Carrion's Disease: the Sound of Silence

Abstract

Carrion's disease (CD) is a neglected biphasic vector-borne illness related to Bartonella bacilliformis. It is found in the Andean valleys and is transmitted mainly by members of the Lutzomyia genus but also by blood transfusions and from mother to child. The acute phase, Oroya fever, presents severe anemia and fever. The lethality is high in the absence of adequate treatment, despite the organism being susceptible to most antibiotics. Partial immunity is developed after infection by B. bacilliformis, resulting in high numbers of asymptomatic carriers. Following infection there is the chronic phase, Peruvian warts, involving abnormal proliferation of the endothelial cells. Despite potentially being eradicable, CD has been expanded due to human migration and geographical expansion of the vector. Moreover, in vitro studies have demonstrated the risk of the development of antimicrobial resistance. These findings, together with the description of new Bartonella species producing CD-like infections, the presence of undescribed potential vectors in new areas, the lack of adequate diagnostic tools and knowledge of the immunology and bacterial pathogenesis of CD, and poor international visibility, have led to the risk of increasing the potential expansion of resistant strains which will challenge current treatment schemes as well as the possible appearance of CD in areas where it is not endemic.

Keywords: Bartonella bacilliformis; Carrion's disease; Oroya fever; Peruvian warts.

FIG 1

Chronology of Carrion's disease. (A) From the pre-Columbian period to Carrion's death (1885). (B) From 1885 onwards. Historic events (blue) and scientific milestones (green) are shown above the timeline bar, while relevant achievements in the knowledge and understanding of Carrion's diseases are shown below the bar.

FIG 2

Maps of areas of endemicity. (A) Geography of Peru. (Reprinted from https://es.wikipedia.org/wiki/Archivo:Mapa_fisico_Peru_fondo_transparente.png [published under a Creative Commons license].) (B) Administrative divisions of Peru. (Adapted from http://d-maps.com/m/america/perou/perou22.pdf.) (C) Administrative divisions of Ecuador. (Adapted from http://d-maps.com/m/america/equateur/equateur22.pdf.) The coast, mountain, and jungle cover 11.7, 27.9, and 60.3% of the Peruvian territory, respectively. Peru is the country most affected by Carrion's disease. In the period from January 2004 to May 2017, only the departments of Arequipa, Moquegua, and Tacna did not report Carrion's disease cases; in addition, in Pasco there was only 1 possible case reported. It is necessary to mention that in some departments, such as Tumbes, the number of reported cases was minimal, while in others, such as Callao, the cases were probably imported or reported as a result of patient movement. Regarding cases in Ecuador, the most recent cases have been described in the Peru-bordering province of Zamora-Chinchipe (bordering San Ignacio, one of the most relevant Peruvian areas of endemicity), as well in Guayas and Manabi (both of which are non-Andean areas). In Colombia during the last decades, only sporadic cases have been reported (9).

FIG 3

Essential data on Carrion's disease (2002 to 2016). (A) Number of Carrion's disease cases in Peru between 2002 and 2016. In this period, the maximum peak was of 11,130 cases reached in 2004. (B) Comparison of annual incidence rates (×100,000 inhabitants) of Carrion's disease, malaria, and dengue in Peru. (C) Comparison of Carrion's disease, malaria, and dengue lethality in Peru. The annual lethality index (LI) was established as LI = number of deaths/total cases. No data for cases of or deaths from malaria and dengue were available in 2002. From the early years of the 21st century years onwards, the number of cases and incidence of Carrion's disease showed a trend to a decrease in Peru. In 2016, the annual incidence rate of Carrion's disease cases was around 50 times lower than that of dengue and >70 times lower than that of malaria. Nonetheless, in the period from 2003 to 2016, the lethality index of Carrion's disease (LI = 0.487) was even greater than those of malaria (LI = 0.008; P < 0.0001) and dengue (LI = 0.095; P < 0.0001). During all of the period analyzed, cases of Peruvian warts represented around 30% of the overall Carrion's disease cases, while only 1 death related to this illness phase was reported. Thus, the specific lethality levels of Oroya fever are even greater, reaching 3.18% in 2010. The graphs were constructed using data from the Boletín Epidemiológico de Peru (http://www.dge.gob.pe/portal/index.php?option=com_content&view=article&id=347&Itemid=249).

FIG 4

Bartonella bacilliformis culture presenting the T1 morphology. (Reprinted from reference [published under a Creative Commons license].)

FIG 5

Deformation of erythrocytes as seen by scanning electron microscopy. (Adapted from reference .)

FIG 6

Model of the course of acute Bartonella infection. (1) In infections by B. bacilliformis primary niche remains controversial; in other Bartonella species, it is considered to include the vascular endothelium as a major constituent. From the hypothetical primary niche, Bartonella is released into the bloodstream, in which it may reinfect the primary niche (if it exists) again. (2) Binding to erythrocytes. (3) Invasion of erythrocytes. (4) Replication. (5) Finally, the infection leads to hemolytic anemia or the organisms persist in a nonreplicative intraerythrocytic state. (Adapted from reference with permission of Macmillan Publishers Ltd.)

FIG 7

Model of Bartonella-triggered vascular tumor formation. PML, polymorphonuclear leukocyte; NF-κB, nuclear factor κB; HIF-1, hypoxia-inducible factor 1; VEGF, vascular endothelial growth factor. The adhesion to and invasion of endothelial cells by Bartonella lead to apoptosis inhibition and direct endothelial cell proliferation. In parallel, Bartonella triggers an NF-κB-dependent proinflammatory phenotype resulting in the recruitment of macrophages and other lymphocytes, which may also be colonized. This colonization results in the activation of HIF-1, therefore upregulating VGEF, which also stimulates endothelial cell proliferation. All these phenomena are thought to mediate vascular tumor formation. (Adapted from reference with permission of Macmillan Publishers Ltd.)

FIG 8

Suspected and confirmed Carrion's disease vectors. (A) Carrion's disease vector classification following the 1965 scheme of Theodor (209). (B) Carrion's disease vector classification following the 2014 scheme of Galati (212). Incertae sedis are not included. Confirmed Carrion's disease vectors are in red. *, among groups and subgenera.