects reported in the literature who must be in China; (C) studies that provided data from general brucellosis cases and presented relevant laboratory results.


## 2.3. Data Extraction

Data was extracted by two reviewers independently including data collection, study design, study location, patient characteristics, the number of male and female patients, clinical manifestations, numbers of subjects with each symptom and complication which were recorded for each study, methods of diagnosis, and laboratory parameters. For the sex-related outcomes of epididymo/orchitis, the study population was considered to be only the male subgroups of the study population. Children patients must be of the age of 0–15 years. We also recorded the information relating to duration of illness prior to treatment, diagnostic delay, and exposure to potential risk factors. The results of data extraction must reach an agreement and consensus between the reviewers.


## 2.4. Statistical Analyses

We defined an event rate as the ratio of number of reported cases with a specific clinical manifestation to the total number of reported cases in each study. R statistical software (version 3.4.2, meta package) will be used for creating Forest plots to summarize composite data, generating proportions and corresponding 95% confidence intervals for each manifestation. Two-sidedP values < 0.05 will be considered statistically significant during hypothesis testing.


## 3. Results

### 3.1. Systematic Review

Literature searches yielded 1991 potential articles, leaving 68 publications that met inclusion and exclusion criteria for data extraction and final analyses. 68 studies represented 12842 patients with human brucellosis in China. The male : female ratio was 2.64 : 1. All 68 articles included in the analysis were case series studies. Figure1 illustrates the detailed search process.Figure 1
Procedure of the selection process.Studies selected from 20 provinces or autonomous regions of China, including 39 studies from pastoral areas (12 from Xinjiang, 9 from Heilongjiang, 7 from Inner Mongolia, 4 from Jilin, 4 from Ningxia, 2 from Gansu, and 1 from Liaoning) and 29 studies from nonpastoral areas (6 from Shandong, 5 from Beijing, 3 from Henan, 3 from Shanxi, 2 from Hebei, 2 from Shaanxi, 2 from Tianjin, 1 from Guangdong, 1 from Hunan, 1 from Jiangsu, 1 from Jiangxi, 1 from Yunnan, and 1 from Zhejiang). The geographic distributions of the numbers of subjects from each selected study are shown in Figure2.Figure 2
The geographic distribution of the numbers of subjects from each selected study.We identified 41 studies which included both children and adult patients [14–54]. 10 studies investigated children with an upper age limit ranging from 0 months to 15 years [55–64]. 17 studies were about the adults who are more than 15 years old [65–81]. The results are presented in detail in Table 1.Table 1
Main characteristics of all studies included in the meta-analysis.
First author & ref. number Year Age category Location Cases Available contact history data Available laboratory data Available blood culture data Available misdiagnosis data Wu et al. [14] 2012 All ages Beijing 44 Yes NA NA Yes Dai et al. [15] 2013 All ages Beijing 23 Yes Yes Yes NA Ge et al. [16] 2011 All ages Beijing 66 Yes Yes Yes Yes Tong et al. [17] 2013 All ages Beijing 35 Yes NA NA NA Guo and Xu [18] 2013 All ages Beijing 21 Yes Yes Yes Yes Wang et al. [19] 2015 All ages Gansu 61 Yes Yes NA NA Gao et al. [20] 2002 All ages Gansu 182 Yes NA NA NA Zhang et al. [21] 2012 All ages Henan 21 Yes Yes Yes NA Li et al. [22] 2016 All ages Henan 905 Yes NA NA NA Zhou [23] 2009 All ages Henan 241 NA NA NA Yes Li et al. [24] 2008 All ages Heilongjiang 165 Yes Yes Yes NA Liu and Zhang [25] 2016 All ages Inner Mongolia 44 NA NA NA NA Liu et al. [26] 2015 All ages Heilongjiang 314 NA Yes Yes NA Meng et al. [27] 2015 All ages Heilongjiang 3318 NA NA Yes NA Gong et al. [28] 2010 All ages Heilongjiang 1470 NA NA NA NA Liu et al. [29] 2012 All ages Heilongjiang 229 Yes Yes Yes Yes Sun et al. [30] 2010 All ages Jilin 270 Yes NA NA NA Wang et al. [31] 2014 All ages Liaoning 88 Yes NA NA NA Xie et al. [32] 2016 All ages Inner Mongolia 166 NA NA NA NA Sheng and Ma [33] 2009 All ages Inner Mongolia 829 NA NA NA NA Sun et al. [34] 2014 All ages Inner Mongolia 126 Yes Yes Yes NA W. Yang and F. Yang [35] 2015 All ages Inner Mongolia 228 Yes Yes NA Yes Duan [36] 2015 All ages Ningxia 57 Yes NA NA NA Zhang and Wang [37] 2013 All ages Ningxia 128 Yes NA NA Yes Wang [38] 2005 All ages Shandong 62 Yes NA NA NA Wang and Xiong [39] 2011 All ages Shandong 235 NA Yes NA Yes Lian et al. [40] 2015 All ages Shandong 232 Yes NA NA Yes Gao [41] 2016 All ages Shandong 94 Yes NA NA NA Wang et al. [42] 2014 All ages Shandong 96 Yes NA Yes Yes Wang [43] 2010 All ages Shanxi 86 Yes NA NA NA Feng and Deng [44] 2016 All ages Shanxi 105 Yes Yes Yes Yes An et al. [45] 2001 All ages Shaanxi 622 Yes NA NA NA Zhang et al. [46] 2016 All ages Yunnan 43 Yes Yes Yes NA Guo et al. [47] 2016 All ages Xinjiang 124 Yes NA NA NA Pan et al. [48] 2013 All ages Xinjiang 153 Yes Yes NA NA Zhang and Liu [49] 2013 All ages Xinjiang 57 Yes Yes Yes Yes Yang et al. [50] 2015 All ages Xinjiang 125 NA NA NA Yes Zhang [51] 2016 All ages Xinjiang 191 Yes Yes NA NA Ju et al. [52] 2011 All ages Xinjiang 156 Yes Yes Yes NA Gao et al. [53] 2012 All ages Xinjiang 426 NA NA NA NA Wang et al. [54] 2015 All ages Xinjiang 117 Yes Yes Yes NA Wang et al. [55] 2014 Children Hebei 80 Yes NA NA NA Zeng et al. [56] 2014 Children Jilin 23 Yes Yes Yes Yes Wang et al. [57] 2016 Children Xinjiang 16 Yes Yes NA NA Fan et al. [58] 2016 Children Xinjiang 24 Yes Yes NA NA Zhang et al. [59] 2006 Children Jilin 25 NA Yes NA NA Yu et al. [60] 2012 Children Heilongjiang 38 NA Yes NA NA Lu and Liu [61] 2015 Children Inner Mongolia 17 Yes Yes NA NA Liu et al. [62] 2016 Children Heilongjiang 94 Yes Yes Yes Yes Bai and Duan [63] 2015 Children Ningxia 48 Yes Yes Yes Yes He [64] 2015 Children Xinjiang 19 Yes Yes Yes Yes Zheng et al. [65] 2016 Adults Guangdong 12 Yes Yes Yes NA Tong et al. [66] 2008 Adults Hebei 25 Yes Yes Yes Yes Chen and Dong [67] 2016 Adults Heilongjiang 60 Yes NA NA NA Huang [68] 2016 Adults Hunan 17 Yes Yes Yes Yes Ji et al. [69] 2006 Adults Heilongjiang 30 NA Yes Yes NA M. Wang and L. Wang [70] 2007 Adults Jilin 26 Yes Yes NA Yes Zhang et al. [71] 2016 Adults Jiangsu 39 Yes Yes Yes Yes Guo et al. [72] 2016 Adults Jiangxi 12 Yes Yes Yes Yes Zhang [73] 2011 Adults Inner Mongolia 27 Yes Yes NA NA Yan et al. [74] 2016 Adults Ningxia 31 NA Yes Yes NA Li et al. [75] 2015 Adults Shandong 21 Yes Yes Yes Yes Wu et al. [76] 2007 Adults Shanxi 28 Yes Yes NA NA Zhang and Li [77] 2015 Adults Shaanxi 35 Yes Yes Yes NA Wang [78] 2014 Adults Tianjin 17 Yes Yes Yes Yes Zhou and Yang [79] 2014 Adults Tianjin 18 Yes Yes Yes NA Xu et al. [80] 2007 Adults Zhejiang 31 Yes NA NA NA Chen et al. [81] 2016 Adults Xinjiang 74 Yes Yes NA NA


### 3.2. Contact History

54 studies provided data about contact history (see Table2). Most of the patients (79.4% [95% CI 76.5%–82.4%]) had histories of closely contacting with cattle, sheep, pigs, and dogs. 11.5% (95% CI 8.4%–15.7%) cases had consumption history of uncooked meat or dairy products. 16.7% (95% CI 13.5%–20.8%) cases got the infection of brucellosis with unknown reason. The brucellosis is mostly associated with direct/indirect contact with infected animals or through the consumption of animal products in China.Table 2
Meta-analysis of the contact history.
Contact n Proportion[95% CI] Contact history 54 0.794[0.7651; 0.8240] Digestive tract contact 31 0.115[0.0844; 0.1567] Unknown 43 0.167[0.1347; 0.2077]


### 3.3. Clinical Syndromes and Complications

Table3 shows the clinical syndromes and complications of patients by age category. There are 17 articles specifically describing the clinical characteristics of adult brucellosis representing 503 patients (male 408, female 95). Fever was the most common clinical syndrome (pooled rate 99% [95% CI 97%–100%]), followed by muscle pain (76% [95% CI 60%–95%]), fatigue (64% [95% CI 55%–74%]), arthralgia (61% [95% CI 52%–70%]), and sweating (57% [95% CI 48%–68%]). 10 articles specifically describe the clinical characteristics of children brucellosis including 384 patients (male 249, female 135). The most common symptoms of children patients were fever (92% [95% CI 87%–97%]), fatigue (68% [95% CI 56%–83%]), sweating (60% [95% CI 45%–79%]), and arthralgia (52% [95% CI 43%–64%]). The remaining 41 articles include pediatric and adult patients, a total of 11955 cases (male 8654, female 3301). Children patients have a higher incidence rate of rash, respiratory and cardiac complications, and orchitis/epididymitis. The morbidity of chills, headache, and weight loss are lower compared to adults.Table 3
Meta-analysis of clinical manifestations of brucellosis by age category.
Manifestation Age category All studies Children Adults All ages General n % [95% CI] n % [95% CI] n % [95% CI] n % [95% CI] Fever 10 92[87; 97] 17 99[97; 100] 41 83 [80; 87] 68 87 [85; 90] Fatigue 7 68[56; 83] 14 64[55; 74] 34 62 [57; 67] 55 63 [59; 67] Chills 3 26[8; 82] 5 53[36; 79] 4 37 [33; 42] 12 43 [33; 55] Sweats 8 60[45; 79] 16 57 [48; 68] 39 54 [49; 59] 63 55 [51; 60] Arthralgia 9 52[43; 64] 17 61 [52; 70] 40 63 [59; 68] 66 62 [58; 65] Headache 4 8[3; 19] 10 29 [19; 42] 27 21 [18; 25] 41 21 [18; 25] Muscle pain 2 31[7; 100] 5 76 [60; 95] 20 53 [47; 59] 27 56 [51; 62] Nausea/vomiting 6 27[16; 43] 8 26 [15; 45] 17 25 [19; 34] 31 26 [21; 33] Rash 3 13[6; 29] 3 7 [3; 19] 9 5 [3; 11] 15 7 [4; 11] Weight loss 0 - 4 26 [14; 47] 5 32 [17; 61] 9 29 [17; 48] Skin petechia 3 8[4; 18] 2 18 [10; 32] 9 5 [3; 8] 14 7 [4; 10] Abdominal pain 2 6[1; 31] 3 6 [3; 14] 3 8 [4; 16] 8 8 [5; 11] Chest pain 0 - 2 7 [3; 17] 1 5 [3; 10] 3 6 [3; 10] Cough 5 12[8; 17] 4 19 [12; 29] 5 10 [8; 14] 14 12 [10; 15] Hepatomegaly 7 28[18; 42] 7 23 [13; 40] 23 13 [10; 17] 37 16 [13; 20] Splenomegaly 7 35[27; 45] 10 29 [22; 39] 23 21 [16; 27] 40 24 [20; 29] Lymphadenectasis 7 38[25; 58] 7 32 [22; 48] 27 16 [12; 21] 41 19 [15; 25] Hepatitis 8 48[34; 67] 15 60 [52; 69] 24 38 [30; 49] 47 45 [38; 54] Neurological 4 8[4; 17] 3 8 [2; 36] 14 4 [2; 9] 21 5 [3; 10] Cardiac 3 19[2; 100] 2 5 [1; 19] 12 9 [6; 14] 17 9 [6; 16] Hemophagocytic syndrome 0 - 0 - 4 6 [2; 23] 4 6 [2; 23] Respiratory 5 26[12; 57] 3 11 [6; 20] 8 9 [4; 23] 16 13 [7; 21] Orchitis/epididymitis 1 67[45; 100] 7 6 [3; 12] 34 9 [7; 12] 42 9 [7; 12] Osteoarthritis 2 16[8; 35] 4 22 [9; 52] 11 23 [17; 31] 17 22 [17; 29]Hepatitis (45% [95% CI 38%–54%]) and osteoarthritis (22% [95% CI 17%–29%]) were the most common complications. Central nervous system dysfunction (5% [95% CI 3%–10%]) which happened in overall patients included meningitis, encephalitis, cerebral infarction, and brain abscess. Cardiovascular diseases (9% [95% CI 6%–16%]) which were reported in overall patients involved the myocarditis, endocarditis, valvular neoplasm, valvular perforation, pericardial effusion, and heart failure. Hemophagocytic syndrome (6% [95% CI 2%–23%]) was only reported in adult patients. There were 13% of patients (95% CI: 7%–21%) suffering from respiratory manifestations, including cough, pneumonia, bronchial pneumonia, pleural effusion, respiratory failure, and pulmonary embolism. Orchitis or epididymitis occurred in 9% of the male patients (95% CI: 7%–12%).


### 3.4. Laboratory Tests

Table4 shows the meta-analysis of the incidence of laboratory tests. There are 37 articles providing data of laboratory indicators of patients including 2999 cases. The mainly common reported abnormal laboratory tests were aleucocytosis (24.1% [95% CI 19.5%–29.8%]), anemia (23.9% [95% CI 18.5%–30.9%]), thrombocytopenia (15.8% [95% CI 12.7%–19.8%]), pancytopenia (13.2% [95% CI 9.3%–18.7%]), and leukocytosis (10.6% [95% CI 8.2%–13.7%]). The agglutination test was positive in 100% cases. Totally 30 articles including 4681 cases were tested by blood culture andBrucella melitensis species were isolated from (48.3% [95% CI 41.5%–56.3%]) cases.Table 4
Meta-analysis of the incidence of laboratory tests.
Laboratory The number of articles Proportion [95% CI] Thrombocytopenia 32 0.158 [0.1268; 0.1979] Aleucocytosis 37 0.241 [0.1951; 0.2984] Leukocytosis 16 0.106 [0.0819; 0.1365] Anemia 28 0.239 [0.1847; 0.3094] Pancytopenia 6 0.132 [0.093; 0.187]


### 3.5. Misdiagnosis

There are 24 articles that provided information of misdiagnosis of patients including 2148 cases. 10 studies were from pastoral areas (3 from Xinjiang, 2 from Heilongjiang, 2 from Ningxia, 1 from Inner Mongolia, and 2 from Jilin) and 14 studies from nonpastoral areas (4 from Shandong, 3 from Beijing, 1 from Henan, 1 from Hebei, 1 from Hunan, 1 from Shanxi, 1 from Tianjin, 1 from Jiangxi, and 1 from Jiangsu). A total of 1287 (62.5% [95% CI 56.4%–69.2%]) patients were misdiagnosed at the first visit (Figure3). The misdiagnosed cases mainly occurred in nonpastoral provinces. Most patients were easily misdiagnosed as cold, rheumatic fever, rheumatoid arthritis, typhoid fever and paratyphoid fever, tuberculosis, malaria, septicemia, and lumbar disc herniation at the first visit in Department of Rheumatology, Hematology, Orthopedics, or Respiration.Figure 3
Forest plot of the incidence of misdiagnosis.


## 3.1. Systematic Review

Literature searches yielded 1991 potential articles, leaving 68 publications that met inclusion and exclusion criteria for data extraction and final analyses. 68 studies represented 12842 patients with human brucellosis in China. The male : female ratio was 2.64 : 1. All 68 articles included in the analysis were case series studies. Figure1 illustrates the detailed search process.Figure 1
Procedure of the selection process.Studies selected from 20 provinces or autonomous regions of China, including 39 studies from pastoral areas (12 from Xinjiang, 9 from Heilongjiang, 7 from Inner Mongolia, 4 from Jilin, 4 from Ningxia, 2 from Gansu, and 1 from Liaoning) and 29 studies from nonpastoral areas (6 from Shandong, 5 from Beijing, 3 from Henan, 3 from Shanxi, 2 from Hebei, 2 from Shaanxi, 2 from Tianjin, 1 from Guangdong, 1 from Hunan, 1 from Jiangsu, 1 from Jiangxi, 1 from Yunnan, and 1 from Zhejiang). The geographic distributions of the numbers of subjects from each selected study are shown in Figure2.Figure 2
The geographic distribution of the numbers of subjects from each selected study.We identified 41 studies which included both children and adult patients [14–54]. 10 studies investigated children with an upper age limit ranging from 0 months to 15 years [55–64]. 17 studies were about the adults who are more than 15 years old [65–81]. The results are presented in detail in Table 1.Table 1
Main characteristics of all studies included in the meta-analysis.
First author & ref. number Year Age category Location Cases Available contact history data Available laboratory data Available blood culture data Available misdiagnosis data Wu et al. [14] 2012 All ages Beijing 44 Yes NA NA Yes Dai et al. [15] 2013 All ages Beijing 23 Yes Yes Yes NA Ge et al. [16] 2011 All ages Beijing 66 Yes Yes Yes Yes Tong et al. [17] 2013 All ages Beijing 35 Yes NA NA NA Guo and Xu [18] 2013 All ages Beijing 21 Yes Yes Yes Yes Wang et al. [19] 2015 All ages Gansu 61 Yes Yes NA NA Gao et al. [20] 2002 All ages Gansu 182 Yes NA NA NA Zhang et al. [21] 2012 All ages Henan 21 Yes Yes Yes NA Li et al. [22] 2016 All ages Henan 905 Yes NA NA NA Zhou [23] 2009 All ages Henan 241 NA NA NA Yes Li et al. [24] 2008 All ages Heilongjiang 165 Yes Yes Yes NA Liu and Zhang [25] 2016 All ages Inner Mongolia 44 NA NA NA NA Liu et al. [26] 2015 All ages Heilongjiang 314 NA Yes Yes NA Meng et al. [27] 2015 All ages Heilongjiang 3318 NA NA Yes NA Gong et al. [28] 2010 All ages Heilongjiang 1470 NA NA NA NA Liu et al. [29] 2012 All ages Heilongjiang 229 Yes Yes Yes Yes Sun et al. [30] 2010 All ages Jilin 270 Yes NA NA NA Wang et al. [31] 2014 All ages Liaoning 88 Yes NA NA NA Xie et al. [32] 2016 All ages Inner Mongolia 166 NA NA NA NA Sheng and Ma [33] 2009 All ages Inner Mongolia 829 NA NA NA NA Sun et al. [34] 2014 All ages Inner Mongolia 126 Yes Yes Yes NA W. Yang and F. Yang [35] 2015 All ages Inner Mongolia 228 Yes Yes NA Yes Duan [36] 2015 All ages Ningxia 57 Yes NA NA NA Zhang and Wang [37] 2013 All ages Ningxia 128 Yes NA NA Yes Wang [38] 2005 All ages Shandong 62 Yes NA NA NA Wang and Xiong [39] 2011 All ages Shandong 235 NA Yes NA Yes Lian et al. [40] 2015 All ages Shandong 232 Yes NA NA Yes Gao [41] 2016 All ages Shandong 94 Yes NA NA NA Wang et al. [42] 2014 All ages Shandong 96 Yes NA Yes Yes Wang [43] 2010 All ages Shanxi 86 Yes NA NA NA Feng and Deng [44] 2016 All ages Shanxi 105 Yes Yes Yes Yes An et al. [45] 2001 All ages Shaanxi 622 Yes NA NA NA Zhang et al. [46] 2016 All ages Yunnan 43 Yes Yes Yes NA Guo et al. [47] 2016 All ages Xinjiang 124 Yes NA NA NA Pan et al. [48] 2013 All ages Xinjiang 153 Yes Yes NA NA Zhang and Liu [49] 2013 All ages Xinjiang 57 Yes Yes Yes Yes Yang et al. [50] 2015 All ages Xinjiang 125 NA NA NA Yes Zhang [51] 2016 All ages Xinjiang 191 Yes Yes NA NA Ju et al. [52] 2011 All ages Xinjiang 156 Yes Yes Yes NA Gao et al. [53] 2012 All ages Xinjiang 426 NA NA NA NA Wang et al. [54] 2015 All ages Xinjiang 117 Yes Yes Yes NA Wang et al. [55] 2014 Children Hebei 80 Yes NA NA NA Zeng et al. [56] 2014 Children Jilin 23 Yes Yes Yes Yes Wang et al. [57] 2016 Children Xinjiang 16 Yes Yes NA NA Fan et al. [58] 2016 Children Xinjiang 24 Yes Yes NA NA Zhang et al. [59] 2006 Children Jilin 25 NA Yes NA NA Yu et al. [60] 2012 Children Heilongjiang 38 NA Yes NA NA Lu and Liu [61] 2015 Children Inner Mongolia 17 Yes Yes NA NA Liu et al. [62] 2016 Children Heilongjiang 94 Yes Yes Yes Yes Bai and Duan [63] 2015 Children Ningxia 48 Yes Yes Yes Yes He [64] 2015 Children Xinjiang 19 Yes Yes Yes Yes Zheng et al. [65] 2016 Adults Guangdong 12 Yes Yes Yes NA Tong et al. [66] 2008 Adults Hebei 25 Yes Yes Yes Yes Chen and Dong [67] 2016 Adults Heilongjiang 60 Yes NA NA NA Huang [68] 2016 Adults Hunan 17 Yes Yes Yes Yes Ji et al. [69] 2006 Adults Heilongjiang 30 NA Yes Yes NA M. Wang and L. Wang [70] 2007 Adults Jilin 26 Yes Yes NA Yes Zhang et al. [71] 2016 Adults Jiangsu 39 Yes Yes Yes Yes Guo et al. [72] 2016 Adults Jiangxi 12 Yes Yes Yes Yes Zhang [73] 2011 Adults Inner Mongolia 27 Yes Yes NA NA Yan et al. [74] 2016 Adults Ningxia 31 NA Yes Yes NA Li et al. [75] 2015 Adults Shandong 21 Yes Yes Yes Yes Wu et al. [76] 2007 Adults Shanxi 28 Yes Yes NA NA Zhang and Li [77] 2015 Adults Shaanxi 35 Yes Yes Yes NA Wang [78] 2014 Adults Tianjin 17 Yes Yes Yes Yes Zhou and Yang [79] 2014 Adults Tianjin 18 Yes Yes Yes NA Xu et al. [80] 2007 Adults Zhejiang 31 Yes NA NA NA Chen et al. [81] 2016 Adults Xinjiang 74 Yes Yes NA NA


## 3.2. Contact History

54 studies provided data about contact history (see Table2). Most of the patients (79.4% [95% CI 76.5%–82.4%]) had histories of closely contacting with cattle, sheep, pigs, and dogs. 11.5% (95% CI 8.4%–15.7%) cases had consumption history of uncooked meat or dairy products. 16.7% (95% CI 13.5%–20.8%) cases got the infection of brucellosis with unknown reason. The brucellosis is mostly associated with direct/indirect contact with infected animals or through the consumption of animal products in China.Table 2
Meta-analysis of the contact history.
Contact n Proportion[95% CI] Contact history 54 0.794[0.7651; 0.8240] Digestive tract contact 31 0.115[0.0844; 0.1567] Unknown 43 0.167[0.1347; 0.2077]


## 3.3. Clinical Syndromes and Complications

Table3 shows the clinical syndromes and complications of patients by age category. There are 17 articles specifically describing the clinical characteristics of adult brucellosis representing 503 patients (male 408, female 95). Fever was the most common clinical syndrome (pooled rate 99% [95% CI 97%–100%]), followed by muscle pain (76% [95% CI 60%–95%]), fatigue (64% [95% CI 55%–74%]), arthralgia (61% [95% CI 52%–70%]), and sweating (57% [95% CI 48%–68%]). 10 articles specifically describe the clinical characteristics of children brucellosis including 384 patients (male 249, female 135). The most common symptoms of children patients were fever (92% [95% CI 87%–97%]), fatigue (68% [95% CI 56%–83%]), sweating (60% [95% CI 45%–79%]), and arthralgia (52% [95% CI 43%–64%]). The remaining 41 articles include pediatric and adult patients, a total of 11955 cases (male 8654, female 3301). Children patients have a higher incidence rate of rash, respiratory and cardiac complications, and orchitis/epididymitis. The morbidity of chills, headache, and weight loss are lower compared to adults.Table 3
Meta-analysis of clinical manifestations of brucellosis by age category.
Manifestation Age category All studies Children Adults All ages General n % [95% CI] n % [95% CI] n % [95% CI] n % [95% CI] Fever 10 92[87; 97] 17 99[97; 100] 41 83 [80; 87] 68 87 [85; 90] Fatigue 7 68[56; 83] 14 64[55; 74] 34 62 [57; 67] 55 63 [59; 67] Chills 3 26[8; 82] 5 53[36; 79] 4 37 [33; 42] 12 43 [33; 55] Sweats 8 60[45; 79] 16 57 [48; 68] 39 54 [49; 59] 63 55 [51; 60] Arthralgia 9 52[43; 64] 17 61 [52; 70] 40 63 [59; 68] 66 62 [58; 65] Headache 4 8[3; 19] 10 29 [19; 42] 27 21 [18; 25] 41 21 [18; 25] Muscle pain 2 31[7; 100] 5 76 [60; 95] 20 53 [47; 59] 27 56 [51; 62] Nausea/vomiting 6 27[16; 43] 8 26 [15; 45] 17 25 [19; 34] 31 26 [21; 33] Rash 3 13[6; 29] 3 7 [3; 19] 9 5 [3; 11] 15 7 [4; 11] Weight loss 0 - 4 26 [14; 47] 5 32 [17; 61] 9 29 [17; 48] Skin petechia 3 8[4; 18] 2 18 [10; 32] 9 5 [3; 8] 14 7 [4; 10] Abdominal pain 2 6[1; 31] 3 6 [3; 14] 3 8 [4; 16] 8 8 [5; 11] Chest pain 0 - 2 7 [3; 17] 1 5 [3; 10] 3 6 [3; 10] Cough 5 12[8; 17] 4 19 [12; 29] 5 10 [8; 14] 14 12 [10; 15] Hepatomegaly 7 28[18; 42] 7 23 [13; 40] 23 13 [10; 17] 37 16 [13; 20] Splenomegaly 7 35[27; 45] 10 29 [22; 39] 23 21 [16; 27] 40 24 [20; 29] Lymphadenectasis 7 38[25; 58] 7 32 [22; 48] 27 16 [12; 21] 41 19 [15; 25] Hepatitis 8 48[34; 67] 15 60 [52; 69] 24 38 [30; 49] 47 45 [38; 54] Neurological 4 8[4; 17] 3 8 [2; 36] 14 4 [2; 9] 21 5 [3; 10] Cardiac 3 19[2; 100] 2 5 [1; 19] 12 9 [6; 14] 17 9 [6; 16] Hemophagocytic syndrome 0 - 0 - 4 6 [2; 23] 4 6 [2; 23] Respiratory 5 26[12; 57] 3 11 [6; 20] 8 9 [4; 23] 16 13 [7; 21] Orchitis/epididymitis 1 67[45; 100] 7 6 [3; 12] 34 9 [7; 12] 42 9 [7; 12] Osteoarthritis 2 16[8; 35] 4 22 [9; 52] 11 23 [17; 31] 17 22 [17; 29]Hepatitis (45% [95% CI 38%–54%]) and osteoarthritis (22% [95% CI 17%–29%]) were the most common complications. Central nervous system dysfunction (5% [95% CI 3%–10%]) which happened in overall patients included meningitis, encephalitis, cerebral infarction, and brain abscess. Cardiovascular diseases (9% [95% CI 6%–16%]) which were reported in overall patients involved the myocarditis, endocarditis, valvular neoplasm, valvular perforation, pericardial effusion, and heart failure. Hemophagocytic syndrome (6% [95% CI 2%–23%]) was only reported in adult patients. There were 13% of patients (95% CI: 7%–21%) suffering from respiratory manifestations, including cough, pneumonia, bronchial pneumonia, pleural effusion, respiratory failure, and pulmonary embolism. Orchitis or epididymitis occurred in 9% of the male patients (95% CI: 7%–12%).


## 3.4. Laboratory Tests

Table4 shows the meta-analysis of the incidence of laboratory tests. There are 37 articles providing data of laboratory indicators of patients including 2999 cases. The mainly common reported abnormal laboratory tests were aleucocytosis (24.1% [95% CI 19.5%–29.8%]), anemia (23.9% [95% CI 18.5%–30.9%]), thrombocytopenia (15.8% [95% CI 12.7%–19.8%]), pancytopenia (13.2% [95% CI 9.3%–18.7%]), and leukocytosis (10.6% [95% CI 8.2%–13.7%]). The agglutination test was positive in 100% cases. Totally 30 articles including 4681 cases were tested by blood culture andBrucella melitensis species were isolated from (48.3% [95% CI 41.5%–56.3%]) cases.Table 4
Meta-analysis of the incidence of laboratory tests.
Laboratory The number of articles Proportion [95% CI] Thrombocytopenia 32 0.158 [0.1268; 0.1979] Aleucocytosis 37 0.241 [0.1951; 0.2984] Leukocytosis 16 0.106 [0.0819; 0.1365] Anemia 28 0.239 [0.1847; 0.3094] Pancytopenia 6 0.132 [0.093; 0.187]


## 3.5. Misdiagnosis

There are 24 articles that provided information of misdiagnosis of patients including 2148 cases. 10 studies were from pastoral areas (3 from Xinjiang, 2 from Heilongjiang, 2 from Ningxia, 1 from Inner Mongolia, and 2 from Jilin) and 14 studies from nonpastoral areas (4 from Shandong, 3 from Beijing, 1 from Henan, 1 from Hebei, 1 from Hunan, 1 from Shanxi, 1 from Tianjin, 1 from Jiangxi, and 1 from Jiangsu). A total of 1287 (62.5% [95% CI 56.4%–69.2%]) patients were misdiagnosed at the first visit (Figure3). The misdiagnosed cases mainly occurred in nonpastoral provinces. Most patients were easily misdiagnosed as cold, rheumatic fever, rheumatoid arthritis, typhoid fever and paratyphoid fever, tuberculosis, malaria, septicemia, and lumbar disc herniation at the first visit in Department of Rheumatology, Hematology, Orthopedics, or Respiration.Figure 3
Forest plot of the incidence of misdiagnosis.


## 4. Discussion

Brucellosis is one of the most widespread zoonoses worldwide [82, 83]. The number of brucellosis patients is increasing year by year in China. Shi et al. [84] analyzed the incidence and spatial-temporal distribution of human brucellosis from 1955 to 2014 in China, and the report showed that human brucellosis had reemerged since the mid-1990s and the affected areas had expanded from northern pastureland provinces to southern coastal and southwestern areas since 2004. In China brucellosis has been increasingly causing huge economic loss, and it has been a population health problem in recent years.In humans, brucellosis involved multiorgans with a complicated and various clinical presentations ranging from nonspecific to severe symptoms [85], which makes brucellosis easily misdiagnosed as other diseases. If a chronic phase is developed for a lack of timely diagnosis and treatment, the disease can lead to a high rate of disability. Since the clinical summary of the relevant cases in China is published in Chinese, these cases are not included in the study using meta-analysis ofBrucella abroad [86]. We analyzed the literature of clinical manifestations of human brucellosis in China.From our analyzed data, it shows that 57% selected studies from pastoral areas and 43% from nonpastoral and coastal areas, consistent with previous epidemiological findings that the disease affected areas have expanded from northern pastureland provinces to southern coastal and southwestern areas over the past decades in China, but brucellosis is still mainly popular in pastoral areas [87]. In this study, there are 79.4% of patients who had close contact with sick animals and 11.5% of cases had consumption of uncooked meat or dairy products, indicating that contacting with infected animals and consuming unsterile animal products are the main transmission routes in China.In the study, we found that the main clinical manifestations of human brucellosis are fever, fatigue, arthralgia, and muscle pain. The most common clinical syndromes of adult patients are fever, muscle pain, arthralgia, and sweating. Similar to our study, in a systematic review of the clinical manifestations of human brucellosis [86], the authors found that fever, arthralgia, myalgia, and back pain affected around half of the patients (78%, 65%, 47%, and 45%, resp.). There is controversy about whether clinical manifestations in children are significantly different from manifestations in adults. It had been reported in the literature that there was no significant difference in clinical manifestations between children and adults [88], which was very different in different literature. Some scholars reported that enlarged lymph nodes, spleen and liver, skin rashes, pharyngitis [89], and hematological and respiratory complications were more frequently observed in children than in adults [90]. Children had higher rates of hepatitis, osteoarticular manifestations [91], and lower rates of meningitis, endocarditis, spondylitis, and the progression to chronicity [92]. In the study, we found clinical differences between children and adults. Children had higher rates of rash, respiratory and cardiac complications, and orchitis/epididymitis. We also noted that chills, headache, and weight loss are less frequently observed in children patients.Multiorgan involvement ofBrucella is probably underrecognised [93]. Bone, CNS, and epididymis are the most commonly included organs [6]. The results of the current study were similar to those in other reported articles [94]. In the current study, results show that hepatitis and osteoarthritis were the more frequent complications. Serious complications such as central nervous system dysfunction, cardiovascular diseases, respiratory manifestations, and hemophagocytic syndromes are also observed. Orchitis or epididymitis occurred in 9% of the male patients. Brucellosis complications remain a major medical problem and it must still be regarded as a serious health problem in China.In the study, results show that there is a high rate of misdiagnosis that mainly occurred in nonpastoral areas. Because of these manifestations such as fever, back pain, cough, gastrointestinal symptoms, and blood abnormalities, brucellosis is often misdiagnosed. Most misdiagnosed patients were admitted in Department of Rheumatology, Hematology, Orthopedics, and Respiration at the first visit.Brucella bacteria culture is the “gold standard” for the diagnosis of brucellosis [95, 96]. In the study, 87% of brucellosis patients have fever. However, we found that only 30 articles including 4681 cases were tested by blood culture and 48.3% of cases were positive ofBrucella melitensis, indicating it may be the main reason of inappropriate diagnosis and inadequate therapy. Therefore, in order to reduce the rate of misdiagnosis effectively especially in the nonpastoral areas and provinces with high incidence of tuberculosis, it is necessary to broaden the ideas of clinical diagnosis with detailed history and carried out agglutination test and blood culture as early as possible for fever patients. One challenge in diagnosis of brucellosis is that the most common laboratory abnormalities are nonspecific. Most patients have normal blood cell counts on presentation. In the study, we found that the common abnormal laboratory tests were aleucocytosis (24.1%), anemia (23.9%), thrombocytopenia (15.8%), pancytopenia (13.2%), and leukocytosis (10.6%). In case of pancytopenia, the diagnosis of secondary hemophagocytosis should be considered. This condition may be triggered byBrucella and other intracellular pathogens [97, 98].Our study has some limitations. First, although the incidence of brucellosis is very high in our country, the quantity and quality of articles reported in some provinces are not high, which leads to partial data omission. We failed to obtain more precise analysis of different clinical stages of brucellosis because part of the included literature did not clearly describe the brucellosis clinical stage and age classification. Second, most of the reported literatures lack detailed data on patient treatment options and prognosis, which results in the failure of analyzing therapeutic effect and prognosis.In summary, we found that brucellosis was mainly popular in pastoral areas, but the disease affected areas had expanded from northern pastureland provinces to southern coastal and southwestern areas in China. The infection is mostly associated with the contact with infected animals or through the consumption of raw animal products. Clinical symptoms include fever, fatigue, arthralgia, sweating, and muscle pain with complication such as osteoarthritis, hepatitis, central nervous system dysfunction, cardiovascular diseases, respiratory manifestations, orchitis or epididymitis, and hemophagocytic syndromes. Further research is needed to characterize the analysis for therapeutic effect and prognosis of brucellosis in China. Our study provides initial evidence for the accurate diagnosis.



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