DR HUGO LUMBRERAS : ULTIMO VIAJE A HUAYOPAMPA: Huaral, 1985

BARTONELLOSIS 2015 Introduction, History and epidemiology

CIRO MAGUIÑA, M.D. Research Vice-Rector, UPCH

Alexander von Humboldt Tropical Medicine Institute

FORMER DEAN OF THE PERUVIAN COLLEGE OF PHYSICIANS

Specialist in Infectious Diseases – Tropical Medicine - Dermatology

BARTONELLOSIS 2015

Bartonella spp. ARE FASTIDIOUS HAEMOTROPIC Gram- negative bacteria which are mainly transmitted by vectors.

Since the last 23 years , the number of Bartonella species or subspecies identified from a wide range of mammals has considerably increased.

Among the 13 species or subspecies known or suspected to be pathogenic for humans, FOUR have been isolated from CATS

DOMESTIC CATS ARE THE MAIN RESERVOIR FOR Bartonella henselae, the main agent of CSD. Also, Bartonella clarridgeiae has been suspected in a few cases of CSD and Bartonella koehlerae has been reported as a causative agent of endocarditis in humans and dogs

BARTONELLOSIS

Bartonellosis Molecular Biology

Christoph Dehio, Infection-associated type IV secretion systems of Bartonella and their diverse roles in host cell interaction, Cellular Microbiology

(2008) 10 (8), 1591–1598

Bartonellosis: Chomel BB, Kasten RW. Journal of aplllied Microbiology, 109 (20) 743-750, 2010

Recently, Bartonella quintana was isolated from a pet cat and its owner.

Domestic dogs have been shown to be infected with a broad range of Bartonellla species, such as B. vinsonii berkhoffii, B. Henselae, B. clarridgeiae, B. rochalimae, B. quintana, B. koehlerae, B. washoensis, and Bartonella elizabethae.

Int J. Syst Evol Microbiology 2009

Bartonella rattaustraliani sp. nov.,

Bartonella queenslandensis sp. nov.

Bartonella coopersplainsensis sp. Nov.

Have been identified in Australian rats.

Bartonella 2010

Bartonella japonica sp. nov.

Bartonella silvatica sp. nov., isolated from Apodemus mice.

Int J. Syst Evol Microbiology 2010 http://www.ncbi.nlm.nih.gov/pubmed/19656930#

New Bartonellas:1993-2015

Bartonella weiss, Bartonella washoensis

Bartonella schoenbuchii,Bartonella birtlessi

Bartonella bovis, Bartonella capreoli

Bartonella rochalimae (Cusco, 2007)

BACTEREMIA, FEVER, AND SPLENOMEGALY CAUSED BY A NEWLY RECOGNIZED BARTONELLA SPECIES JUNE 2007 Marina E. Eremeeva, M.D., Ph.D., Helen L. Gerns, B.A., Shari L. Lydy, Ph.D., Jeanna S. Goo, B.S., Edward T. Ryan, M.D., Smitha S. Mathew, B.S., Mary Jane Ferraro, Ph.D., Judith M. Holden, M.P.H., William L. Nicholson, Ph.D., Gregory A. Dasch, Ph.D., and Jane E. Koehler, M.D.

B. rochalimae: Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 12, December 2009

Recently, B. rochalimae DNA was detected in a dog from Greece . High (43%) prevalence of bacteremia observed in gray foxes in California suggests that they might act as a wildlife reservoir for this newly identified species.

Furthermore, several B.clarridgeiae–like and

B. rochalimae genes have been detected in fleas collected from humans , rodents ,red foxes (Vulpes vulpes) , and the environment in the Democratic Republic of Congo (12) during a plague outbreak.

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 12, December 2009

Conclusions : We report the isolation or detection of

B. rochalimae from red foxes, raccoons, and coyotes from North America, Europe, and the Middle East.

Sequence analysis of 4 genes identified small variations in B. rochalimae isolates from these different geographic regions.

A relatively high percentage (26%) of raccoons had B. rochalimae bacteremia compared with only 9.5% (2/21) coyotes.

B. tamiae (Thailand) J Clin Microbiol. 2008 February; 46 (2): 772–775.

Bartonella tamiae sp. nov., a newly recognized pathogen isolated from three human patients from Thailand. Kosov, et al. J Clin Microbiol. 2008 February; 46 (2): 772–775. Centers for Disease Control and Prevention, Division of Vector Borne Infectious Diseases, 3150 Rampart Road, Fort Collins, CO 80521, USA. mkosoy@cdc.gov

(10) Heller R, Kubina M, Mariet P, Riegel P,Delacour G, Dehio C, et al.Bartonella al-saticasp. nov., a new Bartonella species isolated from the blood of wild rabbits. Int J Syst Bacteriol. 1999;49:283–8

Bartonella spp. are zoonotic agents that infect erythrocytes of mammals in which they cause chronic bacteremia .

B. alsatica was first identified in 1999 in Alsace, France, as an agent of bacteremia in healthy wild rabbits (Heller 10).

However, in 2006, interest in B. alsatica increased when it was considered to be a human pathogen because it caused blood-culture–negative endocarditis in a patient who had contacts with rabbits (5).

The present case confirms that B. alsatica could be a human pathogen, especially in persons who live in contact with rabbits and should also be considered as a cause of lymphadenopathy

Bartonella alsatica: Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 14, No. 12, December 2008

Human Case of Bartonella alsatica lymphadenitis

New species: Bartonella ancashi, July 2013. Emergent Infectious Diseases

This strain was an unknown species .

This CO20 strain underwent genotyping (using rrs, gltA, and rpoB sequences).

It was compared with the genetic bank of Bartonella species.

The sequence 1351-bp from the rrs fragment was very similar to 99.0% of rrs from B. bacilliformis.

Fragments 312 and bp 589, as well as gltA and rpoB fragments , respectively, were similar to some parts of Bartonella bovis : 89.4% (gltA), and 85.9% (rpoB),

Diseases caused by Bartonella species in humans

B. bacilliformis : Carrion’ s disease (acute Oroya fever) and Peruvian warts B. quintana BA, endocarditis, trench fever chronic bacteremia B. henselae CSD, BA, peliosis hepatis endocarditis, bacteremia, neuroretinitis B. clarridgeaie CSD ( serology)

B. elizabethae Endocarditis

B. grahammi Neuroretinis

B. vinsonii

B. rochalimae Bacteremia

Bacillary Angiomatosis (B. henselae and B.

quintana)

CUTANEOUS BARTONELLOSIS

CONTRIBUTION TO STUDIES ON CARRION’S DISEASE AND OTHER

Bartonella spp.

Pre-Columbian Phase

Mochica

pottery

CARRION’S DISEASE: Chronic phase

Krumdieck CF. La Enfermedad de Carrion o Verruga Peruana en el Niño. Anales de la Facultad de Medicina

1949; 32 (4): 227-306.

History of Carrion’s Disease

Between 1870-1890, 7,000 Andean railroad workers died

They were building the highest railroad in the world (Oroya’s railroad 3,800 meters above sea level)

Bartonellosis: History

Mortality rates for the acute febrile phase varied around 40-90% in the pre-antibiotic era.

LIMA-LA OROYA RAILROAD: 3,800 m above sea level

Verrugas bridge (Km 61)

Henry MEIGGS (USA)

highest railroad in the world

(Oroya’s railroad 3,800 meters

above sea level)

(1870-1885)

Carrion’s disease, 2015

´`

A Peruvian medical student, Daniel A. Carrión, self-inoculated fluid obtained from a verruga lesion

Days later he developed the acute phase of the disease with severe anemia and eventually died (Oct 5, 1885)

Chilean soldier with ‘mullar’ lesions. He

probably became infected in the Rimac valley during the South Pacific war

Garcia, U. Historiografia de la Enfermedad de Carrion. Ideas e Imágenes en la enfermedad de Carrión. Análisis Historiográfico

de la Iconografia de la Bartonellosis Humana. Parte II. Folia Dermatológica Peruana 1999; 10 (1): 57-63.

Patient with ‘mullar’ lesions

In 1905, Dr. Alberto Barton discovered the agent of Oroya fever and named it ‘endoglobular body’.

In 1913, Townsend discovered the vector of the disease

(“Titira”-Phlebotomus) (Today, Lutzomyia) (sandfly)

Colombia has reported

in the last 60 years only

two cases of Carrion’s

disease

It is not a public health

issue in Colombia

Ecuador has

reported cases in

the coast at 150 m

above sea level

Alexander B. A review of bartonellosis in Ecuador and Colombia Am J Trop Med

Hyg 1995; 52: 354-359.

In Peru, the disease is endemic at an altitude between 500-3,200 meters above sea level.

Cases have been reported from Andean valleys and the high rain forest.

Bartonellosis (Carrion`s disease):

Epidemiology

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1945

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Años

Tasa x

100 0

00 h

ab.

Bartonelosis en el Perú 1945 – 2005*(SE08)

Tasa de Incidencia - Curva Histórica

Fuente: Ministerio de Salud – ESN-Metaxenicas - DGSP

Año 2004:

Casos : 8,883 (A+V+P)

T.I. : 32 x 100,000hab.

T.M. : 0.18 x 100,000 hab.

Case distribution: January – June

2012

Deaths caused by Carrion’s disease according to Departments and Regional Health Directions, Peru

(2002-2012 June)

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012* Total %

Ancash 2 8 8 9 2 1 1 1 0 0 1 33 13.5

Cajamarca 22 11 40 12 4 5 2 0 1 6 4 107 43.7

Cajamarca 2 0 0 0 1 0 0 0 0 0 0 3

Chota 0 0 1 1 0 0 0 0 0 0 0 2

Cutervo 3 1 9 3 1 2 0 0 0 1 1 21

Jaén 17 10 30 8 2 3 2 0 1 5 3 81

La Libertad 3 1 2 0 4 3 0 0 1 0 0 14 5.7

Amazonas 4 12 10 0 2 2 0 0 1 0 1 32 13.1

Piura Piura 2 12 3 2 1 2 5 2 0 1 1 31 12.7

Cusco 1 0 2 2 1 0 5 1 0 0 0 12 4.9

Lima Lima Norte 0 0 0 0 1 0 0 0 0 0 0 1 0.4

Huánuco 0 0 0 4 1 0 0 0 0 0 0 5 2.0

Ayacucho 0 0 0 0 3 0 0 0 0 0 0 3 1.2

Lambayeque 1 0 0 0 1 3 0 0 0 0 5 2.0

San Martín 0 1 0 0 0 0 0 0 0 0 0 1 0.4

Loreto 0 0 0 0 0 1 0 0 0 0 0 1 0.4

Total 35 45 65 29 20 14 16 4 3 7 7 245 100.0

Fuente: DGE-RENACE. (*) = Datos hasta junio de 2012.

Departamento DISA

Año

Bartonellosis –Carrion’s disease: Microbiology

The agent is Bartonella bacilliformis.

A pleomorphic Gram negative bacilli. Blood smears with Giemsa and Wright stains are useful for the diagnosis.

Special culture media containing hemoglobin, alanine and tryptophan are required for its isolation.

It grows at temperatures ranging from 25 to 28º C

The bacterium has a single pollar flagelum on electronic microscopic evaluation

R. J. Birtles, Norman K. F, P. Ventosilla, A. G. Cáceres,E. Sánchez, H Vizcarra, & D Raoult. Identification of Bartonella bacilliformis Genotypes and

Their Relevance to Epidemiological Investigations of Human Bartonellosis. J Clin Microb. 2002; 40: 3606–3612

Genotypes and Epidemiology

DISTRIBUTION OF THE SIX GENOTYPES OF B.

bacilliformis IN PERU, 1994-1999.

Natives with severe acute forms

BARTONELLOSIS (CARRION'S DISEASE) IN THE MODERN ERA 2001.

Bartonellosis remains a major problem in Peru, but many contemporary aspects of this disease have not been adequately described. We examined the cases of 145 symptomatic patients in Lima, Peru, in whom bartonellosis was diagnosed from 1969 through 1992, including 68 patients in the acute (hematic) phase and 77 patients in the eruptive (verruga) phase. In modern Peru, symptomatic patients who have acute-phase bartonellosis typically present with a febrile illness and systemic symptoms caused by profound anemia; most patients respond successfully to treatment with chloramphenicol. Patients who have eruptive-phase bartonellosis most often present with cutaneous verrugas but may have less specific symptoms, such as fever and arthralgias; diagnosis can be confirmed in such patients by Western immunoblotting, and most patients appear to respond to treatment with rifampin. PMID: 11512081 [PubMed - indexed for MEDLINE]

Maguiña C, García PJ, Gotuzzo E, Cordero L, Spach D

Alexander von Humboldt Tropical Medical Institute, Cayetano

Heredia University of Peru, Lima, Peru.

CLASSIC CONCEPTS FOR CARRION’S DISEASE (old

paradigms)

Oroya fever (acute phase)

‘Intercalar’ phase – asymptomatic

Peruvian ‘verruga (warts) – chronic form

Asymptomatic carriers

Carrion’s disease: Signs and symptoms

Pallor 66 (97%) Hepatomegaly 56 (82%) T > 38 °C 53 (78%) Cardiac murmur 53 (78%) Jaundice 48 (71%) Lymphadenopathy 47 (69%)

Tachycardia 38 (56%)

Splenomegaly 20 (29% )

Anasarca 6 (9%)

Maguina et al. Bartonellosis (Carrion!s Disease) in the Modern Times: Clinical features of 68 patients with acute phase. CID 33:772-9 2001

http://images.google.com.pe/imgres?imgurl=http://www.scielo.org.pe/img/revistas/rmh/glogo.gif&imgrefurl=http://www.scielo.org.pe/scielo.php/script_sci_serial/pid_1018-130X/lng_pt/nrm_iso&h=181&w=319&sz=23&hl=es&start=2&um=1&usg=__ccEMHE4kNVV9W6KUdNvBYkqWutQ=&t

Many clinical patterns are present in Carrion’s disease (NEW!!)

Asymptomatic

Mild febrile illness

Moderate, acute and non complicated febrile illness

Classis acute febrile illness with common complications

Classic acute febrile illness with new features (multiorgan failure)

Recurrent acute febrile illness

Acute febrile illness and then the eruptive phase

No acute febrile illness, just the eruptive phase

Eruptive phase and then acute deterioration

Recurrent eruptive phase

Rheumatoid syndrome reumatoide ??

Poor outcome, tachypnea, hypoxemia, hypotension, cardiac pump failure, myocarditis,

mechanical ventilation, inootropic and vasotropic support. Died after 48 hours post

admission in the ICU

Ig M and G for Toxoplasmosis: (+) AUTOPSY: Toxoplasma myocarditis and pneumonitis

New Complications of Carrion’s disease: 2015

Neurobartonellosis: mental alteration, from somnolence to coma.

Cardiovascular involvement, multiorgan failure

Opportunistic infections

typhi and non-typhi Salmonella ( classic) , malaria, ameba

New conditions: Toxoplasmosis reactivation, TB

Disseminated histoplasmosis

Sepsis: Shigella, Staphylococcus, Enterobacter

P. jiroveci pneumonia

Tifus, Leptospirosis, etc.

Superinfections associated with Human Bartonellosis (Acute Carrion’s Disease) among Inpatients in the Northern Peruvian Forest Pachas PE, Aranda M, Troyes L, Matos Arias J, Padilla C, Ventura G, Canelo A, Huatuco G, Chancafe JA, Suarez-Ognio L.

From 115 subjects enrolled, 75 were confirmed cases. The median age was 9 years old (3months-62 years),

and 61% were male. The main superinfections associated were: leptospirosis 54% (29/53), toxoplasmosis 8.3% (4/48), Chagas disease 1,7% (1/60), P. vivax 1.3% (1/75) and P. falciparum malaria 1.3%(1/75).

Abstracts ASTMH 56th Annual Meeting Philadelphia Marriott Downtown, Philadelphia, Pennsylvania USA, November 4-8, 2007.

New Cardiovascular Findings and Complications

Heart failure 62.5% Effusive pericarditis 56.5%(#) Acute pulmonary edema 40% Cardiac Tamponade 17.5% Cardiovascular shock 15% Myocarditis 2.5% Endocarditis ( 2004, first case)

(#) Ordaya, Maguiña , 2008 Acta Medica

Peruana: constrictive subacute Pericarditis

Oxford textbook of medicine, Vol. 1. Oxford, UK: Oxford University Press; 1996. p. 773. Llanos-Cuentas A,

Maguiña-Vargas C,

Bartonellosis. In: Warrell DA

THE OLDEST PICTURE OF A PATIENT WITH CARRION’S DISEASE, BY Dr. SALAZAR

Bartonellosis. Maguiña C, Guerra H, Ventosilla P. Clin

Dermatol. 2009 May-Jun; 27 (3): 271-80. Review.

CARRION’S DISEASE: CHRONIC PHASE

Krumdieck CF. La Enfermedad de Carrion o Verruga Peruana en

el Niño. Anales de la Facultad de Medicina 1949; 32 (4): 227-306.

PLoS Negl Trop Dis. 2012;6(10):e1819.

doi: 10.1371/journal.pntd.0001819. Epub 2012 Oct 25.

Bartonella bacilliformis: a systematic review of

the literature to guide the research agenda for

elimination.

Sanchez Clemente N, Ugarte-Gil CA, Solórzano N,

Maguiña C, Pachas P, Blazes D, Bailey R,

Mabey D, Moore D.

BROTHERS, THERE IS STILL TOO MUCH TO DO… (DANIEL A. CARRION)

THANK YOU VERY MUCH!!