Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 28, Number 7—July 2022

Natural History of and Dynamic Changes in Clinical Manifestation, Serology, and Treatment of Brucellosis, China

Hongyu Wang1, Hongyan Liu1, Qiran Zhang1, Xiaobo Lu1, Dan Li1, Haocheng Zhang1, Yan A. Wang, Rongjiong Zheng, Yi Zhang, Zhangfan Fu, Ke Lin, Chao Qiu, Yan O. Wang, Ye GuComments to Author , Jingwen AiComments to Author , and Wenhong ZhangComments to Author 
Author affiliations: National Medical Center for Infectious Disease, National Clinical Research Center for Aging and Medicine, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University, Shanghai, China (H. Wang, Q. Zhang, H. Zhang, Y. Zhang, Z. Fu, K. Lin, C. Qiu, J. Ai, W. Zhang); The Sixth People’s Hospital of Shenyang, Shenyang, China (H. Liu, D. Li, Y.A. Wang, Y.O. Wang, Y. Gu); Emergency Treatment and Innovation Center of Public Health Emergencies, Shenyang (H. Liu, D. Li, Y.A. Wang, Y.O. Wang, Y. Gu); Center for Infectious Diseases, the First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China (X. Lu, R. Zheng); Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai (W. Zhang)

Cite This Article


CME Logo


In support of improving patient care, this activity has been planned and implemented by Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at; and (4) view/print certificate.

Release date: June 16, 2022; Expiration date: June 16, 2023
Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe diagnosis and epidemiologic features of human brucellosis, according to a large, retrospective cohort study in China

  • Determine clinical characteristics of human brucellosis during the disease course and after treatment, according to a large, retrospective cohort study in China

  • Identify serologic surveillance of human brucellosis during the disease course and after treatment, and long-term treatment outcomes, according to a large, retrospective cohort study in China

CME Editor

Jill Russell, BA, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Jill Russell, BA, has disclosed no relevant financial relationships.

CME Author

Laurie Barclay, MD, freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed the following relevant financial relationships: stocks, stock options, or bonds from AbbVie Inc. (former).


Hongyu Wang, MD; Hongyan Liu, MD; Qiran Zhang, MD; Xiaobo Lu, MD; Dan Li, MD; Haocheng Zhang, MD; Yan A. Wang, MD; Yi Zhang, MD; Zhangfan Fu, MS; Ke Lin, MS; Chao Qiu, PhD; Yan O. Wang, MD; Ye Gu, MD; Jingwen Ai, MD; and Wenhong Zhang, MD.



Serum agglutination test plus exposure history were used to diagnose most cases of human brucellosis in 2 China provinces. After appropriate treatment, 13.3% of acute brucellosis cases progressed to chronic disease; arthritis was an early predictor. Seropositivity can persist after symptoms disappear, which might cause physicians to subjectively extend therapeutic regimens.

Brucellosis is a zoonosis caused by the bacterium Brucella that typically manifests in insidious onset of fever, malaise, arthralgias, and nonspecific physical findings, including hepatomegaly, splenomegaly, or lymphadenopathy (1). Accurate diagnosis and proper management of human brucellosis continues to challenge clinicians. Several studies have described the clinical characteristics of human brucellosis and evaluated diagnostic methods, but most of these studies are cross-sectional and focused on baseline manifestations or diagnostic accuracy (26). Much remains unclear about the dynamic changes of clinical manifestations, serology, and the tendency of brucellosis to persist and become chronic during development and treatment.

The Study

We conducted a retrospective, real-world cohort study at 8 hospitals in Liaoning and Xinjiang Provinces, 2 of the most brucellosis-endemic areas in China, to investigate the characteristics of brucellosis during natural history and treatment. We enrolled patients confirmed to have brucellosis during 2014–2020. We collected information on contact history, clinical manifestations, laboratory parameters, and antibiotic therapy from the hospital information system and treatment outcome by telephone (Appendix). This research was carried out according to the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committees of Huashan Hospital of Fudan University (KY2019–412). Informed consent was obtained from all patients before diagnosis, and patient data were anonymized.

We included 5,270 patients confirmed to have brucellosis during September 2014–December 2020. Three persons were excluded for positive HIV detection, 668 were excluded because they lacked positive culture or serologic results, and 1,191 were excluded for incomplete clinical information. We ultimately enrolled 3,411 persons; we performed follow-up for 1,676 persons at periods of 14, 28, 42, 90, 180, 360, or 720 days after diagnosis and treatment initiation (Appendix Figure 1).

Median participant age was 48 years (interquartile range 35.8–57.0 years). Most participants were men (2,452; 73.9%) and worked as farmers or herdsmen (2,776; 82.4%). A total of 2,066 (60.6%) had exposure history with suspicious animals, 1,686 (49.4%) had contact history with brucellosis patients, and 1,129 (33.1%) resided in a brucellosis-endemic area (Table 1).

Blood cultures were collected from 1,827 participants for diagnostic purposes; results were positive in 424 (23.2%) persons. Serum agglutination tests (SAT) were collected from 3,381 persons, and 3,351 (99.1%) reported positive results. A total of 1,797 persons received both tests; 394 (21.9%) tested positive on both, 28 (1.6%) tested positive by culture only, and 1,375 (76.5%) tested positive by SAT only. Among 2,264 patients with positive titers on SAT, titers were >1:400 in 36.0%, 1:200 in 28.4%, 1:100 in 35.2%, and 1:50 in 0.4% (Table 1). Seasonal epidemics were observed during March–July each year, whereas total diagnosed cases decreased annually during 2015–2019 (Appendix Figure 2).

We observed the natural history of brucellosis with symptom duration <180 days (early stage) or >180 days (late stage) before patients received antibiotic therapy. The 3 most common symptoms in early-stage disease were fatigue (72.3%), fever (64.0%), and sweating (34.6%). The most common symptoms in late-stage disease were fatigue (71.6%), fever (61.1%), and arthritis (36.6%) (Figure 1, panel A). Arthritis was more common in the late stage than the early stage (20.7%; p<0.0001). We observed neurobrucellosis in 9.9% of patients in the early stage and in 4.1% of patients in the late stage (p = 0.0020). After adjusting for confounding factors through propensity score-matching (PSM) (7), culture-diagnosed patients (compared with patients with SAT-diagnosed brucellosis) had higher incidence of fever (311 [81.8%] vs. 244 [58.9%]; p<0.0001), sweating (177 [46.6%] vs. 95 [25.0%]; p<0.0001), poor appetite (271 [71.3%] vs. 195 [51.3%]; p<0.0001), and hepatosplenomegaly (67 [17.6%] vs. 45 [11.8%]; p<0.0001). These patients also exhibited higher C-reactive protein (34.5 + 1.8 vs. 24.7 + 1.7; p = 0.0002) and erythrocyte sedimentation rate (45.6 + 1.7 vs. 29.3 + 1.4; p = 0.0290), which could be caused by active bloodstream infection (Appendix Table 1).

Among 1,676 participants with whom we conducted follow-up, we observed further clinical characteristics after treatment initiation. Most newly developed manifestations were reported within the first 2 weeks, but most patients recovered with persistent treatment (Appendix Figure 3). Two weeks after treatment initiation, 107 patients had newly developed cardiac inflammation, 112 neurobrucellosis, 140 urogenital inflammation, and 146 arthritis. Overall, 1,453 (86.7%) persons with acute brucellosis symptomatically recovered within 180 days after appropriate treatment, whereas 223 (13.3%) were still symptomatic after 180 days and chronic brucellosis developed (Figure 1, panel B) (8). In the chronic phase, arthritis (89 [25.6%]), fatigue (60 [17.3%]), and fever (57 [16.4%]) became the 3 most common manifestations (Appendix Figure 4).

After conducting PSM for age, sex, nationality, and year of enrollment, we performed multivariate logistic regression to identify risk factors for chronic brucellosis in 148 acute cases and 148 chronic cases (Table 2). Fever, sweating, myalgia, arthritis, and C-reactive protein and erythrocyte sedimentation rates at baseline were possible predictors for chronic brucellosis in univariate analysis (p<0.10). Arthritis was the only risk factor after multivariate analysis (odds ratio 4.11 [95% CI 1.22–16.92]; p = 0.0318).

Dynamic SAT surveillance among 1,676 participants suggested that 53.8% (902/1,676) remained seropositive 42 days after treatment and 33.9% (518/1,676) remained seropositive 180 days after treatment (Figure 2, panel A). In acute cases, 413 remained seropositive and 1,040 seroconverted after 180 days. In chronic cases, 105 remained seropositive and 118 seroconverted (p<0.0001). The overall SAT titers decreased at the chronic phase; fewer patients had a titer of >1:400 (Figure 2, panel B).

We observed treatment outcomes in 432 patients without systemic involvement, of whom 307 (71.1%) received doxycycline and rifampin, 29 (6.7%) received doxycycline and levofloxacin, and 96 (22.2%) received triad therapy. In comparison with the standard 6-week treatment course (810), 75.2% (325/432) patients received antibiotic therapy for >42 days; median course of treatment was 90 (interquartile range 43–193) days (Figure 2, panel C). Further analysis in treatment elongation found that 26/325 (8.0%) were still symptomatic; the most common manifestations were sweating (61.5%), fatigue (50.0%), and fever (26.9%). A total of 174/325 (53.5%) participants were asymptomatic but seropositive, which could lead clinicians to subjectively extend antibiotic treatment; 125/325 (38.5%) participants were asymptomatic and seronegative (Figure 2, panel D). We further analyzed 107 participants who completed treatment within 42 days to determine whether standard treatment led to persistent symptoms or recurrence. Of those participants, 48/107 (44.9%) remained seropositive, 2/107 (1.9%) reported persistent symptoms, and 1/107 (0.9%) participant’s illness was considered a recurrence 2 years later.

The first limitation of our study is that we failed to follow up culture results during treatment. Second, we failed to distinguish transient and persistent exposure history, which might play a role in persistent symptoms or serologic results. Finally, infection was diagnosed by heterogenous methods, including culture and a series of serologic tests, which might introduce bias in baseline and prognosis analysis.


Our study gives a thorough, dynamic description of clinical characteristics and serologic surveillance during the natural history and treatment of human brucellosis in a large population. Culture was 23.2% positive but SAT 99.1% positive in confirmed brucellosis. SAT plus exposure history remained the most effective diagnostic tool. Human brucellosis had variable manifestations at different disease stages. Untreated cases mainly manifested as fatigue, fever, or sweating in the early stage, whereas fatigue, fever, and arthritis were the most common symptoms at the late stage. After appropriate treatment, 13.3% of acute brucellosis cases progressed to chronic disease. Arthritis can serve as an early predictor of chronic brucellosis. Seropositivity can persist after symptoms disappear, which might cause physicians to subjectively and unnecessarily extend therapeutic regimens.



We thank all the physicians that participated in this study for patient enrollment and follow-up and give our greatest appreciation to all health workers for their valuable input to the control of diseases.

This study was funded by Shanghai Municipal Science and Technology Major Project, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University (No. 20dz2260100, 21NL2600100, 20dz2210400), National Natural Science Foundation of China (no. 82002141), Shanghai Youth Science and Technology Talents Sailing Project (20YF1404300) and Key Discipline Construction Plan from Shanghai Municipal Health Commission (GWV-10.1-XK01, GWV-3.1, GWV-2).

The data that support the findings of this study are available from the corresponding author on reasonable request.



  1. Franco  MP, Mulder  M, Gilman  RH, Smits  HL. Human brucellosis. Lancet Infect Dis. 2007;7:77586. DOIPubMedGoogle Scholar
  2. Hasanjani Roushan  MR, Mohrez  M, Smailnejad Gangi  SM, Soleimani Amiri  MJ, Hajiahmadi  M. Epidemiological features and clinical manifestations in 469 adult patients with brucellosis in Babol, Northern Iran. Epidemiol Infect. 2004;132:110914. DOIPubMedGoogle Scholar
  3. Kokoglu  OF, Hosoglu  S, Geyik  MF, Ayaz  C, Akalin  S, Buyukbese  MA, et al. Clinical and laboratory features of brucellosis in two university hospitals in Southeast Turkey. Trop Doct. 2006;36:4951. DOIPubMedGoogle Scholar
  4. Memish  Z, Mah  MW, Al Mahmoud  S, Al Shaalan  M, Khan  MY. Brucella bacteraemia: clinical and laboratory observations in 160 patients. J Infect. 2000;40:5963. DOIPubMedGoogle Scholar
  5. Osoba  AO, Balkhy  H, Memish  Z, Khan  MY, Al-Thagafi  A, Al Shareef  B, et al. Diagnostic value of Brucella ELISA IgG and IgM in bacteremic and non-bacteremic patients with brucellosis. J Chemother. 2001;13(Suppl 1):549. DOIPubMedGoogle Scholar
  6. Ruiz-Mesa  JD, Sánchez-Gonzalez  J, Reguera  JM, Martín  L, Lopez-Palmero  S, Colmenero  JD. Rose Bengal test: diagnostic yield and use for the rapid diagnosis of human brucellosis in emergency departments in endemic areas. Clin Microbiol Infect. 2005;11:2215. DOIPubMedGoogle Scholar
  7. Benedetto  U, Head  SJ, Angelini  GD, Blackstone  EH. Statistical primer: propensity score matching and its alternatives. Eur J Cardiothorac Surg. 2018;53:11127. DOIPubMedGoogle Scholar
  8. Zhang  W, Zhang  Y; Editorial Board of Chinese Journal of Infectious Diseases. Chinese consensus guidelines for diagnosis and management of Brucellosis. 2017 [cited 2020 Oct 24].
  9. Bossi  P, Tegnell  A, Baka  A, Van Loock  F, Hendriks  J, Werner  A, et al.; Task Force on Biological and Chemical Agent Threats, Public Health Directorate, European Commission, Luxembourg. Bichat guidelines for the clinical management of brucellosis and bioterrorism-related brucellosis. Euro Surveill. 2004;9:E156. DOIPubMedGoogle Scholar
  10. Tuon  FF, Cerchiari  N, Cequinel  JC, Droppa  EEH, Moreira  SDR, Costa  TP, et al.; Brucellosis Workgroup. Guidelines for the management of human brucellosis in the State of Paraná, Brazil. Rev Soc Bras Med Trop. 2017;50:45864. DOIPubMedGoogle Scholar




Follow Up

Earning CME Credit

To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 75% passing score) and earn continuing medical education (CME) credit, please go to Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers.

You must be a registered user on If you are not registered on, please click on the “Register” link on the right hand side of the website.

Only one answer is correct for each question. Once you successfully answer all post-test questions, you will be able to view and/or print your certificate. For questions regarding this activity, contact the accredited provider, For technical assistance, contact American Medical Association’s Physician’s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please go to The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits™. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in CME activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA CME credit certificate, and present it to your national medical association for review.

Article Title: 
Natural History of and Dynamic Changes in Clinical Manifestation, Serology, and Treatment of Brucellosis, China
CME Questions
  • Your patient is a 47-year-old male farmer with suspected brucellosis. According to the large, retrospective cohort study in China by Wang and colleagues, which of the following statements about diagnosis and epidemiologic features of human brucellosis is correct?

    • Clinical features were most useful in diagnosing human brucellosis in China

    • More than half of patients diagnosed with brucellosis had positive blood cultures

    • Approximately one-quarter of patients had positive exposure history

    • Seasonal epidemics occurred from March to July each year; total newly diagnosed cases decreased annually between 2015 and 2019

  • According to the large, retrospective cohort study in China by Wang and colleagues, which of the following statements about clinical characteristics of human brucellosis during the disease course and after treatment is correct?

    • Before receipt of antibiotics, fatigue, fever, and arthritis were the 3 most common symptoms in early-stage brucellosis (symptom duration < 180 days)

    • Baseline C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were the best predictors for chronic brucellosis

    • At 2 weeks posttreatment, some patients developed new cardiac inflammation (n = 107), neurobrucellosis (n = 112), urogenital inflammation (n = 140), or arthritis (n = 146)

    • Cases diagnosed by culture vs SAT were less likely to have hepatosplenomegaly

  • According to the large, retrospective cohort study in China by Wang and colleagues, which of the following statements about serologic surveillance of human brucellosis during the disease course and after treatment and long-term treatment outcomes is correct?

    • After appropriate treatment, 13.3% of acute brucellosis cases progressed to chronicity (still symptomatic after 180 days)

    • Treatment should be discontinued once symptoms disappear

    • In the chronic phase, loss of appetite was the most common symptom

    • 15% of brucellosis cases remained seropositive at 180 days posttreatment


Cite This Article

DOI: 10.3201/eid2807.211766

Original Publication Date: June 21, 2022

1These authors contributed equally to this article.

Related Links

Table of Contents – Volume 28, Number 7—July 2022

EID Search Options
presentation_01 Advanced Article Search – Search articles by author and/or keyword.
presentation_01 Articles by Country Search – Search articles by the topic country.
presentation_01 Article Type Search – Search articles by article type and issue.



Please use the form below to submit correspondence to the authors or contact them at the following address:

Jingwen Ai or Wenhong Zhang, Department of Infectious Disease, Huashan Hospital, Fudan University, No. 12, Wulumuqi Rd, Jingan District, Shanghai, 200040, China

Send To

10000 character(s) remaining.


Page created: May 12, 2022
Page updated: June 21, 2022
Page reviewed: June 21, 2022
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.