Author:
- ABSTRACT.
- INTRODUCTION
- MATERIALS AND METHODS
- Study design.
- Sampling.
- Outcomes of SFGR seropositivity in humans and domestic animals.
- Outcomes of household tick infestation.
- Exposures and covariates.
- Capture, identification, and SFGR seropositivity of opossums.
- Identification of ticks collected from canines and SFGR detection.
- Statistical analysis.
- Models for seroprevalence and household infestation studies.
- Models for the seroincidence study.
- Ethics statement.
- RESULTS
- DISCUSSION
- CONCLUSIONS
- ACKNOWLEDGMENTS
- References
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Valbuena G, 2007. Fiebres que no deberían matar. Biomedica 27: 321–324.
-
2.
Quintero JC, Hidalgo M, Rodas JD, 2012. Rickettsiosis, una enfermedad letal emergente y re-emergente en Colombia Introducción Las rickettsias son un género de bacterias intracelulares. Univ Sci (Bogota) 17: 82–99.
-
3.
Arroyave E, Londoño AF, Quintero JC, Agudelo-Flórez P, Arboleda M, Díaz FJ, Rodas JD, 2013. Etiología y caracterización epidemiológica del síndrome febril no palúdico en tres municipios del Urabá antioqueño, Colombia. Biomedica 33: 99–107.
-
4.
Villar LA, Rojas DP, Besada-Lombana S, Sarti E, 2015. Epidemiological trends of dengue disease in Colombia (2000–2011): a systematic review. PLoS Negl Trop Dis 9: 1–16.
-
5.
Cortés JA, Romero-Moreno LF, Aguirre-León CA, Pinzón-Lozano L, Cuervo SI, 2016. Enfoque clínico del síndrome febril agudo en Colombia. Infectio 21: 39–50.
-
6.
Londoño A, Arango C, Acevedo-Gutiérrez Y, Paternina L, Montes C, Ruiz I, Labruna M, Díaz F, Walker D, Rodas JA , 2019. Cluster of cases of Rocky Mountain Spotted Fever in an area of Colombia not known to be endemic for this disease. Am J Trop Med Hyg 101: 346–342.
-
7.
Horta MC, Moraes-Filho J, Casagrande R, Saito TB, Rosa SC, Ogrzewalska M, Matushima ER, Labruna MB, 2009. Experimental infection of opossums Didelphis aurita by Rickettsia rickettsii and evaluation of the transmission of the infection to ticks Amblyomma cajennense. Vector Borne Zoonotic Dis 9: 109–118.
-
8.
Labruna MB, 2009. Ecology of Rickettsia in South America. Ann N Y Acad Sci 1166: 156–166.
-
9.
Drexler N, Yaglom H, Casal M, Fierro M, Kriner P, Murphy B, Kjemtrup A, Paddock CD, 2017. Fatal Rocky Mountain Spotted Fever along the United States–Mexico border, 2013–2016. Emerg Infect Dis 23: 1621–1626.
-
10.
Quintero JC, Paternina LE, Uribe YA, Muskus C, Hidalgo M, Gil J, Cienfuegos AV, Osorio QL, Rojas AC, 2017. Eco-epidemiological analysis of rickettsial seropositivity in rural areas of Colombia: A multilevel approach. PLoS Negl Trop Dis 18: 1–19.
-
11.
Portillo A et al., 2017. Guidelines for the detection of Rickettsia spp. Vector Borne Zoonotic Dis 17: 23–32.
-
12.
Campbell-lendrum DH et al., 2007. House-level risk factors for triatomine infestation in Colombia. Int J Epidemiol 36: 866–872.
-
13.
Londoño AF et al., 2017. Wild and domestic animals likely involved in rickettsial endemic zones of northwestern Colombia. Ticks Tick Borne Dis 8: 887–894.
-
14.
Barros-Battesti D, Arzua M, Bechara G, 2006. Garrapatos de Importancia Médico-Veterinaria Da Regiao Neotropical: Um Guia Ilustrada Para Idetificaçao de Espécies. 1st ed. Sao Paulo: Vox/ICTTD-3/Butantan.
-
15.
Guedes E, Leite RC, Prata MC, 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.
-
16.
Fournier P, Roux V, Raoult D, 1998. Phylogenetic analysis of spotted fever group rickettsiae by study of the outer surface protein rOmpA. Int J Syst Bacteriol 48: 839–849.
-
17.
Beati L, Keirans JE, 2001. Analysis of the systematic relationships among ticks of the genera Rhipicephalus and Boophilus (ACARI: Ixodidae) based on mitochondrial 12S ribosomal DNA gene sequences and morphological characters. J Parasitol 87: 32–48.
-
18.
Penman AD, Johnson WD, 2009. Complementary log-log regression for the estimation of covariate-adjusted prevalence ratios in the analysis of data from cross-sectional studies. Biometrical J. 51: 433–442.
-
19.
Localio AR, Margolis DJ, Berlin JA, 2007. Relative risks and confidence intervals were easily computed indirectly from multivariable logistic regression. J Clin Epidemiol 60: 874–882.
-
20.
Acosta J et al., 2006. Brote de rickettsiosis en Necoclí, Antioquia, febrero–marzo de 2006. Inf Quinc Epidemiol Nac 11: 177–192.
-
21.
Giraldo M, Pacheco O, Galeano A, Alvarez H, Echeverri I, Echavarría L, Pacheco C, 2008. Estudio sindrome febril en el muncipio de Turbo, corregimiento Altos de Mulatos enero 2008. Inf Quinc Epidemiol Nac 13: 145–160.
-
22.
Biggs HM et al.2016. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain Spotted Fever and other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis—United States. Morb Mortal Wkly Report Recomm Reports 65: 1–44.
-
23.
Horta MC, Labruna MB, Sangioni LA, Vianna MCB, Gennari SM, Mafra CL, Vidotto O, Schumaker TTS, Walker DH, 2004. Prevalence of antibodies to Spotted Fever Group rickettsiae in humans and domestic animals in a Brazilian Spotted Fever-endemic area in the state of São Paulo, Brazil: serologic evidence for infection by Rickettsia rickettsii and another Spotted Fever Gr. Am J Trop Med Hyg 71: 93–97.
-
24.
Nasser JT, Lana RC, Silva CMDS, Lourenço RW, Silva DCDCE, Donalísio MR, 2015. Urbanization of Brazilian spotted fever in a municipality of the southeastern region: epidemiology and spatial distribution. Rev Bras Epidemiol 18: 299–312.
-
25.
Álvarez-Hernández G, Roldán JFG, Milan NSH, Lash RR, Behravesh CB, Paddock CD, 2017. Rocky Mountain spotted fever in Mexico: past, present, and future. Lancet Infect Dis 17: e189–e196.
-
26.
Parola P, Socolovschi C, Jeanjean L, Bitam I, Fournier P-E, Sotto A, Labauge P, Raoult D, 2008. Warmer weather linked to tick attack and emergence of severe rickettsioses. PLoS Negl Trop Dis 2: e338.
-
27.
Labruna MB, 2004. Biologia-ecologia de Rhipicephalus sanguineus (Acari: Ixodidae). Rev Bras Parasitol Vet 13: 123–124.
-
28.
Piranda EM, Faccini JLH, Pinter A, Pacheco RC, Cançado PHD, Labruna MB, 2011. Experimental infection of Rhipicephalus sanguineus ticks with the bacterium Rickettsia rickettsii, using experimentally infected dogs. Vector Borne Zoonotic Dis 11. doi: .
-
29.
Pacheco RC, Moraes-Filho J, Guedes E, Silveira I, Richtzenhain L, Leite R, Labruna M, 2011. Rickettsial infections of dogs, horses and ticks in Juiz de Fora, southeastern Brazil, and isolation of Rickettsia rickettsii from Rhipicephalus sanguineus ticks. Med Vet Entomol 25: 148–155.
-
30.
Vieira F de T et al., 2018. Tick-borne infections in dogs and horses in the state of Espırito Santo, southeast Brazil. Vet Parasitol 249: 43–48.
-
31.
Souza CE, Camargo LB, Pinter A , 2016. High seroprevalence for Rickettsia rickettsii in equines suggests risk of human infection in silent areas for the Brazilian Spotted Fever. PLoS One 11: 1–9.
-
32.
Bermudez SE et al., 2017. Synanthropic mammals as potential hosts of tick-borne pathogens in Panama. PLoS One 12: 1–9.
-
33.
Silveira I, Martins TF, Olegário M, Peterka C, Guedes E, Ferreira F, Labruna MB, 2015. Rickettsial infection in animals, humans and ticks in Paulicéia, Brazil. Zoonoses Public Health 62: 525–533.
-
34.
Quintero JC, Aguirre-Acevedo DC, Rodas JDD, Arboleda M, Troyo A, Vega F, Osorio L, Rojas C, 2018. Epidemiological characterization of incident cases of Rickettsia infection in rural areas of Urabá region, Colombia. PLoS Negl Trop Dis 12: e0006911.
-
35.
Faccini-Martínez ÁA, Costa FB, Hayama-Ueno TE, Ramírez-Hernández A, Cortés-Vecino JA, Labruna MB, Hidalgo M, 2015. Rickettsia rickettsii in Amblyomma patinoi ticks, Colombia. Emerg Infect Dis 21: 2010–2012.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 689 | 229 | 33 |
| Full Text Views | 161 | 31 | 2 |
| PDF Downloads | 141 | 28 | 1 |
Epidemiology of Rickettsial Infection in the Municipality of Uramita, Colombia
Juan C. Quintero-Vélez
Juan C. Quintero-Vélez
Grupo de Investigación Ciencias Veterinarias Centauro, Universidad de Antioquia, Antioquia, Colombia;
Grupo de Investigación Microbiología Básica y Aplicada, Universidad de Antioquia, Antioquia, Colombia;
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Grupo de Investigación Microbiología Básica y Aplicada, Universidad de Antioquia, Antioquia, Colombia;
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Astrid V. Cienfuegos-Gallet
Astrid V. Cienfuegos-Gallet
Grupo de Investigación Microbiología Básica y Aplicada, Universidad de Antioquia, Antioquia, Colombia;
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Lisardo Osorio Quintero
Lisardo Osorio Quintero
Grupo de Investigación Salud y Ambiente, Universidad de Antioquia, Antioquia, Colombia;
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Andrés F. Úsuga
Andrés F. Úsuga
Grupo de Investigación Ciencias Veterinarias Centauro, Universidad de Antioquia, Antioquia, Colombia;
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Sebastian Cifuentes
Sebastian Cifuentes
Grupo Mastozoología, Universidad de Antioquia;
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Sergio Solari
Sergio Solari
Grupo Mastozoología, Universidad de Antioquia;
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Juan D. Rodas
Juan D. Rodas
Grupo de Investigación Ciencias Veterinarias Centauro, Universidad de Antioquia, Antioquia, Colombia;
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Francisco J. Diaz
Francisco J. Diaz
Grupo de Investigación Inmunovirología, Universidad de Antioquia, Antioquia, Colombia;
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Carlos A. Rojas
Carlos A. Rojas
Grupo de Epidemiología, Universidad de Antioquia, Antioquia, Colombia
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ABSTRACT.
This study aimed to analyze epidemiological indicators related to seroprevalent and seroincident cases of spotted fever group rickettsiae (SFGR) and to identify housing conditions related to tick infestation. A prospective study (2016–2018) was conducted to examine rickettsial seropositivity in humans, domestic animals, and wild mammals in the municipality of Uramita, Antioquia, Colombia, where a previous Rickettsia rickettsii outbreak was reported from 2014 to 2015. The seroprevalence and its associated factors were estimated at baseline, and the seroincidence and its risk factors for humans were estimated 20 months later. A cross-sectional analysis was performed to evaluate the housing conditions linked to tick infestation. The SFGR seroprevalence was 26.70% (95% confidence interval [CI], 20.79–31.37), and the factors associated with SFGR seropositivity were male sex (adjusted prevalence ratio [PRa], 1.67; 95% CI, 1.19–2.32), age (evaluated in 5-year increments) (PRa, 1.05; 95% CI, 1.01–1.09), and household proximity (PRascattered vs. very near=3.87; 95% CI, 1.12–8.66). The overall seroincidence was 7.40% (95% CI, 4.71–11.06), and the factors associated with SFGR seroincident cases were the presence of wild animals (adjusted relative risk [RRa], 2.46; 95% CI, 1.06–4.72) and the presence of trees in the peri-domiciliary area (RRa, 0.47; 95% CI, 0.23–0.94). The prevalence of house tick infestation was 27.81% (95% CI, 21.93–34.80), and the factors associated with infestation were dirt floors (PRa, 5.88; 95% CI, 2.28–10.31), fiber cement roofs (PRa, 1.76; 95% CI, 1.07–2.83), and the presence of canines in peri-domiciliary or intra-domiciliary areas (PRa, 5.05; 95% CI, 3.31–7.19). Seropositivity rates for canines and opossums were 35.62% (26/73) and 100% (6/6), respectively. Identification of these factors will help to implement efficient surveillance programs in Colombia.
- Supplemental Materials (DOCX 19 KB)
Author Notes
Authors’ addresses: Juan C.s Quintero-Vélez, University of Antioquia, Faculty of Public Health, Medellin, Antioquia, Colombia, E-mail: juan.quintero@udea.edu.co. Astrid V. Cienfuegos-Gallet, University of Antioquia, School of Microbiology, Medellin, Antioquia, Colombia, E-mail: astrid.cienfuegos@udea.edu.co. Lisardo Osorio Quintero, University of Antioquia, Faculty of Public Health, Medellín, Antioquia, Colombia, E-mail: lisardo.osorio@udea.edu.co. Andrés F. Úsuga, University of Antioquia, Faculty of Agricultural Science, Medellín, Antioquia, Colombia, E-mail: felipe.usuga@udea.edu.co. Sebastián Cifuentes, University of Antioquia, Department of Biology, Medellín, Antioquia, Colombia, E-mail: seciak92@hotmail.com. Sergio Solari, University of Antioquia, Department of Biology, Medellín, Antioquia, Colombia, E-mail: sergio.solari@udea.edu.co. Juan D. Rodas, Universidad de Antioquia, Sede de Investigación Universitaria Medellin, Antioquia, Colombia, E-mail: jdavid.rodas@udea.edu.co. Francisco J. Diaz, Universidad de Antioquia, Grupo de Inmunovirología, Medellin, Colombia, E-mail: francisco.diaz@udea.edu.co. Carlos A. Rojas, University of Antioquia, Faculty of Public Health, Medellín, Antioquia, Colombia, E-mail: carlos.rojas@udea.edu.co.
- ABSTRACT.
- INTRODUCTION
- MATERIALS AND METHODS
- Study design.
- Sampling.
- Outcomes of SFGR seropositivity in humans and domestic animals.
- Outcomes of household tick infestation.
- Exposures and covariates.
- Capture, identification, and SFGR seropositivity of opossums.
- Identification of ticks collected from canines and SFGR detection.
- Statistical analysis.
- Models for seroprevalence and household infestation studies.
- Models for the seroincidence study.
- Ethics statement.
- RESULTS
- DISCUSSION
- CONCLUSIONS
- ACKNOWLEDGMENTS
- References
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Valbuena G, 2007. Fiebres que no deberían matar. Biomedica 27: 321–324.
-
2.
Quintero JC, Hidalgo M, Rodas JD, 2012. Rickettsiosis, una enfermedad letal emergente y re-emergente en Colombia Introducción Las rickettsias son un género de bacterias intracelulares. Univ Sci (Bogota) 17: 82–99.
-
3.
Arroyave E, Londoño AF, Quintero JC, Agudelo-Flórez P, Arboleda M, Díaz FJ, Rodas JD, 2013. Etiología y caracterización epidemiológica del síndrome febril no palúdico en tres municipios del Urabá antioqueño, Colombia. Biomedica 33: 99–107.
-
4.
Villar LA, Rojas DP, Besada-Lombana S, Sarti E, 2015. Epidemiological trends of dengue disease in Colombia (2000–2011): a systematic review. PLoS Negl Trop Dis 9: 1–16.
-
5.
Cortés JA, Romero-Moreno LF, Aguirre-León CA, Pinzón-Lozano L, Cuervo SI, 2016. Enfoque clínico del síndrome febril agudo en Colombia. Infectio 21: 39–50.
-
6.
Londoño A, Arango C, Acevedo-Gutiérrez Y, Paternina L, Montes C, Ruiz I, Labruna M, Díaz F, Walker D, Rodas JA , 2019. Cluster of cases of Rocky Mountain Spotted Fever in an area of Colombia not known to be endemic for this disease. Am J Trop Med Hyg 101: 346–342.
-
7.
Horta MC, Moraes-Filho J, Casagrande R, Saito TB, Rosa SC, Ogrzewalska M, Matushima ER, Labruna MB, 2009. Experimental infection of opossums Didelphis aurita by Rickettsia rickettsii and evaluation of the transmission of the infection to ticks Amblyomma cajennense. Vector Borne Zoonotic Dis 9: 109–118.
-
8.
Labruna MB, 2009. Ecology of Rickettsia in South America. Ann N Y Acad Sci 1166: 156–166.
-
9.
Drexler N, Yaglom H, Casal M, Fierro M, Kriner P, Murphy B, Kjemtrup A, Paddock CD, 2017. Fatal Rocky Mountain Spotted Fever along the United States–Mexico border, 2013–2016. Emerg Infect Dis 23: 1621–1626.
-
10.
Quintero JC, Paternina LE, Uribe YA, Muskus C, Hidalgo M, Gil J, Cienfuegos AV, Osorio QL, Rojas AC, 2017. Eco-epidemiological analysis of rickettsial seropositivity in rural areas of Colombia: A multilevel approach. PLoS Negl Trop Dis 18: 1–19.
-
11.
Portillo A et al., 2017. Guidelines for the detection of Rickettsia spp. Vector Borne Zoonotic Dis 17: 23–32.
-
12.
Campbell-lendrum DH et al., 2007. House-level risk factors for triatomine infestation in Colombia. Int J Epidemiol 36: 866–872.
-
13.
Londoño AF et al., 2017. Wild and domestic animals likely involved in rickettsial endemic zones of northwestern Colombia. Ticks Tick Borne Dis 8: 887–894.
-
14.
Barros-Battesti D, Arzua M, Bechara G, 2006. Garrapatos de Importancia Médico-Veterinaria Da Regiao Neotropical: Um Guia Ilustrada Para Idetificaçao de Espécies. 1st ed. Sao Paulo: Vox/ICTTD-3/Butantan.
-
15.
Guedes E, Leite RC, Prata MC, 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.
-
16.
Fournier P, Roux V, Raoult D, 1998. Phylogenetic analysis of spotted fever group rickettsiae by study of the outer surface protein rOmpA. Int J Syst Bacteriol 48: 839–849.
-
17.
Beati L, Keirans JE, 2001. Analysis of the systematic relationships among ticks of the genera Rhipicephalus and Boophilus (ACARI: Ixodidae) based on mitochondrial 12S ribosomal DNA gene sequences and morphological characters. J Parasitol 87: 32–48.
-
18.
Penman AD, Johnson WD, 2009. Complementary log-log regression for the estimation of covariate-adjusted prevalence ratios in the analysis of data from cross-sectional studies. Biometrical J. 51: 433–442.
-
19.
Localio AR, Margolis DJ, Berlin JA, 2007. Relative risks and confidence intervals were easily computed indirectly from multivariable logistic regression. J Clin Epidemiol 60: 874–882.
-
20.
Acosta J et al., 2006. Brote de rickettsiosis en Necoclí, Antioquia, febrero–marzo de 2006. Inf Quinc Epidemiol Nac 11: 177–192.
-
21.
Giraldo M, Pacheco O, Galeano A, Alvarez H, Echeverri I, Echavarría L, Pacheco C, 2008. Estudio sindrome febril en el muncipio de Turbo, corregimiento Altos de Mulatos enero 2008. Inf Quinc Epidemiol Nac 13: 145–160.
-
22.
Biggs HM et al.2016. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain Spotted Fever and other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis—United States. Morb Mortal Wkly Report Recomm Reports 65: 1–44.
-
23.
Horta MC, Labruna MB, Sangioni LA, Vianna MCB, Gennari SM, Mafra CL, Vidotto O, Schumaker TTS, Walker DH, 2004. Prevalence of antibodies to Spotted Fever Group rickettsiae in humans and domestic animals in a Brazilian Spotted Fever-endemic area in the state of São Paulo, Brazil: serologic evidence for infection by Rickettsia rickettsii and another Spotted Fever Gr. Am J Trop Med Hyg 71: 93–97.
-
24.
Nasser JT, Lana RC, Silva CMDS, Lourenço RW, Silva DCDCE, Donalísio MR, 2015. Urbanization of Brazilian spotted fever in a municipality of the southeastern region: epidemiology and spatial distribution. Rev Bras Epidemiol 18: 299–312.
-
25.
Álvarez-Hernández G, Roldán JFG, Milan NSH, Lash RR, Behravesh CB, Paddock CD, 2017. Rocky Mountain spotted fever in Mexico: past, present, and future. Lancet Infect Dis 17: e189–e196.
-
26.
Parola P, Socolovschi C, Jeanjean L, Bitam I, Fournier P-E, Sotto A, Labauge P, Raoult D, 2008. Warmer weather linked to tick attack and emergence of severe rickettsioses. PLoS Negl Trop Dis 2: e338.
-
27.
Labruna MB, 2004. Biologia-ecologia de Rhipicephalus sanguineus (Acari: Ixodidae). Rev Bras Parasitol Vet 13: 123–124.
-
28.
Piranda EM, Faccini JLH, Pinter A, Pacheco RC, Cançado PHD, Labruna MB, 2011. Experimental infection of Rhipicephalus sanguineus ticks with the bacterium Rickettsia rickettsii, using experimentally infected dogs. Vector Borne Zoonotic Dis 11. doi: .
-
29.
Pacheco RC, Moraes-Filho J, Guedes E, Silveira I, Richtzenhain L, Leite R, Labruna M, 2011. Rickettsial infections of dogs, horses and ticks in Juiz de Fora, southeastern Brazil, and isolation of Rickettsia rickettsii from Rhipicephalus sanguineus ticks. Med Vet Entomol 25: 148–155.
-
30.
Vieira F de T et al., 2018. Tick-borne infections in dogs and horses in the state of Espırito Santo, southeast Brazil. Vet Parasitol 249: 43–48.
-
31.
Souza CE, Camargo LB, Pinter A , 2016. High seroprevalence for Rickettsia rickettsii in equines suggests risk of human infection in silent areas for the Brazilian Spotted Fever. PLoS One 11: 1–9.
-
32.
Bermudez SE et al., 2017. Synanthropic mammals as potential hosts of tick-borne pathogens in Panama. PLoS One 12: 1–9.
-
33.
Silveira I, Martins TF, Olegário M, Peterka C, Guedes E, Ferreira F, Labruna MB, 2015. Rickettsial infection in animals, humans and ticks in Paulicéia, Brazil. Zoonoses Public Health 62: 525–533.
-
34.
Quintero JC, Aguirre-Acevedo DC, Rodas JDD, Arboleda M, Troyo A, Vega F, Osorio L, Rojas C, 2018. Epidemiological characterization of incident cases of Rickettsia infection in rural areas of Urabá region, Colombia. PLoS Negl Trop Dis 12: e0006911.
-
35.
Faccini-Martínez ÁA, Costa FB, Hayama-Ueno TE, Ramírez-Hernández A, Cortés-Vecino JA, Labruna MB, Hidalgo M, 2015. Rickettsia rickettsii in Amblyomma patinoi ticks, Colombia. Emerg Infect Dis 21: 2010–2012.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 689 | 229 | 33 |
| Full Text Views | 161 | 31 | 2 |
| PDF Downloads | 141 | 28 | 1 |