International Journal of Infectious Diseases (2009) 13, 3—8

http://intl.elsevierhealth.com/journals/ijid

PERSPECTIVE : emerging pathogen or emerging awareness?

Elin Mogollon-Pasapera, Laszlo Otvos Jr, Antonio Giordano, Marco Cassone *

Sbarro Health Research Organization, College of Science and Technology, Temple University, BioLifeScience Building suite 419, 1900 N 12th Street, 19122 Philadelphia, PA, USA

Received 17 October 2007; received in revised form 26 January 2008; accepted 14 April 2008 Corresponding Editor: William Cameron, Ottawa, Canada

KEYWORDS Summary The number of known Bartonella species is rapidly growing. Some of them are Bartonella; responsible for distinct infectious diseases and show different prevalence and antibiotic suscept- Carrion’s disease; ibility profiles. Not only have some vectors of Bartonella not been fully characterized, but also Epidemiology; intermediate hosts are actually much more numerous and diverse than previously thought. Among Cat-scratch disease; these, dogs differ from cats because they tend to suffer an overt disease similar to humans, thus Therapy providing the base for a useful animal indicator and research model. Among the debilitating conditions with an unclear impact on the course of these infections, specific conditions (e.g., homelessness, alcoholism) have been linked to a much higher prevalence and to high risk of unfavorable outcome. Due to the limited arsenal of antibiotics effective in vivo on this peculiar intracellular pathogen, the risk/benefit balance of antibiotic therapy is sometimes difficult to draw. In this evolving picture, the recent discoveries of new species highlights the importance of basic molecular biology resources that would bring major public health benefits if available in endemic areas, and specifically in many areas of Peru and Bolivia. # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

The growing impact of Bartonella known to infect healthy or immunocompromised humans. Bartonella species are transmitted between the reservoir Many species of Bartonella have been affecting human life for and the final mammal host by insects such as fleas, sand flies, centuries. , for example, has been and possibly ticks, by bites or other means (e.g., feces of flea implied as one of the possible causes of the decline of the in cat-scratch disease). The range of vectors involved in the Inca Empire.1 The genus is named after Alberto Leonardo transmission of the different species of this genus has not Barton Thompson, who in 1905 discovered Bartonella bacil- been fully characterized. liformis, the causative agent of the Oroya fever (or Carrion’s From a clinical point of view, Bartonella infections can disease), a severe febrile illness accompanied by bacteremia, range from self-limited to life-threatening, and may present endocarditis, hemolysis, and circulatory collapse, or by different course and organ involvement, due to a balance of encephalitis.2 Of the 21 species described, about half are host and bacterial factors still not well understood. Our knowledge in all aspects of Bartonella infections is improving * Corresponding author.Tel.: +1 215 204 4265; fax: +1 215 204 9522. and many species have been characterized, but more are E-mail address: [email protected] (M. Cassone). discovered each year. Also, some already-known species have

1201-9712/$36.00 # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2008.04.002 4 E. Mogollon-Pasapera et al. recently shown unexpectedly wide prevalence and different ceramics. The symptomatic disease presents two phases: an antibiotic susceptibility profiles. Interesting novelties also initial, acute or subacute phase in which the symptoms are regard the hosts: dogs, for example, have been recently fever, anemia, and jaundice, and then a chronic phase identified as an important intermediate host for several characterized by the ‘verruga peruana’ (Peruvian wart). species, and in few cases as the definitive host. For many years it was not clear that these are two phases Bartonella infections produce a remarkable range of of the same disease, until 1885, when the medical student symptoms, due to chronic or acute infections with variable and Peruvian hero Daniel Alcides Carrion, inoculated himself pathology. Besides Oroya fever, Bartonella infections cause with B. bacilliformis from a patient in the chronic phase of , bacteremia and endocarditis, cat-scratch dis- the disease. He developed the Oroya fever, losing his life to ease, bacillary angiomatosis, and other granulomatous infec- demonstrate an etiologic link with the ‘verruga peruana’. tions involving several organs.3—5 has been identified in various regions of Peru but is most commonly found in the Andes Valleys between 500 Epidemiology and diagnosis and 3500 meters over sea level, which is the home of the sand fly Lutzomyia verrucarum, the principal vector of B. bacilli- formis. More than 26 000 cases of bartonellosis were reported Besides geographic areas of endemic distribution, for exam- between 2004 and 2006 by the Peruvian National Institute of ple B. bacilliformis in Los Andes in Peru, Bartonella infections Health. Since the mortality can be high in certain outbreaks, have shown an unexpectedly high prevalence worldwide. As especially among pediatric patients,1 it can be estimated an example, it was recently made clear that bartonelloses that in Peru only, hundreds of people die each year from this are common in Europe.6 Specific studies have been con- disease, generally due to lack of preventive measures and for ducted for selected categories such as the homeless, drug not reporting to a health center to be treated. users, and veterinarians.7—9 A case report on cat-scratch Another member of the Bartonella genus is B. quintana,a disease in a family demonstrated that the infection was microorganism that is transmitted by feces of human louse transmitted by the same kitten to four different individuals, into abraded skin or into the conjunctiva. B. quintana is the and each presented with different clinical characteristics, agent of trench fever, a bacteremic disease that was treatment, and evolution.10 A recent report described two described in 1915 and resulted in about 1 million soldiers cases of transverse myelitis in patients that were positive for being infected in Europe during World War I. Its symptoms .11 Also, the geographic distribution of may include high fever, severe headache, pain in moving the the pathogen may be dependent on temporary or permanent eyeballs, soreness of the muscles of the legs and back, and climatic alterations such as tropical storms, as described for frequently hyperesthesia of the shins. Pathologic manifesta- B. bacilliformis, and possibly global warming.1 These alarm- tions of endocarditis have been described in some specimens. ing findings, together with increasing resistance to antimi- Nowadays, B. quintana infection is highly prevalent among crobial agents, are leading Bartonella to be viewed as homeless alcoholics, and is also present among veterinarians emerging, or reemerging pathogens.12 However, what is in the USA and Europe.7—9 especially new is the interest on the science and public Bartonella henselae is well known for causing cat-scratch health side, and the awareness that so much is not yet disease, usually characterized by a mild infection that may understood. be limited to the site of injury, or may present general from the genus Bartonella are fastidious to grow systemic symptoms such as fever, headache, fatigue, and in vitro, and the most used diagnostic means are serology and poor appetite. Recently, it has been observed that this PCR. Both methods are quick, sensitive, and reliable for pathogen may enter human erythrocytes, like B. bacillifor- patient management purposes. Whenever possible, addi- mis and B. quintana.15 This observation raised some concern tional downstream analysis should be performed on PCR regarding the need of transfusion screening practices. Immu- amplicons to screen for new species, especially when dealing nocompromised patients, but also sometimes apparently with uncommon clinical presentations and settings. The healthy subjects, may show severe granulomatous lesions importance of this approach is underlined by the recent case of internal organs. Patients with AIDS are especially at risk for report of the isolation of a new proposed Bartonella species, bacillary angiomatosis, a disease caused by B. henselae and named Bartonella rochalimae, in an American tourist.13 B. quintana characterized by the proliferation of blood vessels. The lesions are found most often in the skin but Clinical presentations may affect almost any organ. The disease may be lethal if not recognized and treated. In Table 1 we report the pathogenic Less than 20 years ago, just a few species of Bartonella were Bartonella species described so far, along with the clinical known: among them B. bacilliformis and B. quintana. With manifestations of disease they can cause in humans and in the discovery, in 1992, that the new species B. henselae dogs. The complete genomes of B. bacilliformis, B. quintana, (originally named Rochalimaea henselae) was the etiologic B. henselae, and Bartonella tribocorum have been agent of the mysterious cat-scratch disease,14 worldwide sequenced so far (http://www.ncbi.nlm.nih.gov/genomes/ interest and scientific efforts started to pour in on this genus, lproks.cgi). and more than one new species each year has been discov- ered in the last decade.12,13 Vectors and reservoirs The most common bartonellosis is the ‘Oroya fever’, or Carrion’s disease. This was one of the first human diseases to DNA of some Bartonella species has been found in several be described, given that the millenary civilizations of the different vectors. A very recent study, for example, reported Mochicas, Chimu, and Nazca in Peru represented it in their the molecular detection of B. tribocorum and Bartonella Bartonella: emerging pathogen or emerging awareness? 5

Table 1 Bartonella species infecting humans

Species Year of Place Author Main vectors Main Main human Recommended Dog diseases description reservoirs diseases a antibiotics B. bacilliformis 1909 Peru Barton Sand fly Human Carrion’s Acute disease: disease ciprofloxacin (amoxicillin clavulanate for children and pregnant women), or chloramphenicol Chronic disease: azithromycin B. quintana 1915 Russia Strong Body louse Human Trench fever Doxycycline Endocarditis CSD BA CA Erythromycin b Bacteremia Erythromycin Endocarditis Gentamicin and doxycycline Septicemia Gentamicin and doxycycline B. henselae 1992 USA Regnery Cat flea Cat CSD Doxycycline Endocarditis BA Erythromycin b Granulomatous hepatitis CA Erythromycin Bacteremia Peliosis hepatis Endocarditis Gentamicin Epistaxis and doxycycline Septicemia B. elizabethae 1993 USA Daly Oriental rat Rat Endocarditis Not established Lethargy flea, rodent fleas Retinitis Anemia Weight loss B. grahamii 1995 UK Birtles Wild mice Retinitis Doxycycline Not diagnosed and rifampin in dogs B. washoensis 1995 USA Regnery Unknown California Fever Not established Endocarditis (flea?) ground squirrel Myocarditis B. vinsonii 1996 Canada Kordick Unknown Coyote, Endocarditis Doxycycline Endocarditis subspecies (tick?) dog plus berkhoffii gentamicin or a quinolone Myocarditis Arrhythmia Uveitis Choroiditis Splenomegaly Polyarthritis Epistaxis B. clarridgeiae 1996 USA Lawson Cat flea Cat CSD Not established Endocarditis Lymphocytic hepatitis B. alsatica 1999 France Heller Unknown Rabbit Endocarditis Not established (flea?) 6 E. Mogollon-Pasapera et al.

Table 1 (Continued ) Species Year of Place Author Main vectors Main Main human Recommended Dog diseases description reservoirs diseases a antibiotics B. vinsonii 1999 Canada Welch Unknown White- Bacteremia Not established subspecies (flea, tick?) footed arupensis mouse B. rochalimae 2007 Peru Eremeeva Unknown Unknown Bacteremia Not established (flea?) a CSD, cat-scratch disease; BA, bacillary angiomatosis; CA, chronic adenopathy.

vinsonii subspecies vinsonii from the fleas Xenopsylla cheo- others.23—25 Nevertheless, some of these antibiotics may pis, Ctenophthalmus pseudagyrtes, and Sternopsylla texa- be ineffective in vivo because of the lack of a bactericidal nus.16 Furthermore, a single tick can harbor Bartonella (such effect, or the intracellular localization of the bacteria. For as B. vinsonii) together with other pathogens.17 When this is a example, penicillin is not effective against B. henselae. Also, concern in the differential diagnosis, amplification and the emergence of resistance to several antibiotics, including detection of pathogen DNA should be carried out using macrolides and quinolones, has been reported, mainly in B. techniques that combine high-throughput and sensitivity, bacilliformis.26,27 such as broad-range PCR, which uses primers that target The general recommendations for the treatment of infec- highly-conserved regions of genes common to all bacteria tions caused by Bartonella species are reported in Table 1, (e.g., 16S rDNA), combined with separation techniques such but may vary according to the type and stage of disease, age as temporal temperature gradient gel electrophoresis of the patient, and their immune status. In a limited Peruvian (TTGE).18 This also allows the prompt detection of unusual case series, 14 of 16 (88%) untreated patients with Oroya patterns possibly pointing to new species. Vectors should be fever died, while all the 10 chloramphenicol-treated much more addressed as a target for prevention efforts: patients survived.28 Notably, there is often uncertainty over altering their environmental niche, as well as enhancing which treatment is best for children. For uncomplicated cat- competition by not receptive peers may be successful stra- scratch disease therapy is often not needed, however many tegies. antibiotic treatments like the combination of doxycycline Pets represent a large reservoir for infections in humans.19 with rifampin in patients with complicated cat-scratch dis- Cats are the main reservoir for species like B. henselae, ease have been successful. Evaluation of the impact that Bartonella clarridgeiae, and Bartonella koehlerae. On the immunodeficiency and other debilitating conditions in gen- other hand, dogs can be infected with Bartonella berkhoffii, eral have on the prevalence, course, and especially therapy B. henselae, B. clarridgeiae, Bartonella washoensis, Barto- outcomes of Bartonella infections, only started in the most nella elizabethae, and B. quintana, but their role as reser- recent years, and still too many areas of uncertainty remain. voirs is not as well understood as for cats because they tend Due to the limited arsenal of antibiotics effective in vivo on to be accidental hosts in non-tropical regions and not the this peculiar intracellular pathogen, drugs with potential primary reservoir.20 Rat and coyote can also be intermediate toxic effects are often used. Thus, the risk/benefit balance hosts. Domestic dogs as opposed to cats are excellent animals of antibiotic therapy must always be carefully evaluated. to study the pathophysiology of infection in humans because Unfortunately, this is a point for which we do not have they manifest similar symptoms and clinical and pathologic enough clinical data, especially regarding children. Specific findings.21 This gives a totally different perspective from the conditions (e.g., homelessness and alcoholism) have been one exemplified by Carrion, who experimented on himself linked to a much higher prevalence and to high risk of thinking that bartonellosis could only occur in humans. unfavorable outcome, and thus should prompt treat- Indeed, the dog may be a useful animal indicator and ment.7,29,30 Treatment also needs careful evaluation and research model, as well as helping epidemiologic and pre- the knowledge of the local epidemiological situation. Anti- vention work. Immunocompromised dogs are more likely to microbial susceptibility testing should be performed when- acquire B. henselae than immunocompetent dogs20 according ever possible. Not surprisingly, the changing knowledge and to studies on healthy and sick dogs in eastern USA that show awareness of the impact of bartonellosis, together with an occurrence of 10% of B. henselae antibodies in healthy evolving susceptibility to antimicrobial drugs, demands con- dogs and 27% in sick dogs, similar to what occurs in humans. A tinuous update, and in some cases a reevaluation of manage- case of cat-scratch disease caused by a domestic dog scratch ment strategies, which also imply recent calls for has been reported in Taiwan.22 development of a vaccine.

Treatment Vaccines

Bacteria of the genus Bartonella are often, but not always, Although very demanding and expensive to generate, vac- susceptible to many antibiotics when they are grown in vitro, cines are theoretically the best choice to prevent infections including penicillin, cephalosporins, aminoglycosides, chlor- endemic in areas where an appreciable proportion of the amphenicol, rifampin, and fluoroquinolones among population has limited access to medical facilities. While a Bartonella: emerging pathogen or emerging awareness? 7 vaccine able to drastically reduce the burden of Oroya fever 5. Maguina C, Garcia PJ, Gotuzzo E, Cordero L, Spach DH. Barto- in humans is still just a dream, the invasion protein IalB of B. nellosis (Carrion’s disease) in the modern era. Clin Infect Dis bacilliformis served as a functional template to select a 2001;33:772—9. candidate Brucella melitensis antigen for a DNA vaccine that 6. Vorou RM, Papavassiliou VG, Tsiodras S. Emerging zoonoses and vector-borne infections affecting humans in Europe. Epidemiol resulted protective in mice.31 Infect 2007;135:1057—73. Veterinarians are pushing for the development of a cat 32 7. Brouqui P,Raoult D. Arthropod-borne diseases in homeless. Ann N vaccine against B. henselae, due to recent impressive data Y Acad Sci 2006;1078:223—35. 9 on its prevalence in pets. A few preliminary studies 8. Chmielewski T, Podsiadly E, Tylewska-Wierzbanowska S. Pre- addressed the immunogenicity of some B. henselae antigens sence of Bartonella spp in various human populations. Pol J and the cross-reactivity between serotypes.33,34 Attenuation Microbiol 2007;56:33—8. of B. henselae by serial passages in vitro, a classic method 9. Comer JA, Flynn C, Regnery RL, Vlahov D, Childs JE. Antibodies to used with other pathogens, has also been attempted, but Bartonella species in inner-city intravenous drug users in Balti- further studies are needed to clarify whether these research more. Md Arch Intern Med 1996;156:2491—5. approaches have the potential to lead to the development of 10. Song AT, Gory M, Roussi J, Salomon J, Cremieux AC, Perronne C, et al. Familial occurrence of cat-scratch disease, with varying a vaccine.35 clinical expression. Scand J Infect Dis 2007;39:728—30. 11. Baylor P, Garoufi A, Karpathios T, Lutz J, Mogelof J, Moseley D. Conclusions Transverse myelitis in 2 patients with Bartonella henselae infec- tion (cat scratch disease). Clin Infect Dis 2007;45:e42—5. The discovery of a new species of Bartonella, presumably 12. Anderson BE, Neuman MA. Bartonella spp as emerging human pathogens. Clin Microbiol Rev 1997;10:203—19. endemic in Peru, in a tourist from a highly developed country 13. Eremeeva ME, Gerns HL, Lydy SL, Goo JS, Ryan ET, Mathew SS, underlines once more the usefulness and the urgent need for et al. Bacteremia, fever, and splenomegaly caused by a newly increased availability of molecular biology resources, such recognized Bartonella species. N Engl J Med 2007;356:2381—7. as those necessary to investigate pathogens at a genomic 14. Dolan MJ, Wong MT, Regnery RL, Jorgensen JH, Garcia M, Peters level, in many areas of Peru and Bolivia. Limitation of J, et al. Syndrome of Rochalimaea henselae adenitis suggesting resources is indeed one of the reasons why many aspects cat scratch disease. Ann Intern Med 1993;118:331—6. concerning to Bartonella infections are not yet specified. For 15. Pitassi LH, Magalha˜es RF, Barjas-Castro ML, de Paula EV, Ferreira example, a recommended treatment for children with reti- MR, Velho PE. Bartonella henselae infects human erythrocytes. nitis, trench fever, chronic bacteremia, and endocardi- Ultrastruct Pathol 2007;31:369—72. tis,3,36 has not been established. Also, data comparing the 16. Reeves WK, Rogers TE, Durden LA, Dasch GA. Association of Bartonella with the fleas (Siphonaptera) of rodents and bats outcome of different treatment regimens during pregnancy, using molecular techniques. J Vector Ecol 2007;32:118—22. or even just suggesting one, are scarce. Doubts exist about 37 17. Halos L, Jamal T,Maillard R, Beugnet F,Le Menach A, Boulouis HJ, the safety of chloramphenicol during pregnancy due to et al. Evidence of Bartonella sp in questing adult and nymphal 5 observed abortion or fetal demiseinsomepregnantwomen. Ixodes ricinus ticks from France and co-infection with Borrelia As suggested by these results, preventive exams that allow burgdorferi sensu lato and Babesia sp. Vet Res 2005;36:79—87. the detection of Bartonella species in women planning to be 18. Halos L, Mavris M, Vourc’h G, Maillard R, Barnouin J, Boulouis HJ, pregnant should be taken into consideration at least in et al. Broad-range PCR-TTGE for the first-line detection of endemic zones. bacterial pathogen DNA in ticks. Vet Res 2006;37:245—53. While epidemiology, clinic, and diagnostics data are con- 19. Chomel BB, Boulouis HJ, Maruyama S, Breitschwerdt EB. Barto- tinuously obtained and updated, a major concern lies in the nella spp in pets and effect on human health. Emerg Infect Dis 2006;12:389—94. increase of the higher-risk population with Bartonella infec- 20. Solano-Gallego L, Bradley J, Hegarty B, Sigmon B, Breitschwerdt tions and immunodeficiency. The number of patients diag- E. Bartonella henselae IgG antibodies are prevalent in dogs from nosed with HIV, cancer, tuberculosis, and many other southeastern USA. Vet Res 2004;35:585—95. debilitating diseases is continuously growing, and we are 21. Kelly P,Rolain JM, Maggi R, Sontakke S, Keene B, Hunter S, et al. just starting to understand how far and in how many ways Bartonella quintana endocarditis in dogs. Emerg Infect Dis Bartonella can affect our health. 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