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    Adult female (A) and male (B) A. cajennense (the Cayenne tick), a vector of RMSF in Latin America. Abundant spotted fever group rickettsiae and rickettsial antigens (red) are stained by IHC in tissues of a patient with fatal RMSF, in vascular smooth muscle cells of a hepatic arteriole [arrow] (C), and in endothelial cells of small vessels in the cerebellar leptomeninges (D). The involved vessels show no appreciable inflammatory cell infiltrates despite extensive infection with large numbers of rickettsiae. Immunoalkaline phosphatase stain with fast red-naphthol phosphate and hematoxylin counterstain (polyclonal anti-Rickettsia rickettsii antibody at 1/500); original magnifications, ×100 (C) and ×50 (D).

  • 1

    Veintemillas F, 1944. Sobre las Rickettsiasis y las Fiebres Exantematicas el Tifus Altiplanico. La Paz, Bolivia: Escuela Tip Salesiana.

  • 2

    Ripoll CM, Remondegui CE, Ordonez G, Arazamendi R, Fusaro H, Hyman MJ, Paddock CD, Zaki SR, Olson JG, Santos-Buch CA, 1999. Evidence of rickettsial spotted fever and ehrlichial infections in a subtropical territory of Jujuy, Argentina. Am J Trop Med Hyg 61: 350–354.

    • Search Google Scholar
    • Export Citation
  • 3

    Webb L, Carl M, Malloy DC, Dasch GA, Azad AF, 1990. Detection of murine typhus infection in fleas by using the polymerase chain reaction. J Clin Microbiol 28: 530–534.

    • Search Google Scholar
    • Export Citation
  • 4

    Ishikura M, Ando S, Shinagawa Y, Matsuura K, Hasegawa S, Nakayama T, Fujita H, Eatanabe M, 2003. Phylogenetic analysis of spotted fever group rickettsiae based in gltA, 17 kDa, and rOmpA genes amplified by nested PCR from ticks in Japan. Microbiol Immunol 47: 823–832.

    • Search Google Scholar
    • Export Citation
  • 5

    Drancourt M, Raoult D, 1999. Characterization of mutations in the rpoB gene in naturally rifampin-resistant Rickettsia species. Antimicrob Agents Chemother 43 :2400–2403.

    • Search Google Scholar
    • Export Citation
  • 6

    Tzianabos T, Anderson BE, McDade JE, 1989. Detection of Rickettsia ricketsii in clinical specimens by using polymerase chain reaction technology. J Clin Microbiol 27: 2866–2868.

    • Search Google Scholar
    • Export Citation
  • 7

    Regnery RL, Spruill CL, Plikaytis BD, 1991. Genotypic identification of rickettsiae and estimation of intraspecies sequence divergence for portions of two rickettsial genes. J Bacteriol 173 :1576–1589.

    • Search Google Scholar
    • Export Citation
  • 8

    Roux V, Fournier PE, Raoult D, 1996. Differentiation of spotted fever group rickettsiae by sequencing and analysis of restriction fragment length polymorphism of PCR-amplified DNA of the gene encoding the protein rOmpA. J Clin Microbiol 34: 2058–2065.

    • Search Google Scholar
    • Export Citation
  • 9

    Piza J, Salles-Gomes F, Salles-Gomes L, Meyer J, Fleury JP, Castro O, Rodrigues C, Rocha Lima H, 1931. Le typhus exanthématique a Sao Paulo. Comp Rend Séances Soc Biol Fil 106 :1020–1022.

    • Search Google Scholar
    • Export Citation
  • 10

    Dyer RE, 1933. Relationship between Rocky Mountain spotted fever and exanthematic typhus of Sao Paulo. Public Health Rep 48 :521–522.

  • 11

    Patino L, Afanador A, Paul JH, 1937. A spotted fever in Tobia, Colombia. Am J Trop Med Hyg 17 :639–653.

  • 12

    Dumler JS, 1991. Fatal Rocky Mountain spotted fever in Maryland, 1901. JAMA 265 :718.

  • 13

    Milam DF, 1934. Rocky Mountain spotted fever in North Carolina. South Med J 27 :788–793.

  • 14

    Cicuttin GL, Rodríguez Vargas M, Jado I, Anda P, 2004. Primera detección de Rickettsia massiliae en la ciudad de Buenos Aires. Resultados preliminaries. Rev Argentina Zoonosis 1 :8–10.

    • Search Google Scholar
    • Export Citation
  • 15

    Labruna MB, Pacheco RC, Nava S, Brandão PE, Richtzenhain LJ, Guglielmone AA, 2007. Infection by Rickettsia bellii and Candidatus “ Rickettsia amblyommii” in Amblyomma neumanni ticks from Argentina. Microb Ecol 54 :126–133.

    • Search Google Scholar
    • Export Citation
  • 16

    Pacheco RC, Moraes-Filho J, Nava S, Brandão PE, Richtzenhain LJ, Labruna MB, 2007. Detection of a novel spotted fever group rickettsia in Amblyomma parvum ticks (Acari: Ixodidae) from Argentina. Exp Appl Acarol 43 :63–71.

    • Search Google Scholar
    • Export Citation
  • 17

    Bustamente ME, Varela G, 1946. III. Estudios de fiebre manchada en Mexico. Hallazgo del Amblyomma cajennense naturalmente infectado, en Veracruz. Rev Inst Salub Enferm Trop 7 :75–78.

    • Search Google Scholar
    • Export Citation
  • 18

    de Rodaniche EC, 1953. Natural infection of the tick, Amblyomma cajenennse, with Rickettsia rickettsii in Panama. Am J Trop Med Hyg 2 :696–699.

    • Search Google Scholar
    • Export Citation
  • 19

    Guedes E, Leite RC, Prata MCA, Pacheco RC, Walker DH, Labruna MB, 2005. Detection of Rickettsia rickettsii in the tick Amblyomma cajennense in a new Brazilian spotted fever-endemic area in the state of Minas Gerais. Mem Inst Oswaldo Cruz 100 :841–845.

    • Search Google Scholar
    • Export Citation
  • 20

    Estrada-Peña A, Guglielmone AA, Mangold AJ, 2004. The distribution and ecological ‘preferences’ of the tick Amblyomma cajennense (Acari: Ixodidae), an ectoparasite of humans and other mammals in the Americas. Ann Trop Med Parasitol 98 :283–292.

    • Search Google Scholar
    • Export Citation
  • 21

    Guglielmone AA, Mangold AJ, Viñbal AE, 1991. Ticks (Ixodidae) parasitizing humans in four provinces of north-western Argentina. Ann Trop Med Parasitol 85 :539–542.

    • Search Google Scholar
    • Export Citation
  • 22

    Guglielmone AA, Beati L, Barros-Battesti DM, Labruna MB, Nava S, Venzal JM, Mangold AJ, Szabó MP, Martins JR, González-Acuña D, Estrada-Peña A, 2006. Ticks (Ixodidae) on humans in South America. Exp Appl Acarol 40 :83–100.

    • Search Google Scholar
    • Export Citation
  • 23

    Montiero JL, Da Fonseca F, Prado A, 1932. Typho exanthematico de S. Paulo, VI. Pesquisas sobre a possibiliadade da transmissao experimental do virus por Ixodidae. Bras Med 46 :49–52.

    • Search Google Scholar
    • Export Citation
  • 24

    Brumpt E, 1933. Tranmission de la fièvre pouprée des Montanges Rocheusse par la tique américaine Amblyomma cayennense. Comp Rend Séances Soc Biol Fil 144 :416–419.

    • Search Google Scholar
    • Export Citation
  • 25

    Parker RR, Philip CB, Jellison WL, 1933. Rocky Mountain spotted fever: potentialities of tick transmission in relation to geographical occurrence in the United States. Am J Trop Med 13 :341–379.

    • Search Google Scholar
    • Export Citation
  • 26

    Moreira JA, de Magalhães O, 1936. Typho exanthematico de Minas Gerais. Bras Med 51 :881–882.

  • 27

    Dias E, Martins AV, 1937. Aspectos do typho exanthematico em Minas Gerais. Bras Med 51 :431–441.

  • 28

    Jones TF, Craig AS, Paddock CD, McKechnie DB, Childs JE, Zaki SR, Schaffner W, 1999. Family cluster of Rocky Mountain spotted fever. Clin Infect Dis 28 :853–859.

    • Search Google Scholar
    • Export Citation
  • 29

    Sexton DJ, Muniz M, Corey R, Breitschwerdt EB, Hegarty B, Dumler S, Walker DH, Pecanha PM, Dietze R, 1993. Brazilian spotted fever in Esprito Santo, Brazil: description of a focus of infection in a new endemic region. Am J Trop Med Hyg 49 :222–226.

    • Search Google Scholar
    • Export Citation
  • 30

    de Lemos ERS, Alvarenga FBF, Cintra ML, Ramos MC, Paddock CD, Ferebee TL, Zaki SR, Ferreira FCC, Ravagnani RC, Machado RD, Guimarães MAAM, Coura JR, 2001. Spotted fever in Brazil: a seroepidemiologic study and description of clinical cases in an endemic area in the state of São Paulo. Am J Trop Med Hyg 65 :329–334.

    • Search Google Scholar
    • Export Citation
  • 31

    Galvão MAM, Dumler JS, Mafra CL, Calic SB, Chamone CB, Filho GC, Olano JP, Walker DH, 2003. Fatal spotted fever rickettsiosis, Minas Gerais, Brazil. Emerg Infect Dis 9 :1402–1405.

    • Search Google Scholar
    • Export Citation
  • 32

    Hildago M, Orejuela L, Fuya P, Carrillo P, Hernandez J, Parra E, Keng C, Small M, Olano JP, Bouyer D, Castaneda E, Walker D, Valbuena G, 2007. Rocky Mountain spotted fever, Colombia. Emerg Infect Dis 13 :1058–1060.

    • Search Google Scholar
    • Export Citation
  • 33

    Philip RN, 2000. Rocky Mountain Spotted Fever in Western Montana: Anatomy of a Pestilence. Hamilton, MT: Bitter Root Valley Historical Society.

  • 34

    Calero C, Núñez JM, Silva Goytia R, 1952. Rocky Mountain spotted fever in Panama. Report of two cases. Am J Trop Med Hyg 1 :631–636.

    • Search Google Scholar
    • Export Citation
  • 35

    Zavala-Velazquez JE, Yu X-J, Walker DH, 1996. Unrecognized spotted fever group rickettsiosis masquerading as dengue fever in Mexico. Am J Trop Med Hyg 55 :157–159.

    • Search Google Scholar
    • Export Citation
  • 36

    Estripeaut D, Aramburú MG, Sáez-Llorens X, Thompson HA, Dasch GA, Paddock CD, Zaki S, Eremeeva ME, 2007. Rocky Mountain spotted fever, Panama. Emerg Infect Dis 13 :1763–1765.

    • Search Google Scholar
    • Export Citation
  • 37

    Lillie RD, 1941. Pathology of Rocky Mountain spotted fever. Natl Inst Health Bull 177 :1–59.

  • 38

    Valbuena G, Bradford W, Walker DH, 2003. Expression analysis of the T-cell-targeting chemokines CXCL9 and CXCL10 in mice and humans with endothelial infections caused by rick-ettsiae of the spotted fever group. Am J Pathol 163 :1357–1369.

    • Search Google Scholar
    • Export Citation
  • 39

    Paddock CD, Greer PW, Ferebee TL, Singleton J, McKechnie DB, Treadwell TA, Krebs JW, Clarke MJ, Holman RC, Olson JG, Childs JE, Zaki SR, 1999. Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease. J Infect Dis 179 :1469–1476.

    • Search Google Scholar
    • Export Citation
  • 40

    Parker RR, 1948. Symptomatology and certain other aspects of Rocky Mountain spotted fever. Moulton FR, ed. Rickettsial Diseases of Man. Washington, DC: American Association for the Advancement of Science, 139–146.

  • 41

    Walker DH, Hawkins HK, Hudson P, 1983. Fulminant Rocky Mountain spotted fever: its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency. Arch Pathol Lab Med 107 :121–125.

    • Search Google Scholar
    • Export Citation
  • 42

    Wolbach SB, 1917. The etiology and pathogenesis of Rocky Mountain spotted fever. The occurrence of the parasite and the pathology of the disease in man. Additional notes on the parasite. J Med Res 37 :499–508.

    • Search Google Scholar
    • Export Citation
  • 43

    Woods ME, Olano JP, 2007. Host defenses to Rickettsia rickettsii infection contribute to increased microvascular permeability in human cerebral endothelial cells. J Clin Immunol 28: 174–185.

    • Search Google Scholar
    • Export Citation
  • 44

    de Rodaniche EC, Rodaniche A, 1950. Spotted fever in Panama: isolation of the etiologic agent from a fatal case. Am J Trop Med 30 :511–517.

    • Search Google Scholar
    • Export Citation
  • 45

    Rozental T, Eremeeva ME, Paddock CD, Zaki SR, Dasch GA, Lemos ERS, 2006. Fatal case of Brazilian spotted fever confirmed by immunohistochemical staining and sequencing methods on fixed tissues. Ann NY Acad Sci 1078 :257–259.

    • Search Google Scholar
    • Export Citation
  • 46

    Zavala-Castro JE, Zavala-Velázquez JE, Walker DH, Ruiz Arcila EE, Laviada-Molina H, Olano JP, Ruiz-Sosa JA, Small MA, Dzul-Rosado KR, 2006. Fatal human infection with Rickettsia rickettsii, Yucatán, Mexico. Emerg Infect Dis 12 :672–674.

    • Search Google Scholar
    • Export Citation
  • 47

    Karpathy SE, Dasch GA, Eremeeva ME, 2007. Molecular typing of isolates of Rickettsia rickettsii using DNA sequencing of variable intergenic regions. J Clin Microbiol 45 :2545–2553.

    • Search Google Scholar
    • Export Citation
  • 48

    Labruna MB, Whitworth T, Bouyer DH, McBride J, Camargo LMA, Camargo EP, Popov V, Walker DH, 2004. Rickettsia bellii and Rickettsia amblyommii in Amblyomma ticks from the state of Rôndonia, Western Amazon, Brazil. J Med Entomol 41 :1073–1081.

    • Search Google Scholar
    • Export Citation
  • 49

    Estrada-Pe A, Venzal JM, Mangold AJ, Cafrune MM, Guglielmone AA, 2005. The Amblyomma maculatum Koch, 1844 (Acari: Ixodidae: Amblyomminae) tick group: diagnostic characters, description of the larva of A. parvitsarum Neumann, 1901, 16S rDNA sequences, distribution, and hosts. Syst Parasitol 60 :99–112.

    • Search Google Scholar
    • Export Citation
  • 50

    Paddock CD, Sumner JW, Comer JA, Zaki SR, Goldsmith CS, Goddard J, McLellan SLF, Tamminga CL, Ohl CA, 2004. Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis 38 :805–811.

    • Search Google Scholar
    • Export Citation
  • 51

    Sumner JW, Durden LA, Goddard J, Stromdahl EY, Clark KL, Reeves WK, Paddock CD, 2007. Gulf Coast ticks (Amblyomma maculatum) and Rickettsia parkeri, United States. Emerg Infect Dis 13: 751–753.

    • Search Google Scholar
    • Export Citation
  • 52

    Venzal JM, Portillo A, Estrada-Pe A, Castro O, Cabrera PA, Oteo JA, 2004. Rickettsia parkeri in Amblyomma triste from Uruguay. Emerg Infect Dis 10 :1493–1495.

    • Search Google Scholar
    • Export Citation
  • 53

    Silveira I, Pacheco RC, Szabó MPJ, Ramos HGC, Labruna MB, 2007. Rickettsia parkeri in Brazil. Emerg Infec Dis 13 :1111–1113.

  • 54

    Conti Dáz IA, 2001. Rickettsiosis por Rickettsia conorii (fiebre botonosa del Mediterreo fiebre de Marsella). Estado actual á en Uruguay. Rev Med Uruguay 17 :119–124.

    • Search Google Scholar
    • Export Citation
  • 55

    Madeira A, 2004. Surto de febre maculosa no estado de Santa Catarina. Rev Bras Parasitol Vet 13 (Suppl):364.

  • 56

    Seijo A, Picollo M, Nicholson WL, Paddock CD, 2007. Fiebre manchada por rickettsias en el Delta Bonaerense. Medicina (B Aires)67: 723–726.

    • Search Google Scholar
    • Export Citation
  • 57

    Parola P, Paddock CD, Raoult D, 2005. Tick-borne rickettsioses around the world: emerging diseases challenging old concepts. Clin Microbiol Rev 18 :719–756.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Rocky Mountain Spotted Fever in Argentina

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  • 1 Infectious Disease Pathology Branch and Rickettsial Zoonoses Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; Hospital Pablo Soria, San Salvador de Jujuy, Jujuy, Argentina; Servicio Infectologia and Tropical Medicine, Hospital San Roque, San Salvador de Jujuy, Jujuy, Argentina

We describe the first molecular confirmation of Rickettsia rickettsii, the cause of Rocky Mountain spotted fever (RMSF), from a tick vector, Amblyomma cajennense, and from a cluster of fatal spotted fever cases in Argentina. Questing A. cajennense ticks were collected at or near sites of presumed or confirmed cases of spotted fever rickettsiosis in Jujuy Province and evaluated by polymerase chain reaction assays for spotted fever group rickettsiae. DNA of R. rickettsii was amplified from a pool of A. cajennense ticks and from tissues of one of four patients who died during 2003–2004 after illnesses characterized by high fever, severe headache, myalgias, and petechial rash. The diagnosis of spotted fever rickettsiosis was confirmed in the other patients by indirect immunofluorescence antibody and immunohistochemical staining techniques. These findings show the existence of RMSF in Argentina and emphasize the need for clinicians throughout the Americas to consider RMSF in patients with febrile rash illnesses.

INTRODUCTION

Argentina encompasses ~2,780,400 km2 (1,073,500 mi2) and is the second largest country in South America in population and area (www.latinamericabureau.org). Cases of epidemic typhus have been reported from Argentina since 19191; however, no confirmed cases of spotted fever rickettsiosis in this country were documented until 1999.2 We describe the first molecular detection of Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever (RMSF), from a tick vector, Amblyomma cajennense (the Cayenne tick; Figures 1A and 1B), and a patient with fatal RMSF from Argentina.

MATERIALS AND METHODS

Tick collection and evaluation.

During October 1999, questing ticks were collected from vegetation using flannel cloth flags from several rural locations in the Departments of El Carmen, Ledesma, and Santa Bárbara in Jujuy Province in northwestern Argentina, at or near sites of presumed or confirmed cases of spotted fever rickettsiosis that had been reported to health authorities during 1993–1998. Ticks were stored in 70% ethanol at room temperature and identified by phenotypic characteristics and standard taxonomic keys. For molecular analyses, individual adult specimens, or pools of 5–15 nymphal stage ticks, were removed from the ethanol solution and allowed to air dry. The ticks were frozen in liquid nitrogen and crushed with a sterile Teflon pestle. Total DNA was extracted from pulverized ticks using an IsoQuick Nucleic Acid Extraction Kit (ORCA Research, Bothell, WA) and eluted in a final volume of 50 μL.

Two microliters of each DNA extract was screened using a polymerase chain reaction (PCR) assay designed to amplify a segment of the rickettsial 17-kd antigen gene, using 1 μmol each of primers 1 and 2, as described.3 Positive samples were evaluated with additional molecular tests that included PCR amplification of a segment of the rickettsial ompA gene, using 1 μmol each of primers Rr190k.71p and Rr190k.720n,4 and the rpoB gene, using 1 μmol each of primers RC1600D and RC2030R.5 PCR products were purified with a QIAquick PCR Purification Kit (QIAGEN, Valencia, CA). Duplicate sequencing reactions were performed with a BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA). PCR primers and excess dye were removed with a DyeEx 2.0 column (QIAGEN). Sequences were determined using an ABI 3100 capillary sequencer (Applied Biosystems). Sequences were assembled with Seqmerge (Accelrys, San Diego, CA) and compared with those in GenBank using the BLAST 2.0 program (NCBI, Bethesda, MD).

Patient evaluation

During 2003–2004, four patients presented to hospitals in Jujuy Province with rapidly fatal, rash-associated, febrile illnesses. Routine blood cultures and serologic assays for dengue, leptospirosis, and hantavirus infection failed to identify a causative agent. Subsequent evaluation of clinical, epidemiologic, and autopsy data suggested that these patients died from a spotted fever rickettsiosis. Serum samples obtained during the patients’ illnesses and tissue specimens obtained at autopsy were sent to the Centers for Disease Control and Prevention (CDC) for confirmatory laboratory tests.

Serum specimens were evaluated for IgG antibodies reactive with R. rickettsii by using an indirect immunofluorescence antibody (IFA) assay.2 Antibody titers were interpreted as the reciprocal of the last dilution of the serum sample showing reactivity with a fluorescein isothiocyanate–conjugated goat anti-human IgG (γ-specific) at a dilution of 1/150.

Tissue specimens obtained at autopsy were fixed in 10% neutral-buffered formalin. Some tissues from one patient were also placed in 70% ethanol. Three-micrometer sections cut from formalin-fixed, paraffin-embedded, tissue samples were stained with hematoxylineosin and using an immuno-alkaline phosphatase technique with a polyclonal rabbit anti-R. rickettsii antibody at a dilution of 1/500.2 DNA was extracted from small pieces of ethanol-fixed tissue using a QIAgen Mini Kit (QIAGEN) and eluted in a final volume of 200 μL. DNA extracts were evaluated using PCR assays designed to amplify a segment of the rickettsial 17-kd antigen gene or the ompA gene. For each 50-μL reaction, 5 μL of extract was added to 45 μL of PCR core reagents using the High Fidelity PCR Master kit (Roche Diagnostics, Indianapolis, IN). Primers Tz-15 and Tz-166 were used for amplification of the 17-kd antigen gene, and primers 190-707 and 190–7018 for the ompA gene, each at a final concentration of 300 nmol. Thermal cycler parameters consisted of an initial denaturation period of 2 minutes at 94°C, followed by 40 cycles of 15 seconds at 94°C, and then 30 seconds at 55°C for the 17-kd antigen gene or 60°C for the ompA gene, 45 seconds at 72°C, and a 5-minute extension period at 72°C.

RESULTS

A total of 16 adult and 100 nymphal stage Amblyomma spp. ticks, including 9 adult and 60 A. cajennense nymphs, were collected from 12 sites in Jujuy Province. One adult male Cayenne tick was deposited in the US National Tick Collection at Statesboro, GA (voucher specimen accession number RML 123729). From the remaining A. cajennense specimens, one pool of five nymphs produced a 208-bp amplicon using the 17-kd antigen gene PCR assay that showed 100% homology to the corresponding segment of the 17-kd gene of several Rickettsia spp. in GenBank, including R. rickettsii (accession no. AY281069). A 608-bp segment of the ompA gene was subsequently amplified from this same extract using the ompA PCR assay and showed 100% identity to only the corresponding sequences of R. rickettsii (U43804, M31227). These ticks were collected at Saladillo, in the Department of Santa Bárbara, near the home of two children who had died of spotted fever in 1994.2 From this same pool of specimens, a 459-bp segment of the rpoB gene was amplified (DQ870673) using the rpoB PCR assay and showed 100% homology to only the corresponding sequence of R. bellii (CP000087).

During September and October 2003–2004, three boys and one man from the Departments of San Salvador de Jujuy and Santa Bárbara in southern Jujuy Province, died after illnesses of ~1 to 1.5-week durations (Table 1). Patients 1, 2, and 3 became ill within a 2-week interval and resided within 5 km of each other in the town of Tilquiza, ~30 km north of the provincial capital, San Salvador de Jujuy. Patient 4 resided in the town of Palma Sola, ~20 km north of Saladillo. The patients presented for initial medical attention a median of 4.5 days after the onset of symptoms. All described one or more tick bites shortly before illness onset and all developed fever, severe headache, malaise, myalgias, and a petechial rash that started on the extremities and spread centrally to involve the trunk. Three patients became severely hypotensive and one patient developed renal failure and pleural and pericardial effusions. Two patients had elevated serum aspartate aminotransferase levels. All patients developed mild to severe hyponatremia (lowest serum sodium level, 122–133 mmol/L) and severe thrombocytopenia (lowest platelet count, 5–20 × 109/L). A hemorrhagic diathesis (retinal hemorrhage or intracranial bleed) was described for three patients. All patients had convulsions and became comatose shortly before death.

Serum specimens were available for Patients 2 and 3, who had IgG antibody titers reactive with R. rickettsii of 128 and 256, respectively. A histopathologic evaluation of tissues from Patients 1 and 4 showed lymphohistiocytic portal triaditis and Kupffer cell erythrophagocytosis in the liver, interstitial pneumonitis with pulmonary edema and hemorrhage, and focal myocarditis. No conspicuous inflammatory cell infiltrates were evident in central nervous system tissues of either patient. The immunohistochemical (IHC) stain showed abundant spotted fever rickettsiae in the endothelium of arterioles, venules, and small arteries and veins of all tissues examined, including cerebral cortex, cerebellum, liver, lung, kidney, spleen, and skin. Rickettsiae were also identified in the smooth muscle of small vessels of several tissues including lung, kidney, and liver (Figure 1C). Many of the involved vessels, particularly leptomeningeal venules and arterioles, showed no appreciable inflammatory cell infiltrates despite extensive infection with large numbers of rickettsiae (Figure 1D).

A 208-bp amplicon, amplified from ethanol-preserved fragments of lung, spleen, liver, heart, and cerebral cortex of Patient 4 using the 17-kd antigen gene PCR assay, matched the corresponding sequences of several Rickettsia spp., including R. rickettsii. A 590-bp fragment of the rompA gene was subsequently amplified from the spleen of this patient that showed 100% homology to only the corresponding segment of the rompA gene of R. rickettsii.

DISCUSSION

These findings show conclusively the occurrence of RMSF in Argentina. Confirmed human infections with R. rickettsii have been documented in Brazil and Colombia for > 70 years911; however, no cases of spotted fever were described from other South American countries until the end of the 20th century.2 Epidemic typhus has been reported from several regions of Argentina, including Jujuy Province, since the 1920s and 1930s.1 It is likely that some early reports of “typhus” in Argentina in fact represented cases of spotted fever, similar to those cases of RMSF misidentified as epidemic or murine typhus in the United States and other regions of South America during the early 20th century.1113 A cluster of severe spotted fever in six young children occurred in southeastern Jujuy Province and neighboring Salta Province during November 1993 to March 1994 and resulted in the death of two patients. Presumably, these patients were also infected with R. rickettsii; however, only spotted fever group–specific assays were used to diagnose cases from that outbreak.2

Spotted fever rickettsiae other than R. rickettsii have been identified previously in Rhipicephalus sanguineus, Amblyomma neumanni, and Amblyomma parvum ticks collected in Argentina,1416 and R. rickettsii has been isolated in culture or detected by molecular methods from naturally infected A. cajennense collected in Brazil, Mexico, and Panama1719; however, this is the first report to identify R. rickettsii in a tick from Argentina. The Cayenne tick is extensively distributed throughout northwestern Argentina, including Jujuy Province, and nymphs and adults are frequently identified from tick bite surveys of humans.2,2022 In Argentina, nymphs are most abundant from August through November and adults from November though January.21 These intervals correspond to the months during which cases of spotted fever have been reported in Jujuy Province.2

Investigators first recognized the vector potential of A. cajennense by showing transovarial and trans-stadial transmission of R. rickettsii in Cayenne ticks during the early 1930s.2325 Epidemiologic surveys subsequently identified R. rickettsii–infected ticks at localities of presumed exposures and attached to patients with spotted fever.26,27 We amplified DNA of R. rickettsii from a pool of A. cajennense ticks collected ~100 m from a household of two children who died of spotted fever 5 years earlier. The adult patient in this series, who died in 2004, lived within 20 km of this same site. These observations reflect one of the peculiar aspects of RMSF, namely persistent foci of infected ticks that create clustered cases of disease in families or communities.28 In this series and in many others from the United States and Latin America, multiple cases of RMSF occurred simultaneously in the same household, causing as many as six deaths of affected family members over the course of several days to weeks.2,11,2932

Children make up a disproportionate number of the patients and deaths in these clusters. This unfortunate characteristic likely represents common exposures to tick-infested habitats during outdoor play.

The high case-fatality rates (40–95%) that characterize historic and contemporary outbreaks of RMSF in Argentina,2 Brazil,2931 and Colombia11,32 rival or exceed the cumulative mortality rate described in western Montana (65%) during 1890–1920.33 Sentinel outbreaks of RMSF, including those rediscovered after several decades of inattention, are often represented predominantly by patients with the most severe manifestations of the illness. The patients described in this report, as well as those from western Montana during the early 20th century, lived in predominantly rural areas with limited access to health care, and most presented for medical attention relatively late in the course of their illnesses. Non-familiarity of many physicians with RMSF, reflected by a failure to administer the recommended antibiotic therapy for this infection (i.e., doxycycline), often contributes to an adverse outcome even in those patients who seek medical attention relatively early during the disease.

The clinical tenets that ensure successful patient outcomes in RMSF, namely consideration of the diagnosis and early initiation of specific antibiotic therapy, apply to health care providers throughout the Americas. In many respects, the challenges faced by health care professionals in Latin America are even greater, where many other endemic infectious diseases clinically mimic RMSF, including dengue, yellow fever, malaria, leptospirosis, hantavirus pulmonary syndrome, and hemorrhagic fevers caused by New World arenaviruses.3436 Vigilance is required of public health authorities throughout the range of RMSF to articulate the early use of doxycycline in patients with a febrile rash illness, particularly in those who also describe a recent tick bite. As shown in this case series and in many others during the last century, untreated RMSF can be a devastating multi-organ system disease and has the capacity to rapidly kill its victims. Because the interval from when a patient first seeks medical attention to the point at which antibiotic therapy is most effective at minimizing morbidity and mortality can be as brief as a few days, early empiric therapy with doxycycline is an important consideration for any patient with supporting clinical features and a history of tick exposure.32

In this series, all patients suffered seizures and coma; however, no prominent inflammatory cell infiltrates were identified by histology in the central nervous system (CNS) of either of the two young patients who died after 7 days of illness and were evaluated at autopsy despite extensive rickettsial infection of vascular endothelium in these tissues. The paucity of inflammation in the CNS of these patients is in agreement with the observation by Lillie37 that conspicuous pathologic lesions are absent or scant in the CNS of patients who die before Day 11 of illness. Recently, investigators have noted that CD8+ T cells, considered crucial for the successful immune clearance of spotted fever rickettsiae, are few or undetectable around the R. rickettsii–infected microvasculature in the brains of patients who die < 9 days after illness onset.38 Indeed, most patients who succumb to RMSF die before Day 10,39 and many will develop severe neurologic manifestations, including stupor, delirium, convulsions, cerebral edema, and coma.40 Patients with glucose-6-phosphate dehydrogenase deficiency who are infected with R. rickettsii often die of fulminating RMSF (i.e., death within 3–7 days40), with extensive vascular damage in the CNS that occurs independent of a localized inflammatory cell response.41 In this study, we frequently identified infection of arteriolar smooth muscle by R. rickettsii in several major organs, including the liver and kidney. This distribution was first noted by Wolbach42 almost 100 years ago; however, its role in the pathogenesis of RMSF remains to be explored. Collectively, these findings support experimental observations that direct, rickettsia-mediated endothelial injury and increased microvascular permeability can occur in the absence of a localized inflammatory cell response43 and may be particularly evident in those patients with severe and relatively brief clinical courses.

Rickettsia rickettsii is the only spotted fever group rickettsia in the Western Hemisphere to be isolated or detected by molecular techniques from patients with a fatal spotted fever rickettsiosis.32,36,4447 In this context, it is likely that R. rickettsii caused each of the spotted fever deaths in Jujuy Province identified in this report and previously.2 Nonetheless, the confirmatory assays (i.e., IFA and IHC) that were used to identify most of these patients do not provide a species-specific diagnosis. The antibody used in the IHC assay reacts strongly with several recognized species of pathogenic spotted fever group rickettsiae indigenous to the Western Hemisphere, including R. rickettsii, R. akari, and R. parkeri.39 Other tick-borne rickettsiae, including R. amblyommii, R. massiliae, and R. bellii, and an incompletely characterized rickettsia designated Rickettsia spp. strain Argentina, have been identified recently in tick species that bite humans in Argentina.1416 R. bellii has been identified in at least seven other Amblyomma spp. in South America15,48; to our knowledge, this is the first report to document its occurrence in A. cajennense. We amplified DNA of this rickettsia from the same pool of five nymphs that also contained DNA of R. rickettsii; however, it is unknown if this represented co-infection of the same tick or separate infections in two or more ticks from that pool.

At least 15 species of ixodid ticks, including many that harbor rickettsiae of undetermined pathogenicity, are reported to bite humans in Argentina.22 Adult and immature ticks of the Amblyomma maculatum tick group49 comprised the remainder of the ticks collected during the 1999 field survey in Jujuy Province. These ticks were not evaluated by molecular assays for rickettsiae; however, all tick species in this group will bite humans, and at least two species in this complex (A. maculatum and A. triste) are putative vectors of Rickettsia parkeri, recently recognized as a cause of eschar-associated spotted fever rickettsiosis in the Western Hemisphere.5053 Eschar-associated rickettsioses after tick bites have been reported recently from Uruguay, Brazil, and Argentina.5456 A serosurvey of 105 persons residing in the Department of Santa Bárbara in Jujuy Province, conducted between two recognized episodes of severe spotted fever in 1994 and 2004, showed antibodies reactive with spotted fever group rickettsiae at titers ≥ 64 in 4% of the participants; however, none of the persons with significant antibody titers recalled an illness of the severity characteristically associated with classic RMSF.2 These data suggest that multiple spotted fever rickettsioses of varying severity may exist in this country similar to many other regions of the world.57

The true, rather than collective, clinical spectrum, epidemiology, and distribution of the various spotted fever rickettsioses indigenous to the Americas will depend on the continued efforts of clinicians and laboratorians to achieve accurate diagnoses by using tissue-based molecular or culture techniques. Renewed interest in RMSF by Latin American investigators also signals a vital and exciting period of scientific exploration in this region of the world and provides hope that future discoveries will enhance clinical awareness and early presumptive diagnosis and treatment of this recalcitrant and life-threatening infectious disease.

Table 1

Demographic, epidemiologic, and clinical features of confirmed and probable cases of fatal Rocky Mountain spotted fever in Jujuy Province, Argentina, 2003–2004

PatientAge (years)/sexTown/departmentMonth/year of onsetDays onset to medical careDays onset to deathAntibiotic therapyConfirmatory tests
18/MaleTilquiza/San Salvador de Jujuy09/0327CefotaximeIHC
231/MaleTilquiza/San Salvador de Jujuy10/0359Ceftriaxone/clarithromycinIFA
316/MaleTilquiza/San Salvador de Jujuy10/0378Ceftriaxone/ciprofloxacinIFA
43/MalePalma Sola/Santa Bárbara10/0447Amoxicillin/chloramphenicolIHC, PCR
Figure 1.
Figure 1.

Adult female (A) and male (B) A. cajennense (the Cayenne tick), a vector of RMSF in Latin America. Abundant spotted fever group rickettsiae and rickettsial antigens (red) are stained by IHC in tissues of a patient with fatal RMSF, in vascular smooth muscle cells of a hepatic arteriole [arrow] (C), and in endothelial cells of small vessels in the cerebellar leptomeninges (D). The involved vessels show no appreciable inflammatory cell infiltrates despite extensive infection with large numbers of rickettsiae. Immunoalkaline phosphatase stain with fast red-naphthol phosphate and hematoxylin counterstain (polyclonal anti-Rickettsia rickettsii antibody at 1/500); original magnifications, ×100 (C) and ×50 (D).

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 78, 4; 10.4269/ajtmh.2008.78.687

*

Address correspondence to Christopher D. Paddock, 1600 Clifton Road, MS G-32, Atlanta, GA 30333. E-mail: cdp9@cdc.gov

Authors’ addresses: Christopher D. Paddock, Infectious Disease Pathology Branch, Mailstop G-32, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, Telephone: 404-639-1309, Fax: 404-639-3043, E-mail: CPaddock@cdc.gov. Susana Fernandez, Hospital Pablo Soria, Guemes 1345, (4600) San Salvador de Jujuy, Jujuy, Argentina, Telephone: 54-388-685-3852, E-mail: nfag10fernandez@hotmail.com. Gustavo A. Echenique, Hospital San Roque, San Martin 330, (4600) San Salvador de Jujuy, Jujuy, Argentina, Telephone: 54-388-424-0390, Fax: 54-388-422-5357, E-mail: gusechenique@hotmail.com. John W. Sumner, Infectious Disease Pathology Branch, Mailstop G-32, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, Telephone: 404-639-1097, Fax: 404-639-3043, E-mail: JSumner@cdc.gov. Will K. Reeves, Rickettsial Zoonoses Branch, Mailstop G-13, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333. Current address: Arthropod-Borne Animal Diseases Research Laboratory, USDA–ARS, College of Agriculture, Dept. 3354, 1000 East University Avenue, Laramie, WY 82071, Telephone: 307-766-3630, E-mail: Will.Reeves@ars.usda.gov. Sherif R. Zaki, Infectious Disease Pathology Branch, Mailstop G-32, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, Telephone: 404-639-3133. Fax: 404-639-3043, E-mail: SZaki@cdc.gov. Carlos E. Remondegui, Servicio Infectologia and Tropical Medicine, Hospital San Roque, San Martin 330, (4600) San Salvador de Jujuy, Jujuy, Argentina, Telephone: 54-388-422-1307, Fax: 54-388-426-0019, E-mail: remondegui@arnet.com.ar.

Acknowledgments: The authors thank Carlos Ripoll (Ministerio de Bienstar Social, Area Epidemiologia, Departamento de Chagas y Patalogia Regional, San Salvador de Jujuy, Jujuy, Argentina) for assisting with tick the collections; Lance Durden (Georgia Southern University, Statesboro, GA) for help with tick identifications; James Gathany (CDC) for the photographs of A. cajenennse; Joseph Singleton, Jr. (CDC) for performing the IFA tests; Patricia Greer, Gillian Genrich, and Michelle Packard (CDC) for performing the IHC tests; and Jeannette Guarner and Giliane Trindade (CDC) for translating several of the references.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily reflect the views of the US Department of Health and Human Services.

REFERENCES

  • 1

    Veintemillas F, 1944. Sobre las Rickettsiasis y las Fiebres Exantematicas el Tifus Altiplanico. La Paz, Bolivia: Escuela Tip Salesiana.

  • 2

    Ripoll CM, Remondegui CE, Ordonez G, Arazamendi R, Fusaro H, Hyman MJ, Paddock CD, Zaki SR, Olson JG, Santos-Buch CA, 1999. Evidence of rickettsial spotted fever and ehrlichial infections in a subtropical territory of Jujuy, Argentina. Am J Trop Med Hyg 61: 350–354.

    • Search Google Scholar
    • Export Citation
  • 3

    Webb L, Carl M, Malloy DC, Dasch GA, Azad AF, 1990. Detection of murine typhus infection in fleas by using the polymerase chain reaction. J Clin Microbiol 28: 530–534.

    • Search Google Scholar
    • Export Citation
  • 4

    Ishikura M, Ando S, Shinagawa Y, Matsuura K, Hasegawa S, Nakayama T, Fujita H, Eatanabe M, 2003. Phylogenetic analysis of spotted fever group rickettsiae based in gltA, 17 kDa, and rOmpA genes amplified by nested PCR from ticks in Japan. Microbiol Immunol 47: 823–832.

    • Search Google Scholar
    • Export Citation
  • 5

    Drancourt M, Raoult D, 1999. Characterization of mutations in the rpoB gene in naturally rifampin-resistant Rickettsia species. Antimicrob Agents Chemother 43 :2400–2403.

    • Search Google Scholar
    • Export Citation
  • 6

    Tzianabos T, Anderson BE, McDade JE, 1989. Detection of Rickettsia ricketsii in clinical specimens by using polymerase chain reaction technology. J Clin Microbiol 27: 2866–2868.

    • Search Google Scholar
    • Export Citation
  • 7

    Regnery RL, Spruill CL, Plikaytis BD, 1991. Genotypic identification of rickettsiae and estimation of intraspecies sequence divergence for portions of two rickettsial genes. J Bacteriol 173 :1576–1589.

    • Search Google Scholar
    • Export Citation
  • 8

    Roux V, Fournier PE, Raoult D, 1996. Differentiation of spotted fever group rickettsiae by sequencing and analysis of restriction fragment length polymorphism of PCR-amplified DNA of the gene encoding the protein rOmpA. J Clin Microbiol 34: 2058–2065.

    • Search Google Scholar
    • Export Citation
  • 9

    Piza J, Salles-Gomes F, Salles-Gomes L, Meyer J, Fleury JP, Castro O, Rodrigues C, Rocha Lima H, 1931. Le typhus exanthématique a Sao Paulo. Comp Rend Séances Soc Biol Fil 106 :1020–1022.

    • Search Google Scholar
    • Export Citation
  • 10

    Dyer RE, 1933. Relationship between Rocky Mountain spotted fever and exanthematic typhus of Sao Paulo. Public Health Rep 48 :521–522.

  • 11

    Patino L, Afanador A, Paul JH, 1937. A spotted fever in Tobia, Colombia. Am J Trop Med Hyg 17 :639–653.

  • 12

    Dumler JS, 1991. Fatal Rocky Mountain spotted fever in Maryland, 1901. JAMA 265 :718.

  • 13

    Milam DF, 1934. Rocky Mountain spotted fever in North Carolina. South Med J 27 :788–793.

  • 14

    Cicuttin GL, Rodríguez Vargas M, Jado I, Anda P, 2004. Primera detección de Rickettsia massiliae en la ciudad de Buenos Aires. Resultados preliminaries. Rev Argentina Zoonosis 1 :8–10.

    • Search Google Scholar
    • Export Citation
  • 15

    Labruna MB, Pacheco RC, Nava S, Brandão PE, Richtzenhain LJ, Guglielmone AA, 2007. Infection by Rickettsia bellii and Candidatus “ Rickettsia amblyommii” in Amblyomma neumanni ticks from Argentina. Microb Ecol 54 :126–133.

    • Search Google Scholar
    • Export Citation
  • 16

    Pacheco RC, Moraes-Filho J, Nava S, Brandão PE, Richtzenhain LJ, Labruna MB, 2007. Detection of a novel spotted fever group rickettsia in Amblyomma parvum ticks (Acari: Ixodidae) from Argentina. Exp Appl Acarol 43 :63–71.

    • Search Google Scholar
    • Export Citation
  • 17

    Bustamente ME, Varela G, 1946. III. Estudios de fiebre manchada en Mexico. Hallazgo del Amblyomma cajennense naturalmente infectado, en Veracruz. Rev Inst Salub Enferm Trop 7 :75–78.

    • Search Google Scholar
    • Export Citation
  • 18

    de Rodaniche EC, 1953. Natural infection of the tick, Amblyomma cajenennse, with Rickettsia rickettsii in Panama. Am J Trop Med Hyg 2 :696–699.

    • Search Google Scholar
    • Export Citation
  • 19

    Guedes E, Leite RC, Prata MCA, Pacheco RC, Walker DH, Labruna MB, 2005. Detection of Rickettsia rickettsii in the tick Amblyomma cajennense in a new Brazilian spotted fever-endemic area in the state of Minas Gerais. Mem Inst Oswaldo Cruz 100 :841–845.

    • Search Google Scholar
    • Export Citation
  • 20

    Estrada-Peña A, Guglielmone AA, Mangold AJ, 2004. The distribution and ecological ‘preferences’ of the tick Amblyomma cajennense (Acari: Ixodidae), an ectoparasite of humans and other mammals in the Americas. Ann Trop Med Parasitol 98 :283–292.

    • Search Google Scholar
    • Export Citation
  • 21

    Guglielmone AA, Mangold AJ, Viñbal AE, 1991. Ticks (Ixodidae) parasitizing humans in four provinces of north-western Argentina. Ann Trop Med Parasitol 85 :539–542.

    • Search Google Scholar
    • Export Citation
  • 22

    Guglielmone AA, Beati L, Barros-Battesti DM, Labruna MB, Nava S, Venzal JM, Mangold AJ, Szabó MP, Martins JR, González-Acuña D, Estrada-Peña A, 2006. Ticks (Ixodidae) on humans in South America. Exp Appl Acarol 40 :83–100.

    • Search Google Scholar
    • Export Citation
  • 23

    Montiero JL, Da Fonseca F, Prado A, 1932. Typho exanthematico de S. Paulo, VI. Pesquisas sobre a possibiliadade da transmissao experimental do virus por Ixodidae. Bras Med 46 :49–52.

    • Search Google Scholar
    • Export Citation
  • 24

    Brumpt E, 1933. Tranmission de la fièvre pouprée des Montanges Rocheusse par la tique américaine Amblyomma cayennense. Comp Rend Séances Soc Biol Fil 144 :416–419.

    • Search Google Scholar
    • Export Citation
  • 25

    Parker RR, Philip CB, Jellison WL, 1933. Rocky Mountain spotted fever: potentialities of tick transmission in relation to geographical occurrence in the United States. Am J Trop Med 13 :341–379.

    • Search Google Scholar
    • Export Citation
  • 26

    Moreira JA, de Magalhães O, 1936. Typho exanthematico de Minas Gerais. Bras Med 51 :881–882.

  • 27

    Dias E, Martins AV, 1937. Aspectos do typho exanthematico em Minas Gerais. Bras Med 51 :431–441.

  • 28

    Jones TF, Craig AS, Paddock CD, McKechnie DB, Childs JE, Zaki SR, Schaffner W, 1999. Family cluster of Rocky Mountain spotted fever. Clin Infect Dis 28 :853–859.

    • Search Google Scholar
    • Export Citation
  • 29

    Sexton DJ, Muniz M, Corey R, Breitschwerdt EB, Hegarty B, Dumler S, Walker DH, Pecanha PM, Dietze R, 1993. Brazilian spotted fever in Esprito Santo, Brazil: description of a focus of infection in a new endemic region. Am J Trop Med Hyg 49 :222–226.

    • Search Google Scholar
    • Export Citation
  • 30

    de Lemos ERS, Alvarenga FBF, Cintra ML, Ramos MC, Paddock CD, Ferebee TL, Zaki SR, Ferreira FCC, Ravagnani RC, Machado RD, Guimarães MAAM, Coura JR, 2001. Spotted fever in Brazil: a seroepidemiologic study and description of clinical cases in an endemic area in the state of São Paulo. Am J Trop Med Hyg 65 :329–334.

    • Search Google Scholar
    • Export Citation
  • 31

    Galvão MAM, Dumler JS, Mafra CL, Calic SB, Chamone CB, Filho GC, Olano JP, Walker DH, 2003. Fatal spotted fever rickettsiosis, Minas Gerais, Brazil. Emerg Infect Dis 9 :1402–1405.

    • Search Google Scholar
    • Export Citation
  • 32

    Hildago M, Orejuela L, Fuya P, Carrillo P, Hernandez J, Parra E, Keng C, Small M, Olano JP, Bouyer D, Castaneda E, Walker D, Valbuena G, 2007. Rocky Mountain spotted fever, Colombia. Emerg Infect Dis 13 :1058–1060.

    • Search Google Scholar
    • Export Citation
  • 33

    Philip RN, 2000. Rocky Mountain Spotted Fever in Western Montana: Anatomy of a Pestilence. Hamilton, MT: Bitter Root Valley Historical Society.

  • 34

    Calero C, Núñez JM, Silva Goytia R, 1952. Rocky Mountain spotted fever in Panama. Report of two cases. Am J Trop Med Hyg 1 :631–636.

    • Search Google Scholar
    • Export Citation
  • 35

    Zavala-Velazquez JE, Yu X-J, Walker DH, 1996. Unrecognized spotted fever group rickettsiosis masquerading as dengue fever in Mexico. Am J Trop Med Hyg 55 :157–159.

    • Search Google Scholar
    • Export Citation
  • 36

    Estripeaut D, Aramburú MG, Sáez-Llorens X, Thompson HA, Dasch GA, Paddock CD, Zaki S, Eremeeva ME, 2007. Rocky Mountain spotted fever, Panama. Emerg Infect Dis 13 :1763–1765.

    • Search Google Scholar
    • Export Citation
  • 37

    Lillie RD, 1941. Pathology of Rocky Mountain spotted fever. Natl Inst Health Bull 177 :1–59.

  • 38

    Valbuena G, Bradford W, Walker DH, 2003. Expression analysis of the T-cell-targeting chemokines CXCL9 and CXCL10 in mice and humans with endothelial infections caused by rick-ettsiae of the spotted fever group. Am J Pathol 163 :1357–1369.

    • Search Google Scholar
    • Export Citation
  • 39

    Paddock CD, Greer PW, Ferebee TL, Singleton J, McKechnie DB, Treadwell TA, Krebs JW, Clarke MJ, Holman RC, Olson JG, Childs JE, Zaki SR, 1999. Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease. J Infect Dis 179 :1469–1476.

    • Search Google Scholar
    • Export Citation
  • 40

    Parker RR, 1948. Symptomatology and certain other aspects of Rocky Mountain spotted fever. Moulton FR, ed. Rickettsial Diseases of Man. Washington, DC: American Association for the Advancement of Science, 139–146.

  • 41

    Walker DH, Hawkins HK, Hudson P, 1983. Fulminant Rocky Mountain spotted fever: its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency. Arch Pathol Lab Med 107 :121–125.

    • Search Google Scholar
    • Export Citation
  • 42

    Wolbach SB, 1917. The etiology and pathogenesis of Rocky Mountain spotted fever. The occurrence of the parasite and the pathology of the disease in man. Additional notes on the parasite. J Med Res 37 :499–508.

    • Search Google Scholar
    • Export Citation
  • 43

    Woods ME, Olano JP, 2007. Host defenses to Rickettsia rickettsii infection contribute to increased microvascular permeability in human cerebral endothelial cells. J Clin Immunol 28: 174–185.

    • Search Google Scholar
    • Export Citation
  • 44

    de Rodaniche EC, Rodaniche A, 1950. Spotted fever in Panama: isolation of the etiologic agent from a fatal case. Am J Trop Med 30 :511–517.

    • Search Google Scholar
    • Export Citation
  • 45

    Rozental T, Eremeeva ME, Paddock CD, Zaki SR, Dasch GA, Lemos ERS, 2006. Fatal case of Brazilian spotted fever confirmed by immunohistochemical staining and sequencing methods on fixed tissues. Ann NY Acad Sci 1078 :257–259.

    • Search Google Scholar
    • Export Citation
  • 46

    Zavala-Castro JE, Zavala-Velázquez JE, Walker DH, Ruiz Arcila EE, Laviada-Molina H, Olano JP, Ruiz-Sosa JA, Small MA, Dzul-Rosado KR, 2006. Fatal human infection with Rickettsia rickettsii, Yucatán, Mexico. Emerg Infect Dis 12 :672–674.

    • Search Google Scholar
    • Export Citation
  • 47

    Karpathy SE, Dasch GA, Eremeeva ME, 2007. Molecular typing of isolates of Rickettsia rickettsii using DNA sequencing of variable intergenic regions. J Clin Microbiol 45 :2545–2553.

    • Search Google Scholar
    • Export Citation
  • 48

    Labruna MB, Whitworth T, Bouyer DH, McBride J, Camargo LMA, Camargo EP, Popov V, Walker DH, 2004. Rickettsia bellii and Rickettsia amblyommii in Amblyomma ticks from the state of Rôndonia, Western Amazon, Brazil. J Med Entomol 41 :1073–1081.

    • Search Google Scholar
    • Export Citation
  • 49

    Estrada-Pe A, Venzal JM, Mangold AJ, Cafrune MM, Guglielmone AA, 2005. The Amblyomma maculatum Koch, 1844 (Acari: Ixodidae: Amblyomminae) tick group: diagnostic characters, description of the larva of A. parvitsarum Neumann, 1901, 16S rDNA sequences, distribution, and hosts. Syst Parasitol 60 :99–112.

    • Search Google Scholar
    • Export Citation
  • 50

    Paddock CD, Sumner JW, Comer JA, Zaki SR, Goldsmith CS, Goddard J, McLellan SLF, Tamminga CL, Ohl CA, 2004. Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis 38 :805–811.

    • Search Google Scholar
    • Export Citation
  • 51

    Sumner JW, Durden LA, Goddard J, Stromdahl EY, Clark KL, Reeves WK, Paddock CD, 2007. Gulf Coast ticks (Amblyomma maculatum) and Rickettsia parkeri, United States. Emerg Infect Dis 13: 751–753.

    • Search Google Scholar
    • Export Citation
  • 52

    Venzal JM, Portillo A, Estrada-Pe A, Castro O, Cabrera PA, Oteo JA, 2004. Rickettsia parkeri in Amblyomma triste from Uruguay. Emerg Infect Dis 10 :1493–1495.

    • Search Google Scholar
    • Export Citation
  • 53

    Silveira I, Pacheco RC, Szabó MPJ, Ramos HGC, Labruna MB, 2007. Rickettsia parkeri in Brazil. Emerg Infec Dis 13 :1111–1113.

  • 54

    Conti Dáz IA, 2001. Rickettsiosis por Rickettsia conorii (fiebre botonosa del Mediterreo fiebre de Marsella). Estado actual á en Uruguay. Rev Med Uruguay 17 :119–124.

    • Search Google Scholar
    • Export Citation
  • 55

    Madeira A, 2004. Surto de febre maculosa no estado de Santa Catarina. Rev Bras Parasitol Vet 13 (Suppl):364.

  • 56

    Seijo A, Picollo M, Nicholson WL, Paddock CD, 2007. Fiebre manchada por rickettsias en el Delta Bonaerense. Medicina (B Aires)67: 723–726.

    • Search Google Scholar
    • Export Citation
  • 57

    Parola P, Paddock CD, Raoult D, 2005. Tick-borne rickettsioses around the world: emerging diseases challenging old concepts. Clin Microbiol Rev 18 :719–756.

    • Search Google Scholar
    • Export Citation
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