Glanders
Glanders is a contagious, zoonotic bacterial disease caused by Burkholderia mallei, a gram-negative, nonmotile, aerobic rod that primarily infects equids such as horses, donkeys, and mules, leading to suppurative inflammation, abscess formation in the lungs, skin, and lymph nodes, with case fatality rates approaching 95% in untreated animals and 50% in humans.[1][2] The pathogen is an obligate parasite incapable of free-living survival outside hosts, transmitted through direct contact with infected nasal secretions, pus from ulcers, or contaminated fomites, and in humans via cutaneous inoculation, inhalation of aerosols, or ingestion, often manifesting as acute septicemia or chronic granulomatous lesions.[3][4] Historically recognized since antiquity—described by Aristotle around 425 BC as a wasting disease of horses—glanders has caused significant equine mortality in military campaigns and civilian herds, prompting eradication efforts through serological testing and culling that succeeded in North America and Europe by the mid-20th century, though sporadic outbreaks persist in Asia, Africa, and the Middle East due to inadequate surveillance and cross-border animal movement.[5] In humans, infections are rare but severe, with no licensed vaccine available and treatment relying on prolonged antibiotics like sulfadiazine or ceftazidime, complicated by the bacterium's intrinsic antimicrobial resistance and potential as a Category B bioterrorism agent due to its stability in aerosols and historical weaponization attempts during World War I.[6][7] Control remains challenging in endemic regions, where molecular typing reveals ongoing circulation among equids without spillover to humans in recent outbreaks.[8]Etiology and Microbiology
Causative Agent
Burkholderia mallei is the sole causative agent of glanders, classified as a Gram-negative, non-motile, aerobic bacillus within the Burkholderiaceae family.[1] As an obligate parasite, it has undergone genomic reduction and adaptation primarily to equids, including horses, donkeys, and mules, enabling efficient intracellular survival and zoonotic spillover to humans through close contact.[9][10] The bacterium's genome consists of two circular chromosomes totaling about 5.8 million base pairs, with no plasmids, fostering high genetic stability that limits rapid evolution and supports consistent virulence across strains.[11][12] Key features enabling persistence include type VI secretion systems for host cell invasion and efflux pumps that confer resistance to multiple antibiotics, allowing chronic infections and carrier states in mammalian hosts.[1] B. mallei is designated a Category B select agent by the CDC, reflecting its environmental durability in certain conditions, resistance to select disinfectants, and potential for weaponization due to these traits.[13][14]Pathogenic Mechanisms
Burkholderia mallei, the causative agent of glanders, invades host tissues primarily through adherence to epithelial cells mediated by type IV pili, such as PilA, and autotransporter adhesins like BpaC, which facilitate initial attachment at mucosal surfaces or skin abrasions.[15][16] Following adhesion, the bacterium employs its type III secretion system (T3SS) effectors, including BipC, to promote phagosomal escape within macrophages, enabling intracellular replication and evasion of lysosomal degradation.[17] The capsular polysaccharide (CPS) further contributes to anti-phagocytic activity by modulating complement deposition and protecting against innate immune clearance, promoting persistence and the formation of suppurative abscesses and granulomatous lesions through chronic inflammation and necrosis. Intracellular survival is bolstered by type VI secretion system (T6SS) components, such as Hcp1 and VgrG5, which facilitate multinucleated giant cell formation and intercellular spread via actin polymerization, allowing dissemination from primary infection sites.[18] Siderophore-mediated iron acquisition systems enhance nutrient uptake in iron-limited host environments, supporting bacterial proliferation and virulence during systemic spread. Secreted effectors from T3SS and T6SS, functioning analogously to exotoxins, disrupt host signaling pathways, including ubiquitination and cytoskeleton rearrangement, via proteins like BMAA0728 and BMAA1865, leading to endothelial cell damage and thrombi formation that exacerbate tissue destruction.[19] These mechanisms culminate in bacteremia, with dissemination to lymph nodes, lungs, and spleen, precipitating septicemia and multi-organ failure; in acute human septicemic cases, untreated mortality reaches 95%, attributable to overwhelming bacterial replication and host inflammatory collapse.[1] Empirical studies in murine models confirm that disruptions in these virulence pathways, such as T3SS or novel host-interacting proteins, significantly attenuate lethality, underscoring their causal role in pathogenesis.[19]Clinical Manifestations
In Equids
In equids, including horses, donkeys, and mules, glanders typically presents in nasal, pulmonary, or cutaneous (farcy) forms, which may occur simultaneously depending on the site of initial infection and the host's immune response. The nasal form features inflammatory nodules and ulcers in the nasal mucosa and septum, accompanied by serous to mucopurulent, yellowish-green discharge, epistaxis, and respiratory distress.[20] [21] Pulmonary involvement manifests as pyrexia, cough, dyspnea, and multifocal nodular lesions in the lungs, often leading to emaciation and exercise intolerance.[22] [10] The cutaneous form, or farcy, is predominantly chronic and characterized by lymphangitis, with firm, chain-like nodules progressing to suppurative ulcers along lymphatic channels, especially in the extremities and ventral abdomen; these lesions may rupture and form stellate scars.[23] [24] In horses, glanders generally follows a subacute to chronic course with intermittent fever and vague signs, whereas donkeys and mules more frequently exhibit acute, rapidly fatal septicemia with high fever, anorexia, and widespread dissemination.[20] [23] Latent carriers, particularly in chronic equine cases, can shed Burkholderia mallei intermittently without overt symptoms.[23] Untreated acute glanders in equids carries fatality rates of 90–95% or higher, especially in pulmonary or septicemic presentations, with death often occurring within weeks due to overwhelming bacterial dissemination.[23] In endemic regions like Brazil, where glanders persists despite control efforts, veterinary outbreaks exhibit high morbidity, with annual case reports across multiple states prompting mandatory culling, prolonged quarantines, and depopulation of affected herds.[25] [26] These events inflict severe economic losses on equine-dependent sectors, including working animal industries, through direct animal losses, restricted international trade, and diminished productivity in agriculture and transport.[27] [28] In communities reliant on draft equids, such as brick kilns in parts of Asia, outbreaks exacerbate poverty by halving seasonal earnings from affected animals and necessitating costly replacements.[29]In Humans
Glanders primarily affects humans through zoonotic transmission from infected equids, posing an occupational hazard to veterinarians, horse trainers, farriers, and laboratory workers handling Burkholderia mallei-contaminated materials.[5] [30] Exposure occurs via cutaneous abrasions, inhalation of aerosols, or mucosal contact with infected secretions, leading to localized or disseminated infection.[1] Human cases are exceedingly rare, with fewer than 20 laboratory-confirmed incidents reported globally since 2000, underscoring the disease's low incidence despite its potential severity.[5] Cutaneous glanders manifests as painful nodules or ulcers at the exposure site, often accompanied by regional lymphadenopathy and lymphangitis, progressing to abscess formation if untreated.[31] Systemic forms involve pneumonic symptoms such as fever exceeding 39°C (102°F), chills, cough, chest pain, and shortness of breath, or septicemic dissemination with myalgias, headache, and multi-organ abscesses.[5] [1] The acute incubation period ranges from 1 to 14 days post-exposure, correlating with high bacterial inoculum, whereas chronic presentations may emerge after weeks to months, featuring intermittent fever, weight loss, and recurrent cutaneous lesions.[32] [14] A recent case in 2024 involved a 73-year-old male from northeastern Brazil hospitalized with fever, respiratory distress, and systemic symptoms attributable to B. mallei infection, highlighting ongoing risks in regions with enzootic equine glanders.[6] [33] While clinical features overlap with melioidosis—caused by the environmentally acquired Burkholderia pseudomallei—glanders lacks a free-living reservoir and is confined to direct equine-to-human jumps, with human-to-human spread undocumented outside rare autopsy or procedural contexts.[1] [34] Untreated mortality approaches 95% in septicemic cases, emphasizing the pathogen's virulence in susceptible hosts.[1]Acute vs. Chronic Forms
The acute form of glanders manifests with rapid progression following high-dose exposure or inhalation of Burkholderia mallei, leading to systemic dissemination, high fever exceeding 40°C, severe sepsis, and nodular abscesses in the lungs and viscera, often culminating in death within 7–10 days in untreated cases.[1] [9] This fulminant course correlates with overwhelming bacterial loads that evade initial host defenses, as lower immunity or intense aerosol challenge bypasses localized containment, driving unchecked replication and toxemia.[23] In contrast, the chronic form arises from partial host resistance or lower exposure doses, resulting in protracted infection with intermittent abscess formation in subcutaneous tissues, lymph nodes, and mucosal surfaces, alongside periods of latency where clinical signs remit.[23] [9] Such dynamics foster asymptomatic carrier states, particularly in equids like horses, where bacteria persist intracellularly in macrophages, enabling sporadic shedding via nasal discharge or pus without overt illness, thus sustaining environmental reservoirs and facilitating undetected zoonotic or lateral transmission.[35] Historical outbreaks, such as those in Asia during the early 2000s, demonstrated chronic persistence in up to 50% of surviving equids, underscoring how immune-mediated containment prolongs infectivity over months to years.[10]| Aspect | Acute Form | Chronic Form |
|---|---|---|
| Incubation Period | 1–14 days[14] | Up to 12 weeks, with latency periods[14] |
| Primary Drivers | High exposure dose, inhalation route, low host immunity[23] | Moderate dose, partial immunity allowing bacterial dormancy[23] |
| Key Pathology | Rapid sepsis, pulmonary nodules, high mortality (>95% untreated)[1] | Recurrent abscesses, carrier state, intermittent dissemination[9] |
| Epidemiologic Role | Explosive outbreaks but self-limiting in hosts[21] | Perpetual reservoirs via subclinical shedding, evading detection[35] |