Etiology
Human bartonellosis is caused by Bartonella species, which are facultative intracellular bacteria, class Protobacteria, family Bartonellaceae. They are gram-negative, oxidase-negative, fastidious, non-carbohydrate fermenting, aerobic rods. The genus consists of 45 species, most of which have an animal reservoir, exceptions being B bacilliformis and B quintana.[3][5][10]
Cat-scratch disease is a zoonotic infection caused by B henselae. Humans acquire infections from the natural reservoir, which is cats, commonly through a cat scratch or bite, and less commonly via the cat flea (Ctenocephalides felis). Contact with cats has been reported in 87% to 99% of patients, and >50% of patients have had a definite history of a cat scratch or bite.[24] The risk increased if the cat was ≤12 months old and had fleas.[24] Seasonal breeding of domestic cats and close proximity to family pets most likely contribute to the disease occurring mainly between September and March in temperate zones.[4] Polymerase chain reaction studies have demonstrated DNA of Bartonella species in ticks and some believe that B henselae is transmissible by the Ixodes scapularis tick. After review, experts have concluded that transmission of any Bartonella species by ticks does not occur to animals or humans.[25]
B quintana is the causative agent of trench fever. Its only known natural reservoir is humans. It is transmitted from human to human by the human body louse (Pediculus humanus humanus) to a new host 5 to 6 days after feeding on an infected person. Infected lice excrete the organism for life.[26][27] There is an independent correlation between homelessness, poor living conditions, and alcohol misuse with B quintana infections.
B bacilliformis causes Carrion disease (Oroya fever and verruga peruana). Humans are its natural reservoir. It is transmitted by the female sand fly (Lutzomyia verrucarum).
Although Bartonella infections do occur in immunocompetent individuals, they can become systemic, chronic, and increasingly life threatening in immunocompromised patients, such as those with AIDS, alcohol-use disorder, other compromising health problems, or those on immunosuppressive medication.[4]
Other species of Bartonella reported to cause human infections include, but are not limited to, B elizabethae, B clarridgeae, B vinsonii, B koehlerae, B grahamii, B alsatica, B rochalimae, and B washoensis.[5][6][7][8][9][10][11]
Four genotypes of B vinsonii subsp. berkhoffii have been identified. To date, genotype II has been the most frequently isolated from human blood samples. Primary reservoirs are dogs, wild canines such as foxes and coyotes, and wild felids. Rats have been reported as possible reservoirs in Thailand.[13] Various arthropods that may transmit B vinsonii include biting flies, fleas, keds, lice, and sandflies.[13]
Pathophysiology
Infection with Bartonella species causes prolonged intraerythrocytic bacteremia in the natural reservoir host. Transmission to humans from a bacteremic host occurs as a result of a direct bite or scratch by the infected animal (e.g., cat-scratch disease) or via blood-sucking insect vectors (e.g., Carrion disease and trench fever).[28]
Following inoculation, Bartonella is believed to initially infect the CD34+ human progenitor cells and then invade the red blood cells.[29][30] The bacteria become associated with and then enter the mature erythrocytes. They replicate up to 8 bacteria per cell and persist within erythrocytes for the cell's lifetime.
Bartonella also invades vascular endothelial cells, which were previously believed to be the primary niche of the bacteria. In vitro studies have shown that invasion of vascular endothelium by Bartonella causes peri- and intracellular parasitism, cytoskeletal rearrangement, cell proliferation, bacterial multiplication, apoptosis inhibition, and signal transduction pathway activation. These cascades of events result in systemic inflammatory response and angioproliferative lesions. The latter results in the formation of new capillaries. The bacteria are also seeded directly into the blood stream from infected endothelia.[30]
In immunocompetent hosts, bacterial invasion leads to lymphoid hyperplasia, arteriolar proliferation, and arterial widening, which result in the formation of necrotizing granulomas. The transcription nuclear factor NF-kappa B is believed to be the primary regulator of the proinflammatory response that leads to polymorphonuclear cell adhesion to the infected endothelial cells. IL-8 secretion by endothelial cells adds by stimulating transendothelial migration of the polymorphonuclear cells. Thrombin-activated endothelial cells produce monocyte chemoattractant protein-1 (MCP-1), which in turn helps in recruiting monocytes and macrophages, initiating chronic inflammatory changes and granuloma formation. Infection of these macrophages by Bartonella leads to the secretion of high levels of proinflammatory cytokines including tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6. All these events lead to the formation of granulomatous and suppurative lesions in immunocompetent hosts.[28][31]
Immunocompromised hosts, on the other hand, develop angiogenic skin lesions characteristic of bacillary angiomatosis. These lesions are a result of vasoproliferative changes secondary to Bartonella infection. The mechanism of this vasoproliferation may be a direct triggering effect of Bartonella infection leading to angiogenesis and inhibiting apoptosis of endothelial cells. Another potential mechanism is the indirect stimulation of cytokines, such as vascular endothelial growth factor, a potent inducer of angiogenesis, and IL-1beta, a vascular endothelial growth factor potentiator.[28][31]
Classification
Clinical syndromes
Cat-scratch disease
A systemic infection caused by B henselae, characterized by chronic lymphadenopathy.[4][5]
Also causes culture-negative endocarditis, prolonged fever of unknown origin, hepatosplenic disease, or ocular infection.
Bacillary angiomatosis is a vascular proliferative manifestation of Bartonella infections (B henselae and B quintana) that occurs in immunocompromised individuals, predominantly in people with HIV.[4][5] It is characterized by unique vascular lesions that involve mostly the skin, but can also affect other organs, such as the respiratory tract, gastrointestinal tract, bone, lymph nodes, and brain.
Trench fever
A vector-borne systemic infection caused by B quintana and transmitted by the body louse (Pediculus humanus humanus).[4][5]
Also known as 5-day fever, quintana fever, shinbone fever, shank fever, His-Werner disease, Wolhynian fever.
May also present as culture-negative endocarditis, especially in urban homeless people. Immunocompromised patients may also present with bacillary angiomatosis.
Carrion disease
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