Bartonellosis

Introduction

Bartonella bacilliformis was described more than 100 years ago as the cause of Carrión disease (CD) but it remained a medical curiosity until the description of bacillary angiomatosis (BA) in the late 1980s. The genus Bartonella has received great attention since, and research on the matter has flourished. This is a group of bacteria that are selective mammalian pathogens requiring specific vectors to be transmitted. Some bacteria in this group are capable of stimulating endothelial cells in vitro and inducing angiogenesis in vivo; in Carrión disease the mechanisms include stimulation of production of vascular endothelial growth factor (VEGF), its receptors VEGFR-1 and VEGFR-2, and angiopoetin-2. Except for VEGF, which is produced by epidermal cells, all other factors are produced by the proliferating endothelium, revealing a close interaction among those two cell populations.

B. bacilliformis is known to induce immunosuppression in cases of CD by lowering the number of T-helper lymphocytes. Both B. bacilliformis and B. henselae are capable of entering red blood cells by the action of specific proteins called deformins, causing hemolytic disease in human and cats. Different species of Bartonella have different mammalian reservoirs: B. bacilliformis and B. quintana have a predilection for humans, whereas B. henselae and B. clarridgeae seems to prefer felines. The preferences of B. bacilliformis for humans and B. henselae for cats may be explained on the basis of red-blood-cell receptor differences as well as the characteristic motility of B. bacilliformis .

History

The first condition linked to this bacterium was Carrión disease. Caused by B. bacilliformis , it has two remarkable different clinical phases: one of systemic involvement characterized by fever, septicemia, and anemia, also known as Oroya fever (OF), and later an eruptive phase of angiomatous papular and nodular skin lesions, known as verruga peruana (VP). Although the reported cases were restricted to small endemic areas of Peru and Ecuador, the condition was briefly mentioned in major textbooks of medicine.

The history of VP goes back hundreds of years. Pottery from pre-Inca cultures such as the Huaylas shows human faces with papular lesions that could be interpreted as those of the eruptive phase of VP.

In colonial times (sixteenth and seventeenth centuries) a chronicle described an epidemic outbreak of bleeding, oozing, and exophytic lesions affecting the face and body of Spanish troops belonging to Francisco Pizarro (the conqueror of Peru), in the area of Coaque, Ecuador.

By the 1870s, nothing was known about the relation between the eruptive angiomatous lesions known as VP and a systemic disease, with extremely high mortality, affecting a group of workers on the trans-Andean railroad in the central Sierra. The disease was named Oroya fever, after the location where most cases were detected.

By 1872 the possibility that OF and VP were parts of the same unique process was raised. That current of opinion led to the experiments conducted by Daniel Alcides Carrión.

Carrión was a medical student, born in 1857, who developed a great interest in VP and OF. On 17 August 1885, in a self-promoted experiment that took his scientific curiosity to an extreme, and lacking complete awareness of the risk involved, he was inoculated with material from verruga. He was expecting to develop just the anemia, not the febrile illness. Unfortunately, the disease went on to its most severe state: first fever, then severe anemia, to finally provoke his death on 5 October 1885, at the age of 28. Carrión's experiment, at the expense of his own life, proved that both clinical manifestations were truly part of a unique process, as well as establishing that the disease could be transmissible by the infectious material.

In 1909 Alberto Barton, a Peruvian doctor working at the Guadalupe Hospital of Callao, discovered the presence of what he called “X bodies” inside the red blood cells of patients affected by OF; this is considered the first description of the etiologic agent and hereafter the bacteria was called Bartonella .

Bartonella became a medical curiosity, although interesting research continued to be done on a minor scale in Peru, the USA, UK, and France.

Before the 1980s the etiology of cat-scratch disease (CSD) was unknown. After an original publication implicating a new bacterial agent, Afipia felis , in the etiology of CSD, later reports failed to confirmed that observation; however, there was agreement on the bacterial origin of the disease, and also its capability of being stained with silver techniques. Those were the arguments used by LeBoit and colleagues to establish the link between CSD and a disease described by Stoler in New York, in 1984, affecting AIDS patients. Once the microorganism causing such disease, by then denominated bacillary angiomatosis, was isolated, it was initially described as being part of a new genus named Rochalima ; further genetic analysis allowed scientists to unify concepts and reclassify it as a member of the already existent Bartonella genus.

Microbiology

The Bartonella family is best classified as belonging to the α ₂ subgroup of bacteria, in the Protobacteriae class, that also includes closely related microorganisms such as Brucella, Agrobacterium, Afipia, and Rickettsia .

The Bartonella spp. are mammalian intracellular pathogens that require a vector for their transmission. The family had only one element, Bartonella bacilliformis , up until 1993. By then, DNA–DNA hybridization data and comparisons of existing 16S rRNA gene sequences gave sufficient evidence for merging the Rochalima genus with Bartonella . Similar studies led to the incorporation of Grahamella species into the same genus in 1995.

The prototype bacterium is B. bacilliformis , and currently the family includes 31 validated species ( http://www.bacterio.net/index.html ), some of which are known to cause disease in humans: B. bacilliformis, B. quintana, B. henselae, B. elizabethae, B. clarridgeiae, B. vinsonii, B. rochalimae , and B. khoelerae ( Table 25-1 ). Multilocus sequence typing puts B. clarridgeiae and B. rochalimae as the species with the closest relation to B. bacilliformis , followed by B. henselae and B Quintana . Afipia felis , a putative agent causing CSD, is in fact closer to Rickettsia than to Bartonella . The close relation with other bacteria such as Agrobacterium tumefaciens becomes more intriguing if one takes into consideration that this last organism is capable of inducing tissue proliferation in infected plants, similar to that seen in VP and BA.

The members of this family can be described as Gram-negative, oxidase-negative, fastidious, aerobic rods. Although they are intracellular microorganisms in vivo, they are not obligate intracellular pathogens, which is another difference from the Rickettsia family. B. bacilliformis has a unique polar flagellum adapted for motility.

The organisms are difficult to grow. They require blood agar media, and temperature and CO ₂ requirements vary depending on the species. Growth is optimal at 37°C, with the exception of B. bacilliformis , which requires lower temperatures of 25–28°C. B. bacilliformis is also unique because it grows better without CO ₂ supplements. The primary isolates are obtained after a period of 12–14 days, but this may extend up to 45 days. First subcultures are also difficult, with colony formation taking 10–15 days. Repeated subcultures may take only 3–5 days, but with subsequent variations in morphology.