Brucellosis is one of the most common zoonotic infections globally [
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 [
Brucellosis was first reported in China in 1905 [
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.
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.
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.
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.
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-sided
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. Figure
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 Figure
The geographic distribution of the numbers of subjects from each selected study.
We identified 41 studies which included both children and adult patients [
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. [ | 2012 | All ages | Beijing | 44 | Yes | NA | NA | Yes |
Dai et al. [ | 2013 | All ages | Beijing | 23 | Yes | Yes | Yes | NA |
Ge et al. [ | 2011 | All ages | Beijing | 66 | Yes | Yes | Yes | Yes |
Tong et al. [ | 2013 | All ages | Beijing | 35 | Yes | NA | NA | NA |
Guo and Xu [ | 2013 | All ages | Beijing | 21 | Yes | Yes | Yes | Yes |
Wang et al. [ | 2015 | All ages | Gansu | 61 | Yes | Yes | NA | NA |
Gao et al. [ | 2002 | All ages | Gansu | 182 | Yes | NA | NA | NA |
Zhang et al. [ | 2012 | All ages | Henan | 21 | Yes | Yes | Yes | NA |
Li et al. [ | 2016 | All ages | Henan | 905 | Yes | NA | NA | NA |
Zhou [ | 2009 | All ages | Henan | 241 | NA | NA | NA | Yes |
Li et al. [ | 2008 | All ages | Heilongjiang | 165 | Yes | Yes | Yes | NA |
Liu and Zhang [ | 2016 | All ages | Inner Mongolia | 44 | NA | NA | NA | NA |
Liu et al. [ | 2015 | All ages | Heilongjiang | 314 | NA | Yes | Yes | NA |
Meng et al. [ | 2015 | All ages | Heilongjiang | 3318 | NA | NA | Yes | NA |
Gong et al. [ | 2010 | All ages | Heilongjiang | 1470 | NA | NA | NA | NA |
Liu et al. [ | 2012 | All ages | Heilongjiang | 229 | Yes | Yes | Yes | Yes |
Sun et al. [ | 2010 | All ages | Jilin | 270 | Yes | NA | NA | NA |
Wang et al. [ | 2014 | All ages | Liaoning | 88 | Yes | NA | NA | NA |
Xie et al. [ | 2016 | All ages | Inner Mongolia | 166 | NA | NA | NA | NA |
Sheng and Ma [ | 2009 | All ages | Inner Mongolia | 829 | NA | NA | NA | NA |
Sun et al. [ | 2014 | All ages | Inner Mongolia | 126 | Yes | Yes | Yes | NA |
W. Yang and F. Yang [ | 2015 | All ages | Inner Mongolia | 228 | Yes | Yes | NA | Yes |
Duan [ | 2015 | All ages | Ningxia | 57 | Yes | NA | NA | NA |
Zhang and Wang [ | 2013 | All ages | Ningxia | 128 | Yes | NA | NA | Yes |
Wang [ | 2005 | All ages | Shandong | 62 | Yes | NA | NA | NA |
Wang and Xiong [ | 2011 | All ages | Shandong | 235 | NA | Yes | NA | Yes |
Lian et al. [ | 2015 | All ages | Shandong | 232 | Yes | NA | NA | Yes |
Gao [ | 2016 | All ages | Shandong | 94 | Yes | NA | NA | NA |
Wang et al. [ | 2014 | All ages | Shandong | 96 | Yes | NA | Yes | Yes |
Wang [ | 2010 | All ages | Shanxi | 86 | Yes | NA | NA | NA |
Feng and Deng [ | 2016 | All ages | Shanxi | 105 | Yes | Yes | Yes | Yes |
An et al. [ | 2001 | All ages | Shaanxi | 622 | Yes | NA | NA | NA |
Zhang et al. [ | 2016 | All ages | Yunnan | 43 | Yes | Yes | Yes | NA |
Guo et al. [ | 2016 | All ages | Xinjiang | 124 | Yes | NA | NA | NA |
Pan et al. [ | 2013 | All ages | Xinjiang | 153 | Yes | Yes | NA | NA |
Zhang and Liu [ | 2013 | All ages | Xinjiang | 57 | Yes | Yes | Yes | Yes |
Yang et al. [ | 2015 | All ages | Xinjiang | 125 | NA | NA | NA | Yes |
Zhang [ | 2016 | All ages | Xinjiang | 191 | Yes | Yes | NA | NA |
Ju et al. [ | 2011 | All ages | Xinjiang | 156 | Yes | Yes | Yes | NA |
Gao et al. [ | 2012 | All ages | Xinjiang | 426 | NA | NA | NA | NA |
Wang et al. [ | 2015 | All ages | Xinjiang | 117 | Yes | Yes | Yes | NA |
Wang et al. [ | 2014 | Children | Hebei | 80 | Yes | NA | NA | NA |
Zeng et al. [ | 2014 | Children | Jilin | 23 | Yes | Yes | Yes | Yes |
Wang et al. [ | 2016 | Children | Xinjiang | 16 | Yes | Yes | NA | NA |
Fan et al. [ | 2016 | Children | Xinjiang | 24 | Yes | Yes | NA | NA |
Zhang et al. [ | 2006 | Children | Jilin | 25 | NA | Yes | NA | NA |
Yu et al. [ | 2012 | Children | Heilongjiang | 38 | NA | Yes | NA | NA |
Lu and Liu [ | 2015 | Children | Inner Mongolia | 17 | Yes | Yes | NA | NA |
Liu et al. [ | 2016 | Children | Heilongjiang | 94 | Yes | Yes | Yes | Yes |
Bai and Duan [ | 2015 | Children | Ningxia | 48 | Yes | Yes | Yes | Yes |
He [ | 2015 | Children | Xinjiang | 19 | Yes | Yes | Yes | Yes |
Zheng et al. [ | 2016 | Adults | Guangdong | 12 | Yes | Yes | Yes | NA |
Tong et al. [ | 2008 | Adults | Hebei | 25 | Yes | Yes | Yes | Yes |
Chen and Dong [ | 2016 | Adults | Heilongjiang | 60 | Yes | NA | NA | NA |
Huang [ | 2016 | Adults | Hunan | 17 | Yes | Yes | Yes | Yes |
Ji et al. [ | 2006 | Adults | Heilongjiang | 30 | NA | Yes | Yes | NA |
M. Wang and L. Wang [ | 2007 | Adults | Jilin | 26 | Yes | Yes | NA | Yes |
Zhang et al. [ | 2016 | Adults | Jiangsu | 39 | Yes | Yes | Yes | Yes |
Guo et al. [ | 2016 | Adults | Jiangxi | 12 | Yes | Yes | Yes | Yes |
Zhang [ | 2011 | Adults | Inner Mongolia | 27 | Yes | Yes | NA | NA |
Yan et al. [ | 2016 | Adults | Ningxia | 31 | NA | Yes | Yes | NA |
Li et al. [ | 2015 | Adults | Shandong | 21 | Yes | Yes | Yes | Yes |
Wu et al. [ | 2007 | Adults | Shanxi | 28 | Yes | Yes | NA | NA |
Zhang and Li [ | 2015 | Adults | Shaanxi | 35 | Yes | Yes | Yes | NA |
Wang [ | 2014 | Adults | Tianjin | 17 | Yes | Yes | Yes | Yes |
Zhou and Yang [ | 2014 | Adults | Tianjin | 18 | Yes | Yes | Yes | NA |
Xu et al. [ | 2007 | Adults | Zhejiang | 31 | Yes | NA | NA | NA |
Chen et al. [ | 2016 | Adults | Xinjiang | 74 | Yes | Yes | NA | NA |
54 studies provided data about contact history (see Table
Meta-analysis of the contact history.
Contact | | Proportion |
---|---|---|
Contact history | 54 | 0.794 |
Digestive tract contact | 31 | 0.115 |
Unknown | 43 | 0.167 |
Table
Meta-analysis of clinical manifestations of brucellosis by age category.
Manifestation | Age category | All studies | ||||||
---|---|---|---|---|---|---|---|---|
Children | Adults | All ages | ||||||
General | | % [95% CI] | | % [95% CI] | | % [95% CI] | | % [95% CI] |
Fever | 10 | 92 | 17 | 99 | 41 | 83 [80; 87] | 68 | 87 [85; 90] |
Fatigue | 7 | 68 | 14 | 64 | 34 | 62 [57; 67] | 55 | 63 [59; 67] |
Chills | 3 | 26 | 5 | 53 | 4 | 37 [33; 42] | 12 | 43 [33; 55] |
Sweats | 8 | 60 | 16 | 57 [48; 68] | 39 | 54 [49; 59] | 63 | 55 [51; 60] |
Arthralgia | 9 | 52 | 17 | 61 [52; 70] | 40 | 63 [59; 68] | 66 | 62 [58; 65] |
Headache | 4 | 8 | 10 | 29 [19; 42] | 27 | 21 [18; 25] | 41 | 21 [18; 25] |
Muscle pain | 2 | 31 | 5 | 76 [60; 95] | 20 | 53 [47; 59] | 27 | 56 [51; 62] |
Nausea/vomiting | 6 | 27 | 8 | 26 [15; 45] | 17 | 25 [19; 34] | 31 | 26 [21; 33] |
Rash | 3 | 13 | 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 | 2 | 18 [10; 32] | 9 | 5 [3; 8] | 14 | 7 [4; 10] |
Abdominal pain | 2 | 6 | 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 | 4 | 19 [12; 29] | 5 | 10 [8; 14] | 14 | 12 [10; 15] |
Hepatomegaly | 7 | 28 | 7 | 23 [13; 40] | 23 | 13 [10; 17] | 37 | 16 [13; 20] |
Splenomegaly | 7 | 35 | 10 | 29 [22; 39] | 23 | 21 [16; 27] | 40 | 24 [20; 29] |
Lymphadenectasis | 7 | 38 | 7 | 32 [22; 48] | 27 | 16 [12; 21] | 41 | 19 [15; 25] |
Hepatitis | 8 | 48 | 15 | 60 [52; 69] | 24 | 38 [30; 49] | 47 | 45 [38; 54] |
Neurological | 4 | 8 | 3 | 8 [2; 36] | 14 | 4 [2; 9] | 21 | 5 [3; 10] |
Cardiac | 3 | 19 | 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 | 3 | 11 [6; 20] | 8 | 9 [4; 23] | 16 | 13 [7; 21] |
Orchitis/ | 1 | 67 | 7 | 6 [3; 12] | 34 | 9 [7; 12] | 42 | 9 [7; 12] |
Osteoarthritis | 2 | 16 | 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%).
Table
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] |
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 (Figure
Forest plot of the incidence of misdiagnosis.
Brucellosis is one of the most widespread zoonoses worldwide [
In humans, brucellosis involved multiorgans with a complicated and various clinical presentations ranging from nonspecific to severe symptoms [
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 [
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 [
Multiorgan involvement of
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.
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.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
This work was supported by Key Research and Development Projects of the Xinjiang Uygur Autonomous Region (no. 2016B03047-1).