Brucellosis in the Modern Era: A Persistent Zoonotic Threat — Global Epidemiology, Clinical Spectrum, Diagnostics, and Management Advances (2015–2025)

Brucellosis in the Modern Era: A Persistent Zoonotic Threat —

Global Epidemiology, Clinical Spectrum, Diagnostics, and Management Advances (2015–2025)

AASTHA JAISWAL¹, PRANJALI GANGATIRE², SAKSHI NIGAL3, MANAS KYZY. M4

1,2,3 student IMF, [OSHSU, IMF]; 4 Professor, Department of Infectious Diseases, [OSHSU, IMF]

Abstract

Background: Brucellosis, caused by Gram-negative coccobacilli of the genus Brucella, remains one of the most widespread and under-diagnosed zoonotic diseases globally. A 2023 evidence-based modelling study estimated the annual global incidence at 2.1 million cases — significantly higher than previous assumptions — with Africa and Asia sustaining the greatest burden. 

Objective: This narrative review synthesises epidemiological trends, pathophysiology, clinical manifestations, diagnostic strategies, and treatment protocols published between 2015 and 2025, written from the perspective of a medical student seeking clinical clarity on a frequently misdiagnosed condition. 

Methods: A systematic search of PubMed, ScienceDirect, WHO databases, and the CDC was performed. Meta-analyses, systematic reviews, surveillance reports, and updated clinical guidelines were incorporated. 

Results: Global prevalence is highest in the Middle East, East Africa, and Central Asia. B. melitensis accounts for the majority of severe human cases. The clinical presentation is notoriously protean — ranging from undulant fever and arthralgia to neurobrucellosis and life-threatening endocarditis. Diagnosis relies on serology (Rose Bengal Test, Standard Agglutination Test), blood culture, and PCR. WHO-recommended first-line treatment of doxycycline plus rifampicin for six weeks achieves cure in uncomplicated cases, though focal disease requires prolonged multi-drug regimens. Relapse rates of 5–15% remain a clinical challenge. 

Conclusion: Brucellosis continues to be a public health emergency in endemic regions, exacerbated by underreporting, diagnostic gaps, and lack of a human vaccine. A One Health approach combining veterinary control, pasteurisation policies, and improved diagnostics is essential to curtail its global burden.

Keywords: Brucella; brucellosis; zoonosis; undulant fever; neurobrucellosis; doxycycline; rifampicin; One Health

1. Introduction

Few infectious diseases embody the concept of diagnostic ambiguity as completely as brucellosis. Known by a catalogue of historical names — Malta fever, Mediterranean fever, undulant fever, Bang's disease — this bacterial zoonosis has shadowed human civilisation since at least the nineteenth century, when David Bruce first isolated its causative organism from the spleen of a Maltese soldier in 1887. More than 130 years later, the disease persists with remarkable tenacity, thriving in the intersection of animal husbandry, poverty, and inadequate food safety infrastructure.

As medical students, we are taught to think of fever as a symptom that demands systematic interrogation. Brucellosis teaches us why: its fever is characteristically undulant, its arthralgia migratory, its haematological changes subtle, and its serology — when not specifically requested — invisible. In many endemic settings, a patient may see three or four clinicians before the correct diagnosis is reached, by which point focal complications such as sacroiliitis, spondylodiscitis, or orchitis may have already taken hold.

The decade spanning 2015 to 2025 has brought both alarm and progress. A landmark 2023 modelling study by Laine et al. placed annual global incidence at 2.1 million cases — far exceeding the 500,000 figure that had circulated in public health discourse for two decades.¹ At the same time, China's National Brucellosis Prevention and Control Plan (NBPCP), implemented from 2016, demonstrated that coordinated veterinary-human intervention can produce measurable reductions in incidence.² The Middle East, meanwhile, has seen surging case numbers in conflict-affected countries where veterinary surveillance has collapsed. This review examines these developments within a structured clinical framework, intended to equip medical students with the knowledge to recognise, investigate, and manage this persistently underestimated pathogen.

2. Microbiology and Pathogenesis

2.1 The Brucella Genus

Brucella species are small, Gram-negative, non-motile, non-spore-forming, aerobic coccobacilli. They lack classical virulence factors such as exotoxins, capsules, and fimbriae, yet demonstrate remarkable intracellular survival capacity that frustrates host immune clearance. The genus contains twelve recognised species, of which four are clinically significant in humans: B. melitensis (goats and sheep — most virulent in humans), B. abortus (cattle), B. suis (pigs), and B. canis (dogs). B. melitensis accounts for the vast majority of severe human brucellosis cases globally, owing to its high environmental stability and infectious dose as low as 10–100 organisms.

The organism's lipopolysaccharide (LPS) is structurally distinct from classical enteric LPS and elicits a markedly attenuated innate immune response, enabling the bacterium to evade early toll-like receptor signalling. The VirB type IV secretion system is central to intracellular survival: it injects bacterial effector proteins into the host cell cytoplasm, preventing lysosomal fusion and redirecting the Brucella-containing vacuole to the endoplasmic reticulum, where active replication proceeds.³

2.2 Transmission Routes

Human infection arises through three primary routes. Ingestion of unpasteurised dairy products — particularly soft cheeses, raw milk, and fermented dairy — accounts for the majority of cases in endemic settings and is the dominant route in foodborne outbreaks. Direct contact with infected animal tissues, placentas, and aborted foetal material is the key occupational route, placing farmers, veterinarians, abattoir workers, and laboratory personnel at significantly elevated risk. Inhalation of aerosolised organisms — in animal pens, slaughterhouses, or laboratory settings — is the third route and the reason Brucella is classified as a potential bioterrorism agent (Category B) by the CDC. Person-to-person transmission is rare but documented through breastfeeding, sexual contact, and blood transfusion.

3. Global Epidemiology (2015–2025)

The 2023 study by Laine et al., using three independent statistical models (weighted average interpolation, bootstrap resampling, and Bayesian inference), produced a conservative evidence-based estimate of 2.1 million annual human brucellosis cases globally — a figure that fundamentally reframes our understanding of this disease's public health footprint.¹ Prior estimates relied on passive surveillance data from the World Organisation for Animal Health (WOAH), which a parallel analysis found to be only 48.4% complete as of 2019, with approximately 47.3% of the world population represented.

Country-level data reveal striking heterogeneity. Kenya leads reported incidence rates at 203.07 cases per 100,000 population, with Yemen at 89.96 and Syria at 47.26.⁴ Greece, at 42.96 per 100,000, remains the highest-incidence country in the European Union, primarily driven by B. melitensis in small ruminant populations. In East Africa more broadly, reported human cases rose from 84,755 in 2013 to 154,096 in 2019, and in Eritrea the annual incidence climbed from 0.33 to 44.11 per 100,000 between 2014 and 2018 — a 130-fold increase in four years.⁵

In China, the NBPCP achieved a measurable reduction in reported cases from 47,139 in 2016 to 37,947 in 2018, but this progress was reversed in 2019 when cases rebounded — illustrating the fragility of control gains without sustained veterinary infrastructure.² Occupational risk cohorts across Africa and Asia demonstrate average seroprevalence of approximately 11% among livestock handlers, veterinarians, and slaughterhouse workers.⁶ These figures reflect the fundamental socioeconomic determinants of brucellosis burden: inadequate pasteurisation, proximity to animals, and limited laboratory capacity for diagnosis.

Region / Country

Annual Incidence (per 100,000)

Trend 2015–2025

Key Risk Factors

Middle East (Yemen)

89.96

↑ Rising

Livestock density, unpasteurised dairy

Middle East (Syria)

47.26

↑ Rising (conflict)

Disrupted veterinary services, raw milk

East Africa (Kenya)

203.07

↑ Sharply rising

Pastoral communities, poor sanitation

Iran

18.6

→ Stable/fluctuating

Animal husbandry; rural B. melitensis

Europe (Greece)

42.96

↓ Declining

Ongoing vaccination; improved surveillance

China

~7.0 (2019)

↓ Post-NBPCP decline

Rebounded 2019 after 2016–2018 drop

Global (pooled estimate)

~26–29

↑ Underreported

Resource-limited settings; Africa & Asia

Table 1. Regional and country-level brucellosis incidence rates and trends, 2015–2025. Data compiled from WOAH surveillance reports, Laine et al. (2023)¹, and Dong et al. (2020)⁴. NBPCP = National Brucellosis Prevention and Control Plan (China).

4. Clinical Manifestations

4.1 Acute Brucellosis

The incubation period of brucellosis ranges from one to three weeks, though periods of up to several months have been documented, complicating epidemiological linkage. The onset is typically insidious, although acute presentations do occur. The hallmark clinical feature is undulant fever — a pattern of rising and falling temperature over days to weeks, reaching 38–40°C, invariably accompanied by drenching night sweats that patients describe as characteristically malodorous. This combination of fever, night sweats, arthralgia, and malaise in a patient with any animal exposure history constitutes a clinical red flag that every medical student must internalise.

On examination, hepatomegaly is found in 45–65% of cases, splenomegaly in 20–30%, and lymphadenopathy in approximately 10–20%. The peripheral blood film shows relative lymphocytosis; pancytopenia from bone marrow involvement occurs in severe disease. Raised alkaline phosphatase and transaminases reflect granulomatous hepatitis — a finding on liver biopsy that, while not pathognomonic, strongly supports the diagnosis in the appropriate clinical context.

4.2 Focal Complications

Musculoskeletal involvement is the most frequent focal complication, occurring in 20–40% of cases. Sacroiliitis is the single most common focal manifestation, presenting with unilateral or bilateral lower back pain, positive FABER and FADIR tests, and characteristic sclerosis on MRI. Spondylodiscitis — brucella infection of the intervertebral disc and adjacent vertebrae — carries risk of epidural abscess and spinal cord compression, particularly in the lumbar spine, and typically requires prolonged antibiotic courses of twelve weeks or longer alongside orthopaedic surveillance.

Orchitis and epididymo-orchitis affect 2–20% of male patients with brucellosis and may represent the presenting complaint in endemic regions, mimicking testicular torsion or tumour. Prompt recognition avoids unnecessary orchidectomy. Neurobrucellosis, though rare (1–5%), carries significant morbidity: its clinical spectrum encompasses meningitis, meningoencephalitis, cranial nerve palsies, myelitis, and psychiatric manifestations including psychosis and personality change that can persist long after microbiological cure.³ Brucella endocarditis, affecting fewer than 2% of patients, is the most lethal manifestation, responsible for the majority of brucellosis-associated deaths, and typically requires combined surgical valve replacement with prolonged antibiotics.

System Involved

Frequency

Clinical Features

Complications

Constitutional

95–100%

Undulant fever (38–40°C), night sweats, malaise, anorexia, weight loss

Chronic fatigue syndrome-like picture

Musculoskeletal

20–40%

Sacroiliitis, spondylodiscitis, peripheral arthritis, myalgia

Vertebral osteomyelitis, epidural abscess

Hepatosplenic

45–65%

Hepatomegaly, splenomegaly, raised LFTs, granulomatous hepatitis

Liver abscess (rare)

Genitourinary

2–20% (males)

Orchitis, epididymo-orchitis, scrotal pain and swelling

Testicular atrophy, infertility

Neurobrucellosis

1–5%

Meningitis, meningoencephalitis, myelitis, psychosis

Permanent neurological deficit

Cardiovascular

<2%

Endocarditis (most lethal complication)

Valvular destruction, cardiac failure, death

Ocular

<1%

Uveitis (iridocyclitis, multifocal choroiditis)

Visual impairment

Pulmonary

1–5%

Pneumonia, pleural effusion, hilar adenopathy

Chronic pulmonary brucellosis

Table 2. Clinical spectrum of human brucellosis by organ system, with frequency estimates, key manifestations, and major complications. LFTs = liver function tests. (Adapted from Dean et al. PLoS NTD 2012⁷; MSF Medical Guidelines 2024⁸; Freire et al. PLoS NTD 2024⁹)

5. Diagnosis

5.1 Serology

Serology remains the backbone of brucellosis diagnosis in most clinical settings due to the technical demands and biosafety requirements of culture. The Rose Bengal Test (RBT) is a rapid, inexpensive card agglutination test used as a screening tool, with sensitivity approaching 95–99% in acute disease. Any RBT-positive result must be confirmed by the Standard Agglutination Test (SAT, also known as Wright's agglutination test), which quantifies antibody titres: a titre of ≥1:160 is considered diagnostically significant in symptomatic patients from endemic regions. The 2-Mercaptoethanol (2-ME) modification of the SAT distinguishes IgM (inactivated by 2-ME) from IgG, aiding in the differentiation of acute from chronic or relapsed infection.

The Enzyme-Linked Immunosorbent Assay (ELISA) for Brucella IgM and IgG offers superior sensitivity and specificity and is increasingly available in referral laboratories. Cross-reactions with Yersinia enterocolitica O:9, Francisella tularensis, and Vibrio cholerae LPS antigens are a recognised limitation of agglutination tests and must be considered in the differential. In chronic brucellosis, antibody titres may be paradoxically low or negative, and a blocking antibody phenomenon can produce false-negative SAT results.

5.2 Culture and Molecular Diagnostics

Blood culture remains the gold standard for definitive diagnosis, with sensitivity highest in the first two weeks of febrile illness when bacteraemia is most pronounced. Automated continuous-monitoring blood culture systems (BACTEC, BacT/Alert) have improved detection sensitivity; cultures typically turn positive within 3–7 days, though extended incubation up to 21 days is recommended given Brucella's fastidious growth. Bone marrow culture demonstrates 15–20% higher sensitivity than blood culture and is the preferred sample in culture-negative suspected cases. Laboratory personnel must be alerted when brucellosis is suspected, given the organism's classification as a biosafety level 3 (BSL-3) pathogen and its documented history of laboratory-acquired infections.

PCR assays targeting the bcsp31 gene, IS711 element, or omp gene have demonstrated sensitivity of 83–100% and specificity approaching 98–100% in recent meta-analyses, outperforming both serology and culture in chronic and focal disease.⁹ Real-time PCR platforms offer same-day results and are increasingly used in resource-adequate settings for rapid confirmation. A 2024 systematic review by Freire et al. confirmed PCR as the most diagnostically accurate single test across all clinical phases, supporting its integration into routine diagnostic algorithms in endemic settings.

6. Results and Contemporary Clinical Insights

Synthesising data from 2015 to 2025 across epidemiological, clinical, and therapeutic domains, several findings emerge with direct bearing on clinical and public health practice.

The most consequential finding of the decade is the recalibration of global burden. The 2.1 million annual cases estimated by Laine et al. (2023) dwarfs official WHO figures and demands a re-evaluation of brucellosis as a neglected disease.¹ This undercount stems from multiple structural factors: passive surveillance systems that only capture hospital-presenting cases, limited laboratory capacity for culture and serology in rural endemic settings, and frequent misattribution of brucellosis symptoms to malaria, typhoid, or viral hepatitis in co-endemic regions. The practical implication for clinicians is the necessity of maintaining a high index of suspicion — particularly in febrile patients with animal contact history, regardless of whether the local health system flags brucellosis as prevalent.

In terms of clinical outcomes, the decade has reinforced the disproportionate burden of spondylodiscitis and neurobrucellosis in delayed or undertreated cases. A comprehensive 2023 epidemiological review noted that in conflict-affected Middle Eastern settings, rates of focal complications including spinal brucellosis and orchitis were substantially higher than in matched non-conflict cohorts — a finding attributable to diagnostic delays averaging 6–12 weeks from symptom onset.⁵ This delay interval remains one of the most modifiable determinants of long-term morbidity.

The therapeutic landscape has not changed dramatically, but the evidence base supporting existing regimens has strengthened. Doxycycline-rifampicin for six weeks remains the WHO-endorsed first-line regimen for uncomplicated adult brucellosis, with relapse rates of 5–15% — driven predominantly by inadequate treatment duration, poor adherence, or re-exposure rather than true antibiotic resistance.¹⁰ True Brucella antibiotic resistance remains rare but has been sporadically reported for rifampicin in isolates from China and the Middle East, representing an emerging concern that warrants surveillance. The combination of doxycycline with an aminoglycoside (streptomycin or gentamicin) for the first two to three weeks demonstrates marginally lower relapse rates than doxycycline-rifampicin in some meta-analyses, and remains preferred by some guidelines for severe or high-risk cases.

The absence of a licensed human vaccine continues to represent the most critical gap in brucellosis control. Veterinary vaccines — live attenuated B. abortus S19 and RB51 for cattle, Rev-1 for small ruminants — have proven effective in reducing animal reservoir burden and secondarily human incidence in sustained national programmes. China's NBPCP experience (2016–2019) demonstrates both the potential and the limitations of this approach: initial successes were undermined by inconsistent implementation and were followed by case rebound.² For human medicine, subunit vaccine candidates targeting outer membrane proteins (Omp16, Omp19, Omp28) and LPS components are in preclinical development, but none have advanced to Phase III trials as of 2025.

Clinical Scenario

First-Line Regimen

Alternative Regimen

Duration / Notes

Uncomplicated adult brucellosis

Doxycycline 100 mg BD + Rifampicin 600–900 mg OD

Doxycycline 100 mg BD + Streptomycin 1 g IM/day (2–3 wks)

6 weeks; WHO-preferred regimen

Neurobrucellosis

Doxycycline + Rifampicin + Ceftriaxone 2 g IV OD

TMP-SMX + Rifampicin + doxycycline

≥3–6 months; high relapse risk

Spondylodiscitis

Doxycycline + Rifampicin ± aminoglycoside

TMP-SMX + Rifampicin

≥12 weeks; orthopaedic review

Brucella endocarditis

Doxycycline + Rifampicin + TMP-SMX or aminoglycoside

Individualise; cardiothoracic surgery often required

≥6 weeks post-op; lifelong in some

Paediatric brucellosis (<8 yr)

TMP-SMX + Rifampicin

Rifampicin monotherapy in mild disease

6 weeks; avoid doxycycline <8 yrs

Pregnancy

Rifampicin 900 mg OD monotherapy (1st/2nd trimester)

TMP-SMX (avoid 1st trimester and near term)

≥6 weeks; doxycycline contraindicated

Relapse prophylaxis / re-treatment

Doxycycline + Rifampicin (re-start full course)

Add aminoglycoside for 2–3 weeks

Relapse rate 5–15%; re-check serology

Table 3. Evidence-based antibiotic treatment regimens for human brucellosis across clinical scenarios, based on WHO guidelines, MSF Medical Guidelines (2024)⁸, and Medscape/CHI treatment protocols (2024)¹⁰. TMP-SMX = trimethoprim-sulfamethoxazole; BD = twice daily; OD = once daily; IM = intramuscular; IV = intravenous.

7. Conclusion

Brucellosis is a disease that rewards clinical vigilance and punishes diagnostic complacency. Its protean presentation — fever that undulates, joints that ache and migrate, an enlarged spleen in a farmer or a veterinarian — is not rare in the countries where most of the world's population lives and herds its animals. Yet it remains profoundly underdiagnosed, misattributed, and absent from the differential in settings where it should be foremost.

The decade from 2015 to 2025 has sharpened the picture in important ways. The true global burden is now understood to be closer to 2.1 million annual cases, not the 500,000 figure that guided policy for two decades. Focal complications — spondylodiscitis, neurobrucellosis, endocarditis — carry outcomes that are dramatically worse when diagnosis is delayed by weeks or months. Treatment regimens are effective but long, requiring patient education and adherence support that healthcare systems in endemic regions often cannot reliably provide. And the absence of a human vaccine means that control depends entirely on animal reservoir management, food safety policies, and clinician awareness.

As future doctors, the most powerful tool we carry is a well-calibrated clinical suspicion. A febrile patient who works with livestock, who drinks unpasteurised milk, who has returned from Yemen or Kenya or a rural region of Iran — that patient needs a Rose Bengal Test and a SAT. They need a blood culture held for three weeks. They need a clinician who knows that brucellosis is not a historical curiosity but an active, present, and frequently missed diagnosis. Closing the gap between what we know about this disease and what we do with that knowledge remains the defining challenge for the next generation of physicians.

References

1. Laine CG, Johnson VE, Scott HM, Arenas-Gamboa AM. Global Estimate of Human Brucellosis Incidence. Emerg Infect Dis. 2023;29(9):1789–1797. doi:10.3201/eid2909.230052

2. China CDC Weekly Editorial Board. Human Brucellosis: An Ongoing Global Health Challenge. China CDC Wkly. 2021;3(34):718–721. doi:10.46234/ccdcw2021.172

3. Qian J, Shen Y, Wang Y, Gao S, Ding J, Liu Z. Unraveling brucellosis: advances in pathogenesis, diagnostic strategies, therapeutic innovations, and public health perspectives. Front Microbiol. 2025;16:1586821. doi:10.3389/fmicb.2025.1586821

4. Dong Y, Wang X, Wu L. Global prevalence of human brucellosis. Chin J Endemiol. 2020;39(10):1376–1381. [PubMed PMID: 33297632]

5. Mailles A, Rautureau S, Le Horgne JM, Posse C, Vaillant V, Garin-Bastuji B, et al. Long ignored but making a comeback: a worldwide epidemiological evolution of human brucellosis. Emerg Microbes Infect. 2023;12(2):2290839. doi:10.1080/22221751.2023.2290839

6. McDermott JJ, Grace D, Zinsstag J. Economics of brucellosis impact and control in low-income countries. Rev Sci Tech Off Int Epiz. 2013;32(1):249–261. doi:10.20506/rst.32.1.2197

7. Dean AS, Crump L, Greter H, Hattendorf J, Schelling E, Zinsstag J. Clinical manifestations of human brucellosis: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2012;6(12):e1929. doi:10.1371/journal.pntd.0001929

8. Médecins Sans Frontières. Brucellosis. In: MSF Medical Guidelines [Internet]. Geneva: MSF; 2024 [cited 2025 May]. Available from: https://medicalguidelines.msf.org/en/viewport/CG/english/brucellosis-16689930.html

9. Freire ML, Machado de Assis TS, Silva SN, Cota G. Diagnosis of human brucellosis: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2024;18(3):e0012069. doi:10.1371/journal.pntd.0012069

10. CHI Formulary Development Project. Brucellosis Clinical Management Guidelines. Riyadh: CHI; January 2024. Available from: https://www.chi.gov.sa/brucellosis-indication.pdf

11. Hasanjani Roushan MR, Ebrahimpour S. Human brucellosis: An overview. Casp J Intern Med. 2015;6(1):46–47. [PMC4478362]

12. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis. 2006;6(2):91–99. doi:10.1016/S1473-3099(06)70382-6

13. Arenas-Gamboa AM, Rossetti CA, Chaki SP, Garcia-Gonzalez DG, Adams LG, Rice-Ficht AC, et al. Human brucellosis and adverse pregnancy outcomes. Curr Trop Med Rep. 2016;3(4):164–172. doi:10.1007/s40475-016-0092-0

15. World Health Organization. Brucellosis in humans and animals [Internet]. Geneva: WHO; 2006 [cited 2025 May]. Available from: https://www.who.int/publications/i/item/9241547138

15. Solera J. Update on brucellosis: therapeutic challenges. Int J Antimicrob Agents. 2010;36(Suppl 1):S18–S20. doi:10.1016/j.ijantimicag.2010.06.015