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The following essay by Dr. John S. Marr, MD, was posted 26 July 2000
Bartonellosis Introduction. Bartonellosis, until recently, was an unambiguous term denoting an acute, often fatal human disease characterized by high fevers and progressive anemia with a case-fatality rate of from 10 to 90% (1). The disease, caused by a specific bacterium, Bartonella bacilliformis, is also known as Oroya fever, Guáitira Fever, Verruga peruana and Carrión’s disease. These names for the same illness names arise from two epidemic sites (Oroya, Peru, Guáitira, Colombia); the warty-like growths noted in the subacute phase (verruga = L, wart); and the medical martyr to the disease, Daniel Alcides Carrión, who died of the disease in 1885 (2,3). Bartonellosis is considered a unique disease of humans, transmitted from human to human by the bite of a vector, a blood-sucking insect, a sand fly. Invertebrate and vertebrate reservoir hosts have not been demonstrated. Bartonellosis was once thought to be found exclusively in certain locales between 2,000 and 9,200 feet in the Andes Mountains of Peru, Ecuador and Colombia. However (vide infra), recent outbreaks have now documented a more extensive distribution by longitude, latitude and altitude. Taxonomic history. The genus Bartonella
(1913), is named after the Peruvian bacteriologist, Alberto Barton, who in 1909,
noted organisms in red blood cells (RBC’s) of patients suffering from Oroya
fever. Although he thought the agent was a protozoan, later species designation,
B. bacilliformis, confirmed a bacterium as the cause. With proper
staining (Gram ) the organism is seen as Gram negative bacillary organism
measuring 2 X 0.5mm; with a Giemsa stain its morphologic appearance is that of
both rods and in chains of rods; under electron microscopy the bacteria can be
shown to possess flagella. New Bartonella species have been discovered
which infect a variety of warm blooded (dogs, rodents) and cold blooded
(reptiles, amphibians) vertebrates. Other established human diseases, once
previously classified as the cause of cat scratch disease and bacillary
angiomatosis (BA), and trench fever (B quitana), are now Rochalimea and
Afipia (4). Prior to these new findings and taxanomic reclassifications, B.
bacilliformis was considered an "orphan" species within the genus.
In this paper, unless otherwise noted, the term Bartonellosis refers to
the infection caused by B. bacilliformis. Oroya fever. After the bite of an infected sand fly acute disease usually occurs after 16 to 22 days, although the incubation period may be as long as 3-4 months (6). Acute disease is characterized by fever, headache, musculoskeletal pain, and enlargement of lymph nodes. A progressive anemia develops due to the attachment by B. bacilliformis organisms and their destruction of up to 90% of RBC’s. Secondary superinfections due protozoan and Salmonella are common. Recovery may be complete, but may lead to a carrier state, or development of Verruga peruana. Verruga peruana. This chronic manifestation of bartonellosis may be preceded by Oroya fever or develop without previous acute illness. Prior to the onset of dermatological lesions, victims may experience irregular bouts of musculoskeletal pain. When skin lesions develop they can be either a multiple, discrete reddish lesions 0.2 cm in diameter; this "miliary" eruption appears primarily on the face and extremities. Larger, cherry-pink grape-like nodules (0.3-1cm) may also develop within the mouth, esophagus, and linings of the gastrointestinal tract, urinary bladder, uterus and vagina; these lesions may lead to internal bleeding. The largest nodular lesions (4cm) develop on the knees and elbows, and may be the size of pigeon-eggs; they are highly vascularized and may rupture, bleed or ulcerate, or eventually become detumescent and sluff off without scaring (6). Another stage, neurobartonellosis, is recognized during the acute stage, and is due to invasion of central nervous system (CNS) by the bacteria that cause meningoencephalitis leading to seizures, spastic and flaccid paralysis and death (7). Reservoir and carrier state. Scott states that the main reservoir of bartonellosis is asymptomatic cases, stating that in "Verruga zones" up to 10-15% of otherwise well individuals have positive blood cultures for this organsim, and that nodules of recovering victims may be the source of continuing transmission by sand flies (5). Weinman stated that 5-10% of individuals living in endemic zones have these bacteria in their circulating blood (8). Geographic distribution. Since its discovery in 1909 standard textbooks on infectious diseases have varied as to the geographic expanse of the disease. Earliest references believed the disease was restricted to Peru. Later citations defined the limits as between the 9th and 16th parallels of southern latitude -- which would include southern Colombia, Ecuador, Peru, Bolivia and northern Chile (9). (However, the most recent edition of Manson omits the latter two countries (5)) In 1951 an even more restrictive latitude was suggested by Groot as being between 2 N and 13 S -- corresponding to southern Colombia, Ecuador and the northern half of Peru, and excluding Bolivia and Chile. (10). Similarly, most texts define a restrictive altitude range corresponding to narrow valleys (quebradas) in the western slopes of the Andes between 500 and 3,000 meters. However, Alexander has recently expanded the disease distribution by both latitude and altitude, stating, "...it appears that the information that appears in most texts regarding bartonellosis is oversimplified. The disease is not restricted to elevations greater than 800 meters and occurs in areas where Lu. verrucarum [the sand fly vector] is absent." (11). He cites Rebagliati’s report of cases from Esquina de Asia (200 m), and Huasta (3,375 m) as the lower and upper altitudinal extremes, respectively. New and Old World sand fly vectors of diseases.
As stated above, bartonellosis is a unique sand fly-borne disease exclusive to
the New World. The following summary of sand fly-borne diseases separates New
and Old World diseases and addresses the potentially confusing numerous
cutaneous New World disease eponymns transmitted by sand flies. Old World
(family Psychodidae, genus Phlebotimae) sand flies transmit
various diseases in Europe, Asia, and Africa, including sand fly fever (family Bunyaviridae);
cutaneous leishmaniasis (Leishmania tropica) the cause of Oriental sore,
Bagdad boil, bouton d’Orient, Delhi boil, bouton de Biskra, Aleppo boil, Salek,
Pendeh sore; and Old World visceral leishmaniasis (L. donovani) the cause
of kala-azar, black sickness, Sirkari disease, Sahib’s diseases, Burdwan
fever, Dum Dum fever; Pono, and Mard el Bicha. New World sand flies (Lutzomyia
and Brumptomyia) transmit various diseases in North, Central and South
America and the Caribbean Islands, including cutaneous leishmanisis (L.
mexicana), the cause of chicerlos ulcer; mucocutaneous leishmaniasis (L.
brasilienesis) cause espundia, bubas Braziliana, uta, pian bois, forest
yaws, and Bosch yaws; the New World counterpart to Old World visceral
leishmaniasis ( L. donovani) is L. chagasi. New World sand fly vectors of diseases. Sand fly fever (vide supra) does not occur in the New World. The various cutaneous, mucocutaneous and visceral forms of leishmaniasis do occur in Central and South America, transmitted by multiple species of sand flies. In 1963 over 230 species within the genera Lutzomyia and Brumptomyia were summarized by Theodor (12) More recently, numerous additional species have been discovered, primarily in the pursuit of new vectors of leismaniasis, although some new vector species for bartonellosis have been suggested (13-15). New World sand fly vectors of bartonellosis. In 1913 Townsend suggested that Phlebotomus verrucarum was the vector of bartonellosis (16). In 1929 Noguchi et al. proposed that a new species, P. noguchii, was the primary vector, noting that P. verrucarum may also be contributory, and dismissed P. peruensis as a vector (17). However, subsequent research confirmed Lu. verrucarrum (formerly P. verrucarum) as the primary vector in Peru (18). Alexander (and others) maintain that additional unknown species must exist since bartonellosis occurs in areas of Peru, Ecuador and Colombia where Lu. verrucarum does not exist (11). Lu. bicornutus was identified as a vector of an epidemic the Mantaro valley, above 2600 m, in the absense of Lu. verrucarum (18). Lu. colombianus was incriminated in an outbreak in Southwestern Colombia. Vector bionomics. Sand fly bionomics have been summarized by Herms (19). Its life cycle consist of four stages (egg, larva, pupa, adult) with an egg-to-egg cycle of seven to ten weeks. Breeding places vary widely depending on genus and species, and include underneath stones, in masonry cracks, beneath leaves, in animal burrows, and under natural and man-made structures (tree stumps, buildings, etc) -- all of which provide darkness, humidity and organic matter for larvae to develop (20). Microenvironment for egg and larva development require 100% humidity. Adults measure 1.5-4 mm and are considered weak fliers. Feeding activity is restricted to dusk, at night and dawn, presumably due to less wind currents. Only adult females take blood meals from a variety of warm and cold-blooded animals. Frequency of re-feeding habits of females determines, in part, likelihood of disease transmission. Pre-contact paleopathologic evidence of bartonellosis. A male mummy estimated to be 19-20 years of age was removed from a typical Tiahuanaco burial gallery discovered in 1960 in southern Peru (Huari culture, 600-1000 AD) (21). An autopsy was performed which revealed numerous nodules varying in size from a pinhead to pea-size in diameter over the back, arms and hands. Tissue from a hand was re-hydrated and a series of lesions were visualized consisting of vesicles and "pendulous tumor-like" lesions, areas of healing, as well as acute excoriations. Tissue sections were stained (Gram, Giemsa) and revealed bacterial clusters of within the skin lesions as well as blood vessels within the same skin lesions. Scanning electron microscopic examination of the bacteria in blood vessels revealed organisms with single polar flagella. The authors concluded that the man had Verruga peruana. Pre-contact archeological evidence of bartonellosis. Allison et al. also noted that others, interpreting pre-Columbian ceramic vases, have suggested earliest evidence for the disease as long ago as 2,000 years (21-22). Contact evidence of bartonellosis. In 1847 Prescott, citing Naharro and Garcilasso, summarized Pizzaro’s encounter with a new affliction during his march along the Ecuadorian coast towards Puerto Viejo : "To add to their distresses, a strange epidemic broke out in the little army. It took the form of ulcers, or rather hideous warts of great size, which covered the body, and when lanced, as was the case with some, discharged such a quantity of blood, as proved fatal to the sufferer. Several died of this frightful disorder, which was so sudden in its attack, and attended with such prostation of strength, that those who lay down well at night were unable to lift their hands to their heads in the morning. The epidemic, which made its first appearance during this invasion, spread over the country, sparing neither native nor white man. It was one of those plagues from the vial of wrath, which the destroying angel, who follows in the path of the conquest, pours out on the devoted nations." (23) Many historians have believed that the above account is consistent with bartonellosis.(24-29). Post-contact history of bartonellosis. In 1968 Schultz summarized the history of bartonellosis (3). Since then, new outbreaks have occurred which have been summarized by Alexander (11). References: 1. Control of Communicable Disease Manual, 17th edition. 2000. James Chin (ed). American Public Health Association, Washington, DC, pp 66-8. 2. Schultz MG A history of Bartonellosis (Carrión’s disease). 1968. Am J of Trop Med & Hyg. (17): 503-15. 3. Schultz MG. Daniel Carrión’s Experiment. N Engl J Med 1968; (278):????. 4. Maguiña, C, Gotuzzo E. Bartonellosis new and old. Emerging and re-emerging diseases in Latin America. 2000, Infectious Disease Clinics of North America, (14): 1-22. 5. Ricketts WE. Carrion’s disease. A study of
the incubation period of thirteen cases. Am J Trop Med 1947 ((27): 657-59. 6. Scott, G. Bartonellosis, Chapter 46, Manson’s Tropical Diseases, twentieth edition. Gordon C. Cook (ed), 1996. WB Sanders Company Ltd, London, pp.895-96. 7. Trelles JO, Palamino l, Trelles L. Formas neurologicas de la enfermedad de Carrión. Estudio anatomico-clinico de 9 casos. Rev Neuropsiquiatr. 1969 (4): 245-306. 8. Weinman D. Infectious anemias due to Bartonella and related red cell parasites. 1944 Trans Am Phil Soc; (33): 243. 9. Manson-Bahr PH. Fevers caused by Bartonella and Rickettsia Bodies, Chapter XI, Bartonellosis. Manson’s Tropical Diseases A Manual of Diseases of Warm Climates, sixteenth edition. (with the editorial assistance of Wilcocks C. Williams & Wilkins Company, Baltimore. 1966. 10. Groot H. Human bartonellosis or Carrión’s disease. Gradwohl RBH, Benitez-Soto, Jelsenfeld O (eds). Clinical Tropical Medicine. St Louis: CV Mosby, 1951: 615-40. 11. Alexander B. A review of bartonellosis in Ecuador and Colombia. Am J Trop Med Hyg 1995 52 (4): 358. 12. Theodor O. On the classification of American Phlebotominae. 1965 J Med Ent (2): 171-97. 13.
Llanos BZ, Martins AV,, Da Silva JE. Estudos sobre os Flebotomíneos do Perú (Diptera,
Psychodiae, Phlebotominae) I -- Departmento de Cuzco: 1 -- Descriçáo de trés
espécies novas. Rev Brasil Biol. 1975 (4): 653-54. 14.
Martins AV, Llanos BZ, Da Silva JE. Estudos sobre os Flebotomíneos do Perú (Diptera,
Psychodiae, Phlebotominae) I -- Departmento de Cuzco: 2: Descriçáo das fêmeas
dr Lutzomyia campelli e Lutzomyia sherlocki e Redescriçao do much e descriv o
de f mea de Lutzomyia octavoi. Rev Brasil Biol. 1975 (4): 662-64. 15.
Llanos BZ, Martins AV,, Da Silva JE. Estudos sobre os Flebotomíneos do Perú (Diptera,
Psychodiae, Phlebotominae) I -- Departmento de Cuzco: 3: Descriçáo do macho e
redescriçao da f mea de Lutzomyia (Psychodopygus) amazonensis (Root 1934) e
lista dad especies coletadas. Rev Brasil Biol. 1975 (4): 668-72. 16. Townsend CHT. The transmission of Verruga by Phlebotomus. JAMA 1913 (LXI): 1717. 17. Noguchi H, Shannon RC, Tilden EB, Tyler JR. Etiology of Oroya fever. XIV: The insect vectors of Carrión’s disease. 1928; J Exp Med ((47): 993-1008. 18. Herrer A, Blanca F. Estuios sobre la enfermidad de Carrión en el valle interandino del Matvjaro. I. Observaciones entomolgicas. Rev Med Exp. 1959; (13): 27-45. 19. Herm’s Medical Entomolgy, sixth
edition. James MT, Harwood RF (eds). MacMillan and Company 1969, pp.156-161. 20. Hertig M. Phlebotomus and Carrión’s disease. Am J Trop Med Hyg 1942; 22 (Supp): 1-81. 21. Allison MJ, Pezzia A, Gersten E, et al. A case
of Carrion’s disease associated with human sacrifice from the Huari culture of
Southern Perú. Am J Phys Anthrop 1974 (41): 295-300. 22. D’Harcourt R. La Médicine dans L’Ancient Perou 1939. Librarie Maloine, Paris. 23. Prescott WH. History of the Conquest of
Peru. 1998 Modern Library Edition. NY p. 231 24.
Valdizan H. Apuntes para la historia de la Verruga peruana. 1925 An Fac
Med N Extraordinario. 25.
Salazar T. Historia de las Verrugas. 1858. Gaceta Medica de Lima. Ano II, 38-39. 26.
Castillo JC. Verruga Peruana. Lecciones Clinica 1894 La Cron Medica Ano XI:
13939. 27.
Ordiozola E. La maladie de Carrión ou la Verruga Peruvienne 1898. G Carre et C
Naud (eds), Paris. 28.
Lavoreria DE. Elarte de curar entre los antiguos Peruanos 1902. Anales de la U
de San Marcos, tomo 29. 29. Weiss P. Contributiones estudios de la Verruga Peruana o enfermidad de Carrión 1932. Rev Med Peruana; (37):5-25, (38): 55-70. DISCUSSION The origins of human infections, infectious diseases evolutionary pathways, and routes of contagion have long fascinated medical historians (1,2). A subset of these speculations has been the re-interpretation of ancient and historical epidemics. Interdisciplinary scientific endeavors over the last quarter century have included re-visitations of mal-explained and unexplained disease outbreaks. These attempts to correct and refine previous accounts include analyses of the ten plagues of Egypt, the plague of Athens, the European Black Death, the English sweating sickness, the Mexican huey cocolitztli, and a refinement of the 1854 London cholera epidemic. (3-10). Many of these research endeavors have relied on the recognition of new disease causing agents, or newly discovered documents unavailable to previous historians. Similarly, newer diagnostic techniques to correctly identify specific infectious agents have become available. However, with few exceptions, the redaction of infectious disease interpretations have dealt with Old World disease. It is largely assumed (with the exception of Chagas’ disease, bartonellosis, and perhaps espundia) that most New World epidemics were due to Old World importations (11). References: 1. Cockburn A. Where did our infectious diseases
come from? The evolution of infectious disease. Ciba Foundation Symposium 1977 (49):103-12. 2. Siegfried A. Itinéraires de contagions: Epidémies et idéologies. 1960. Librarie Armand Colin, Paris. 3. Marr JS, Malloy CD. An epidemiologic analysis of the ten plagues of Egypt. Caduceus. 1996; (1):7-24. 4. Ceccarelli G. The ten plagues of Egypt and their medical interpretations. Minerva Med. 1994; (5): 271-7. 5. Retif FP, Cilliers, L. The epidemic of Athens, 430-426 BC. S Afr Med J. 1998; (1): 50-3 6. Olson PE, Benenson AS, Genovese, EN. Ebola/Athens revisted. Emerg Infect Dis 1998; (1): 134. 7. Taviner, M, Thwaites G, Gant V. The English sweating sickness, 1485-1551: a viral pulmonary disease? Medical History 1998; (42): 96-98. 8. Dyer, A The English sweating sickness of 1551: and epidemic anatomized. Medical History 1997; (41): 362-84. 9. Marr JS, Kiracofe JB. Was the huey cocolitztli a haemorrhagic fever? Medical History 2000; (44): 341-62. 10. Brody H, Rip MR, Vinten-Johansen P et al. Map-making and myth-making in Broad Street: the London cholera epidemic, 1854. Lancet 2000; (356):64-68. 11. Crosby AW. The Columbian Exchange Biological and Cultural Consequences of 1492. 1972. Greenwood Press, Westport, CT. |