Metrics details. Bartonella bacilliformis is endemic to South American Andean valleys and is transmitted via sand flies Lutzomyia spp. Humans are the only known reservoir for this old disease and therefore no animal infection model is available. In the present review, we provide the current knowledge on B. The causative agent of this neglected disease is Bartonella bacilliformis , which is a motile, aerobic, facultative intracellular alphaproteobacterium. These two syndromes typically occur sequentially but sometimes independently.
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Bartonelosis Carrion's Disease in the pediatric population of Peru: an overview and update. Bartonellosis, or Carrion's Disease, is an endemic and reemerging disease in Peru and Ecuador.
Carrion's Disease constitutes a health problem in Peru because its epidemiology has been changing, and it is affecting new areas between the highland and the jungle. During the latest outbreaks, and previously in endemic areas, the pediatric population has been the most commonly affected. The main signs are pallor, hepatomegaly, lymphadenopathies, cardiac murmur, and jaundice. Arthralgias and weight loss have also commonly been described. The morbidity and mortality of the acute phase is variable, and it is due mainly to superimposed infections or associated respiratory, cardiovascular, neurological or gastrointestinal complications.
The eruptive phase, also known as Peruvian Wart, is characterized by eruptive nodes which commonly bleed and arthralgias. The mortality of the eruptive phase is currently extremely low. The diagnosis is still based on blood culture and direct observation of the bacilli in a blood smear. In the chronic phase, the diagnosis is based on biopsy or serologic assays. There are nationally standardized treatments for the acute phase, which consist of ciprofloxacin, and alternatively chloramphenicol plus penicillin G.
However, most of the treatments are based on evidence from reported cases. During the eruptive phase the recommended treatment is rifampin, and alternatively, azithromycin or erythromycin. Bartonellosis, or Carrion's disease, has classically been described as an exotic disease in South America. There are a few reviews about human Bartonellosis , but some publications contain incomplete information regarding treatment or historical aspects .
This article is the first review that focuses on the pediatric population. Bartonellosis has been described in Peru since the age of the pre-Columbian cultures [6,7]. The death of the Inca Huayna Capac, and of a large number of inhabitants of the Inca Empire, has been attributed to this disease. The first written report by Spanish conquerors in Ecuador dates from and the one in Peru dates from .
Carrion's Disease is the eponym in honor of the Peruvian medical student Daniel A. He died in after two self-inoculations of an aspirate of the "Peruvian Wart" of a patient, in an attempt to describe the evolution of this disease [4,10]. Traditionally, Bartonellosis has been mainly reported between and 3, meters over sea level mosl .
However, some cases have been reported at 3, mosl in Peru, and below mosl in Ecuador [12,13]. The first written report of this disease was published in in Ancash, Peru . Currently, Ancash is still the region with the highest incidence of Bartonellosis in Peru, followed by Cajamarca, Amazonas, the highland of Lima, and Cusco. Although during the necropsy of Carrion there was a report of bacilli in his blood , it was not until that the etiologic agent was accurately described in detail by Alberto Barton .
The organism that causes Bartonellosis is Bartonella bacilliformis , an aerobic, pleomorphic and monopolar, flagellated Gram-negative bacterium. It is surrounded by pili and aggregative fimbriae . It has a circular genome, estimated at 1, Kbp, in which two loci that are associated with the ability to invade erythrocytes have been identified [16,17]. Bartonella bacilliformis is characterized by being catalase, oxidase, urease and nitrate reductase negative. The members of the Bartonella genus have a fairly neutral biochemical profile, except for the production of peptidases, which varies among species .
Birtles et al. This would explain the diversity in mortality and number of people affected. Although the pathogenic factors of B. The erythrocyte membrane proteins glycophorins A and B [20,21] interact with the flagellas of the bacterium, which loosens during erythrocyte invasion . Also of importance are the following proteins secreted by the bacterium: the deformin protein, which deforms the erythrocyte surface membrane without direct contact , and the hemolysin protein, which produces a contact-dependent hemolysis .
There are 20 other members of the Bartonella genus [1,], which includes B. Bartonella henselae and B. Other members of the genus Bartonella affect animals, and their role in human disease has not been well studied [2,8,18,24,26].
The vector implicated in Bartonellosis is a female sandfly Lutzomyiae sp. Sandflies were implicated as vectors as early as , but this was not demonstrated until the Battistini experiment was done. Battistini collected L. In Peru, the main vector species is L. Lutzomyiae peruensis was the vector implicated in the outbreak that occurred in Cusco , and other species have been studied in northern Peru .
There is no known animal reservoir for Bartonellosis [1,8,18]. Bartonellosis has been described in Peru, Colombia  and Ecuador . In Peru, the epidemiology of Bartonellosis has been changing since the last decade. Recently, a new endemic area known as the upper jungle, located between the highland and the jungle, has been reported in Peru .
During the latest outbreaks of Bartonellosis in Peru, the pediatric population has been the most affected, and has had the highest mortality rate, compared to the other age groups. Indeed, it has been recently demonstrated that the Carrion's Disease outbreaks that occurred in Ancash and Cusco were related to climatic factors, mainly the ENSO . In a national case review done in Peru between and , it was found that the most commonly affected group comprised patients younger than 20 years of age .
In a prospective study done in Ancash and Cajamarca, Solano  found that the most commonly affected group comprised patients between 10 and 19 years of age, followed by the group of patients between 0 and 9 years of age. All of them were younger than 15 years old. During the first reported outbreak in Cusco in , A cohort study, with a two-year follow-up, recently done in Ancash, found that the highest incidence of Bartonellosis occurred in patients younger than 5 years of age .
Thus, age and a household contact with Bartonellosis were described as the best predictors for the disease. Of these cases, Bartonella bacilliformis produces a disease known as Carrion's Disease, with two clinically distinct phases: an acute or hematic phase, known as Oroya Fever, and an eruptive or tissue phase, known as Peruvian Wart. It was not known that the two phases were different manifestations of the same disease until the experiment done by Daniel A. Carrion in [4,14].
Any infected person can have either one or both phases, which can occur once or more than once during a lifetime [1,8]. Asymptomatic bacteremia has been described in ancient endemic areas, affecting 0.
However, in endemic areas the most common clinical presentation is the eruptive phase, which mainly affects the pediatric population [1,8]. The acute or hematic phase is characterized by fever. The activation of the alternative complement pathway, the increment of acute reactant proteins, and the increment of IgM with activation of the classic complement pathway [42,43], produces a severe hemolytic anemia, evidenced by hepatosplenomegaly, pallor, and jaundice.
Additionally, a transient cellular immunosuppression due to decrement and alteration in the number and function of T lymphocytes [,42], but without humoral immunodeficiency , predisposes the patients to superimposed infections. In a retrospective study done in Lima between and , Espinoza  described 39 patients with Bartonellosis, with a mean age of 10 years ages ranged from 2 months to 14 years.
The most common signs were hepatomegaly, lymph node enlargement, pallor, and a systolic murmur. Common signs of the acute phase were pallor, hepatomegaly, fever, cardiac murmur, jaundice, and lymphadenopathy. During the epidemic in Jaen and San Ignacio in , Rupay found cases of the acute phase The most common clinical presentations in his series were fever, malaise, headache and abdominal pain; and the most common signs were pallor, jaundice, and lymph node enlargement Table 1.
Frequently, a patient with Bartonellosis will have a complication during the evolution of the disease [1,8]. Salmonellosis sp. Non-infectious complications can also occur, and they include hyperbilirubinemia in newborns, myocarditis, pericarditis, congestive heart failure, thrombocytopenia, severe anemia, neurobartonellosis, seizures, intracranial hypertension, and multi-organ dysfunction [1,8,41].
Weight loss is especially common in children, and it can end up as severe malnutrition . Espinoza  and Rupay unpublished data found concomitant respiratory infections as the most common pediatric complication.
In a study done between and at the Childrens Hospital in Lima, Diaz et al. In the early 70's, Oliveros et al. Two of those patients died: the first one due to pneumonia and the second one due to acute renal failure. Espinoza  described 39 patients with Bartonellosis; of these, three died due to cerebral edema associated with meningeal signs or tonic-clonic seizures.
No fatal cases have been described in the eruptive phase of Bartonellosis for many decades [1,3,8,46]. During pregnancy, the acute phase of Bartonellosis produces a high mortality, both in the mother and fetus. This high mortality has been described in the offspring of pregnant women that develop the acute phase during pregnancy, even if the infection occurs in the third trimester . Furthermore, trans-placental infection has been reported in a well-studied case of a day old infant born in an endemic area , and in a one-week old premature infant whose teenage mother had Peruvian Wart .
Among three pregnant women with the eruptive phase, none of their newborns had complications . A cohort of newborns with complicated Bartonellosis was found to have a relative risk of dying of 3. When the eruptive phase follows the acute phase, it usually does so after one to two months .
The pathogenesis of the eruptive phase also has not been well studied, but it is known that B. Bartonella bacilliformis is efficiently internalized into endothelial cells by means of a GTPase Rho protein . Peruvian Wart is characterized by angioblastic hyperplasia, loss of cell-to-cell contact, formation of stress fibers with an increase in focal contacts, activation of the Langerhans cells, IgM and IgA intra-cytoplasmic deposits, C3 complement and IgM endothelial deposits, and positive factor VIII in endothelial cells, as in Kaposi's Sarcoma [43,52,53].
Commonly, the eruptive phase adopts three patterns: a miliary eruption, with multiple and widely distributed lesions 2 to 3 mm in diameter; a nodular eruption, characterized by few eruptions 8 to 10 mm in diameter; and a "mular" eruption, a unique, large, deep-seated lesion [1,4]. The eruptive phase clinically resembles Kaposi's Sarcoma or Bacillary Angiomatosis [2,54,55].
Of those, The eruptive phase has a low morbidity and there are no reports of mortality [8,11]. The most common diagnostic method is a Giemsa stain of the blood smear, where the blue-colored extra or intra-erythrocytic bacilli or coco-bacilli can be observed. However, B. Colonies are small, translucent, and do not produce hemolysis in the blood agar [1,3,11]. Rapid PCR assays were used during the Cusco outbreak, and they helped with the confirmation of the initial cases; however, there are no studies about their sensitivity or specificity [41,60].
Bartonelosis (Carrion's Disease) in the Pediatric Population of Peru: An Overview and Update
Since then, numerous outbreaks have been documented in endemic regions, and over the last two decades, outbreaks have occurred at atypical elevations, strongly suggesting that the area of endemicity is expanding. Approximately 1. Although disease manifestations vary, two disparate syndromes can occur independently or sequentially. The first, Oroya fever, occurs approximately 60 days following the bite of an infected sand fly, in which infection of nearly all erythrocytes results in an acute hemolytic anemia with attendant symptoms of fever, jaundice, and myalgia.
Carrion’s disease: more than a neglected disease
The bacterium was discovered by Peruvian microbiologist Alberto Barton in , but it was not published until Barton originally identified them as endoglobular structures, which actually were the bacteria living inside red blood cells. Until , the genus Bartonella contained only one species; there are now more than 23 identified species, all of them within family Bartonellaceae. Bartonella bacilliformis is found only in Peru , Ecuador , and Colombia and some areas of south Florida. For its isolation, special cultures are required, containing complemental soy agar , proteases , peptones , some essential amino acids , and blood.