Fatal case of spotted fever in a patient from Northeastern Brazil

ABSTRACT

Spotted fevers are diseases caused by bacterial agents belonging to the spotted-fever (SF) group of the genus Rickettsia. The first documented case of SF in Pernambuco State, Northeast Brazil, was reported here. Also, it is the first case described of fatal SF in Northeast region of Brazil. The patient was a resident of Arcoverde municipality and the probable site of infection lies in Sertania municipality, both in Pernambuco State, a semi-arid region of Brazil. The patient had not visited other areas where SF is endemic. The patient showed clinical manifestations and epidemiological exposure compatible with SF, and the infection was confirmed by molecular biology techniques.

Rickettsia; Differential diagnosis; Tick-borne diseases; Brazilian semi-arid, Caatinga biome

INTRODUCTION

Spotted fever (SF) is an infectious, acute, febrile disease of varying severity, mainly transmitted by ticks^1,2. It has a non-specific symptomatology, during which early clinical-epidemiological diagnosis is a great challenge³. The rash, considered the only clinical marker, is not always present, which delays diagnosis and hinders appropriate medical action⁴.

In Brazil, the occurrence of other diseases of epidemic nature and more incidents (with similar symptomatology) add to the diagnostic difficulty, since it is necessary to consider the occurrence of other acute febrile diseases during assessment of cases⁵.

SF is widespread, with the highest incidence rate in the South and Southeast⁶. Classically, severe cases were associated with Rickettsia rickettsii, which have been recorded in anthropized areas of the Cerrado and Atlantic Rainforest biomes. The lethality rate of R. rickettsii infection in Brazil exceeds 50%, and may even reach 100%^7-10.

In the Atlantic Rainforest, SF is also caused by Rickettsia sp. Atlantic Rainforest strain, a species genetically close to Rickettsia parkeri, Rickettsia sibirica and Rickettsia africae. In these area, both milder clinical forms were observed, having as common characteristics the presence of inoculation eschars (lesion at the tick attachment site) and lymphadenopathy^2,11-17. In the Northeast of Brazil, Rickettsia sp. Atlantic Rainforest strain has been recorded from fragments of Atlantic Rainforest in the States of Bahia and Ceara, though there were no reports of associated deaths^6,15-17. Here we described the first fatal case of spotted fever in the Northeast Brazil.

Case presentation

A 78-year-old male patient with Alzheimer’s disease, resident of Arcoverde municipality, State of Pernambuco, was admitted to hospital on November 14, 2015, with fever, oliguria and palmar and plantar rash. Symptom onset was reported to have begun approximately seven days before, accompanied by a progressive decline in general conditions. After admission, there was worsening of the clinical state, with tachypnea and decline in renal function. The patient was hospitalized, and management for pulmonary sepsis and renal dysfunction were initiated.

After 24 hours, a seizures occurred (there was no history of epilepsy). The patient was sedated (dormonid [midazolam] + fentanyl), intubated and transferred to the State referral hospital in Recife, Pernambuco (PE), where he was admitted to the intensive care unit. There, the following were observed: bilateral pleural effusion, leukocytosis with left upper shift; distended abdomen; Miotic pupils, GOT/AST - 188 U/L; GPT/ALT - 76 U/L; Total Bilirubin - 2.10 mg/dL, Direct - 2.00 mg/dL, Indirect - 0.10 mg/dL; CK MB - 12 U/L; CK Total - 438 U/L. The diagnostic hypotheses were severe viral meningoencephalitis; metabolic encephalopathy; acute respiratory failure or metabolic ileus. Treatment with intramuscular ceftriaxone and acyclovir was initiated.

On November 21^st, 2015, the patient’s condition got worsened, secretions were accumulating in the respiratory tract in moderate quantity. Teicoplanin was included in the treatment.

On November 24^th, suspicion of rickettsiosis was raised as a result of the family information about the patient’s routine visit to a rural property, located in Sertania municipality, State of Pernambuco, where he had direct and indirect contact with animals (dogs, horses, goats, armadillos, cows). Doxycycline treatment administered twice a day was initiated. The patient did not improve during treatment and died on January 16^th, 2016.

A blood sample collected on November 24^th, 2015 and kept at -20ºC, was sent for analysis of Rickettsia sp. using the Polymerase Chain Reaction (PCR). We used gene-specific primers CS-78 (forward [5’-GCAAGTATCGGTGAGGATGTAAT-3’]), CS-323 (reverse [5’-GCTTCCTTAAAATTCAATAAATCAGGAT’-3’]) - which amplify a 401-bp fragment of the Citrate Synthase gene (gltA). Ultrapure milli-Q water was used, free of DNA, as the negative control, and Rickettsia parkeri genomic DNA as the positive control. PCR temperature conditions included an initial cycle at 95 °C for 3 min; 40 cycles of 15 s at 95 °C, 30 s at 48 °C and 30 s at 72 °C and one final cycle at 72 °C for 7 min^18,19.

The blood sample tested positive. However, the obtained sequence did not allow the construction of a phylodendrogram to determine the identity of the detected rickettsia.

DISCUSSION

Although the indirect immunofluorescence test is considered the gold standard for SF diagnosis, there was initially no clinical suspicion. Thus, the sampling procedure did not follow the protocol established by the Brazilian Ministry of Health¹⁹ and, thus, it was not possible to evaluate the serological conversion by using paired samples collected with a minimum interval of 14 days. However, case confirmation can be made by other laboratory criteria, including molecular methods¹⁹. The performed molecular assays detected a genomic-specific gene fragment, confirming the patient’s infection by Rickettsia sp.

The absence of initial clinical and epidemiological indicators, coupled with the rapid evolution of SF, has resulted in rickettsial deaths in several Brazilian States^3,5,6. Rickettsia rickettsii shows the strongest pathological alterations associated with the most severe and lethal clinical conditions. The effects of this pathogenic mechanism result in localized inflammation and procoagulant processes, causing increased vascular permeability, edema, hypovolemia and hypotension with vascular insufficiency associated with the subsequent leukocyte mononuclear response of the host²⁰. However, even if the patient’s clinical evolution is compatible with R. rickettsii infections¹⁹, existing data are insufficient to infer which rickettsia species was responsible for the infection. Also, it is not possible to evaluate whether the infection got worsened due to comorbidity/patient’s advanced age, or whether the use of different antimicrobials during treatment could have interfered in the disease progression, which had a morbidity period distinct from that known for R. rickettsii⁸.

During the epidemiological investigation of the case, it was considered that the patient had no history of travel to any area where SF is known to be endemic, and that the probable site of infection (PSI) (in Sertania municipality, PE) was the only environment frequented by the patient possessing favorable conditions for development of the rickettsial enzootic and epidemic cycle. The rural property, about 60 km from the patient’s home, was frequently visited, primarily serving as a recreation area, as well as for the rearing of a few wild animals (armadillos), kept in captivity as a food source, and a variety of domestic animals (cows, goats etc.). An environmental investigation in the PSI, conducted during the patient’s hospitalization period, did not detect any of the ticks known in Brazil for transmitting rickettsia².

This result indicates the possibility of a still unknown transmission scenario in the country. The SF foci closer to the Caatinga biome have been detected only in the State of Ceara so far. However, these areas were located in Atlantic forest fragments and, like other foci in Brazilian Atlantic forests, involved dogs, Amblyomma ovale ticks and Rickettsia sp. strain Atlantic Rainforest, and mild to moderate disease associated with inoculation swelling and lymphadenopathy^15,17. In contrast, both Sertania municipality and Arcoverde municipality (where the patient resided) lie within the Caatinga biome, in a typical area of the Brazilian semi-arid region²¹. This area lacks any previous known epidemiological context for SF establishment. R. rickettsii was recently detected in Rhipicephalus sanguineus in areas of spotted fever transmission in Northeastern Brazil²², indicating the presence of this tick in areas where the ecoepidemiological profile is still unknown. However, this tick has a wide geographic distribution and is responsible for SF transmission in other parts of the world¹. This potential vector was found during the PSI investigation, but a PCR for Rickettsia was negative for the analyzed samples²³.

Considering that this is the first SF case in this region, to confirm identification of the transmission site and increase the robustness of the existing laboratory results, blood collection of contact people, area residents and animals (dogs and horses), as well as a seasonal monitoring of vector fauna, could reinforce the identity of the probable site of infection and support characterization of this new transmission scenario.

CONCLUSIONS

The first SF case is reported from Pernambuco State, in the Brazilian semiarid area, Caatinga biome, as the first death in the Northeast of Brazil associated with Rickettsia sp.

ACKNOWLEDGMENTS

We would like to thank the team from the Zoonosis Surveillance Technical Unit, the technical group for rodent-related diseases from the Brazilian Ministry of Health, and the team for epidemiological and environmental surveillance of Pernambuco. We also thank Adrian Paul Ashton Barnett for the English review and comments to manuscript.

REFERENCES

• ¹
  Parola P, Paddock CD, Socolovschi C, Labruna MB, Mediannikov O, Kernif T, et al. Update on tick-borne rickettsioses around the world: a geographic approach. Clin Microbiol Rev. 2013;26:657-702.
• ²
  Szabó MP, Pinter A, Labruna MB. Ecology, biology and distribution of spotted-fever tick vectors in Brazil. Front Cell Infect Microbiol. 2013;3:27.
• ³
  Oliveira SV, Caldas EP, Colombo S, Gazeta GS, Labruna MB, Santos FC, et al. A fatal case of Brazilian spotted fever in a non-endemic area in Brazil: the importance of having health professionals who understand the disease and its areas of transmission. Rev Soc Bras Med Trop. 2016;49:653-5.
• ⁴
  Biggs HM, Behravesh CB, Bradley KK, Dahlgren FS, Drexler NA, Dumler JS, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis - United States. MMWR Recomm Rep 2016;65:1-44.
• ⁵
  Lopez DM, de Mello FL, Giordano Dias CM, Almeida P, Araújo M, Magalhães MA, et al. Evaluating the surveillance system for spotted fever in Brazil using machine-learning techniques. Front Public Health. 2017;5:323.
• ⁶
  Oliveira SV, Guimarães JN, Reckziegel GC, Neves BM, Araújo-Vilges KM, Fonseca LX, et al. An update on the epidemiological situation of spotted fever in Brazil. J Venom Anim Toxins Incl Trop Dis. 2016;22:22.
• ⁷
  Lemos E, Rozental T, Villela CL. Brazilian spotted fever: description of a fatal clinical case in the State of Rio de Janeiro. Rev Soc Bras Med Trop. 2002;35:523-5.
• ⁸
  Angerami RN, Câmara M, Pacola MR, Rezende RC, Duarte RM, Nascimento EM, et al. Features of Brazilian spotted fever in two different endemic areas in Brazil. Ticks Tick Borne Dis. 2012;3:346-8.
• ⁹
  Labruna MB, Mattar V S, Nava S, Bermudez S, Venzal JM, Dolz G, et al. Rickettsioses in Latin America, Caribbean, Spain and Portugal. Rev MVZ Córdoba. 2011;16:2435-57.
• ¹⁰
  Faccini-Martínez AA, Muñoz-Leal S, Acosta IC, Oliveira SV, Duré AI, Cerutti Jr C, et al. Confirming Rickettsia rickettsii as the etiological agent of spotted fever group rickettsiosis in human lethal cases from Espírito Santo state, Brazil. Ticks Tick Borne Dis. 2018;9:496-9.
• ¹¹
  Silva N, Eremeeva ME, Rozental T, Ribeiro GS, Paddock CD, Ramos EA, et al. Eschar-associated spotted fever rickettsiosis, Bahia, Brazil. Emerg Infect Dis. 2011;17:275-8.
• ¹²
  Vizzoni VF, Silva AB, Cardoso KM, Santos FB, Stenzel B, Amorim M, et al. Genetic identification of Rickettsia sp. strain Atlantic rainforest in an endemic area of a mild spotted fever in Rio Grande do Sul state, Southern Brazil. Acta Trop. 2016;162:142-5.
• ¹³
  Krawczak FS, Munõz-Leal S, Guztzazky AC, Oliveira SV, Santos FC, Angerami RN, et al. Rickettsia sp. strain Atlantic rainforest infection in a patient from a spotted fever-endemic area in southern Brazil. Am J Trop Med Hyg. 2016;95:551-3.
• ¹⁴
  Oliveira SV. Regarding the ecoepidemiology of a tick-borne spotted fever Southernmost state of Brazil. Ann Clin Cytol Pathol. 2017;3:1048.
• ¹⁵
  Oliveira SV. Tick-borne spotted fever in the northeast of Brazil: the series of cases a new endemic area. Rev Med UFC. 2016;56:8-9.
• ¹⁶
  Spolidorio MG, Labruna MB, Mantovani E, Brandão PE, Richtzenhain LJ, Yoshinari NH. Novel spotted fever group rickettsiosis, Brazil. Emerg Infect Dis. 2010;16:521-3.
• ¹⁷
  Moerbeck L, Vizzoni VF, Machado-Ferreira E, Cavalcante RC, Oliveira SV, Soares CA, et al. Rickettsia (Rickettsiales: Rickettsiaceae) vector biodiversity in high altitude Atlantic Forest fragments within a semiarid climate: a new endemic area of spotted-fever in Brazil. J Med Entomol.2016;53:1458-66.
• ¹⁸
  Labruna MB, Whitworth T, Horta MC, Bouyer DH, McBride JW, Pinter A, et al. Rickettsia species infecting Amblyomma cooperi ticks from an area in the state of São Paulo, Brazil, where Brazilian spotted fever is endemic. J Clin Microbiol. 2004;42:90-8.
• ¹⁹
  Brasil. Ministério da Saúde, Secretaria de Vigilância em Saúde. Coordenação-Geral de Desenvolvimento da Epidemiologia em Serviços. Guia de vigilância em saúde: volume único. 2ª ed. Brasília: Ministério da Saúde; 2017. [cited 2018 Feb 5] Available from: http://portalarquivos.saude.gov.br/images/pdf/2017/outubro/06/Volume-Unico-2017.pdf
  » http://portalarquivos.saude.gov.br/images/pdf/2017/outubro/06/Volume-Unico-2017.pdf
• ²⁰
  Walker DH, Raoult D. Rickettsia ricketsii and other spotted fever group rickettsiae (Rocky Mountain spotted fever and other spotted fever). In: Mandell GL, Bennett JE, Dolin R. editors. Mandell, Douglas, and Bennett’s Principles and practices of infectious diseases. 6th ed. New York: Elsevier/Churchill Livingstone; 2005. p.2287-95.
• ²¹
  Borsato R, coordenação. Ecorregiões do Brasil: prioridades terrestres e marinhas. Curitiba: Instituto Life; 2015.
• ²²
  Silva AB, Duarte MM, Cavalcante RC, Oliveira SV, Vizzoni VF, Duré AI, et al. Rickettsia rickettsii infecting Rhipicephalus sanguineus sensu lato (Latreille 1806), in high altitude atlantic forest fragments, Ceará state, Brazil. Acta Trop. 2017;173:30-3.
• ²³
  Silva AB, Cardoso KM, de Oliveira SV, Costa RM, Oliveira G, Amorim M, et al. Rickettsia amblyommatis infecting Amblyomma pseudoconcolor in area of new focus of spotted fever in northeast Brazil. Acta Trop. 2018;182:305-8.

Publication Dates

• Publication in this collection
  28 May 2018
• Date of issue
  2018

History

• Received
  24 Nov 2017
• Accepted
  1 Mar 2018