• View in gallery

    A 75-year-old woman was admitted with chills and rash as the primary complaints. (A) Eschar lesion identified on the head. (B) Erythematous rash on the face. (C) Conjunctival suffusion in both the eyes. (D) Maculopapular rash on the abdomen. (E) Phylogenetic tree for Rickettsia spp. based on the partial outer membrane protein A (ompA) gene (521 nucleotides). The number at the node represents the bootstrap confidence levels for 1,000 replicates. The black triangles represent the isolates obtained in our study. (F) Phylogenetic tree for Orientia tsutsugamushi based on the partial 56-kDa protein gene (435 nucleotides). The number at the node represents bootstrap confidence levels for 1,000 replicates. The black triangles represent the isolates obtained in our study. This figure appears in color at www.ajtmh.org.

  • 1.

    Pretorius AM, Jensenius M, Birtles RJ, 2004. Update on spotted fever group Rickettsiae in South Africa. Vector Borne Zoonotic Dis 4: 249260.

  • 2.

    Lee HJ, Park CY, Park SG, Yoon NR, Kim DM, Chung CH, 2017. Activation of the coagulation cascade in patients with scrub typhus. Diagn Microbiol Infect Dis 89: 16.

    • Search Google Scholar
    • Export Citation
  • 3.

    Kim YS, Choi YJ, Lee KM, Ahn KJ, Kim HC, Klein T, Jiang J, Richards A, Park KH, Jang WJ, 2017. First isolation of Rickettsia monacensis from a patient in South Korea. Microbiol Immunol 61: 258263.

    • Search Google Scholar
    • Export Citation
  • 4.

    Choi SH, Kim DM, Lee J, Yun NR, 2017. Endoscopic characteristics of infection-associated peptic ulcers. Helicobacter 2017 Dec;22(6). doi: 10.1111/hel.12427.

    • Search Google Scholar
    • Export Citation
  • 5.

    Park JW 2018. Molecular epidemiology of an Orientia tsutsugamushi gene encoding a 56-kDa type-specific antigen in chiggers, small mammals, and patients from the southwest region of Korea. Am J Trop Med Hyg 98: 616624.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kato CY, Chung IH, Robinson LK, Austin AL, Dasch GA, Massung RF, 2013. Assessment of real-time PCR assay for detection of Rickettsia spp. and Rickettsia rickettsii in banked clinical samples. J Clin Microbiol 51: 314317.

    • Search Google Scholar
    • Export Citation
  • 7.

    Jeung YS, Kim CM, Yun NR, Kim SW, Han MA, Kim DM, 2016. Effect of latitude and seasonal variation on scrub typhus, South Korea, 2001-2013. Am J Trop Med Hyg 94: 2225.

    • Search Google Scholar
    • Export Citation
  • 8.

    Simser JA, Palmer AT, Fingerle V, Wilske B, Kurtti TJ, Munderloh UG, 2002. Rickettsia monacensis sp. nov., a spotted fever group Rickettsia, from ticks (Ixodes ricinus) collected in a European city park. Appl Environ Microbiol 68: 4 5594566.

    • Search Google Scholar
    • Export Citation
  • 9.

    Jado I 2007. Rickettsia monacensis and human disease, Spain. Emerg Infect Dis 13: 1405140 7.

  • 10.

    Madeddu G, Mancini F, Caddeo A, Ciervo A, Babudieri S, Maida I, Fiori ML, Rezza G, Mura MS, 2012. Rickettsia monacensis as cause of Mediterranean spotted fever-like illness, Italy. Emerg Infect Dis 18: 702704.

    • Search Google Scholar
    • Export Citation
  • 11.

    Lee KM, Choi YJ, Shin SH, Choi MK, Song HJ, Kim HC, Klein TA, Richards AL, Park KH, Jang WJ, 2013. Spotted fever group rickettsia closely related to Rickettsia monacensis isolated from ticks in South Jeolla Province, Korea. Microbiol Immunol 57: 487495.

    • Search Google Scholar
    • Export Citation
  • 12.

    Tijsse-Klasen E, Sprong H, Pandak N, 2013. Co-infection of Borrelia burgdorferi sensu lato and Rickettsia species in ticks and in an erythema migrans patient. Parasit Vectors 6: 347.

    • Search Google Scholar
    • Export Citation
  • 13.

    Miťková K, Berthová L, Kalúz S, Kazimírová M, Burdová L, Kocianová E, 2015. First detections of Rickettsia helvetica and R. monacensis in ectoparasitic mites (Laelapidae and Trombiculidae) infesting rodents in south-western Slovakia. Parasitol Res 114: 24652472.

    • Search Google Scholar
    • Export Citation
  • 14.

    Huang Y 2017. Detection of a novel Rickettsia from Leptotrombidium scutellare mites (Acari: Trombiculidae) from Shandong of China. J Med Entomol 54: 544549.

    • Search Google Scholar
    • Export Citation

 

 

 

Case Report: Coinfection with Rickettsia monacensis and Orientia tsutsugamushi

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  • 1 Department of Neurosurgery, College of Medicine, Chosun University, Gwangju, Republic of Korea;
  • 2 Premedical Science, College of Medicine, Chosun University, Gwangju, Republic of Korea;
  • 3 Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, Republic of Korea

Rickettsia monacensis and Orientia tsutsugamushi are bacteria of the family Rickettsiaceae, which causes fever, rash, and eschar formation; outdoor activities are a risk factor for Rickettsiaceae infection. A 75-year-old woman presented with fever, rash, and eschar and was confirmed as being scrub typhus based on a nested-polymerase chain reaction (N-PCR) test for a 56-kDa gene of O. tsutsugamushi; the genome was identified as the Boryong genotype. In addition, a pan-Rickettsia real-time PCR test was positive and a N-PCR test using a Rickettsia-specific partial outer membrane protein A (rOmpA) confirmed R. monacensis. This is the first case wherein a patient suspected of having scrub typhus owing to the presence of rash and eschar was also found to be coinfected with O. tsutsugamushi and R. monacensis based on molecular testing.

INTRODUCTION

Rickettsia monacensis is a pathogen that causes spotted fever group rickettsial infection; the main symptoms of infection include fever, headache, and myalgia, as well as eschar or rash.1 Orientia tsutsugamushi, the causative bacterium of scrub typhus, is a rickettsial infectious agent; clinical manifestations of infection include fever, eschar, and rash.2 Although R. monacensis was previously isolated from a patient in Korea,3 there has been no report of R. monacensis and O. tsutsugamushi coinfection to date. Herein, we report the first case of a patient admitted owing to fever who was found to have rash and eschar, thus leading to suspicion of scrub typhus; however, subsequent molecular testing confirmed R. monacensis and O. tsutsugamushi coinfection.

CASE REPORT

A 75-year-old woman presented with chills as her main complaint. Her chills continuously persisted for 4 days before her hospital visit on October 16. Moreover, she had engaged in frequent outdoor activity of collecting persimmons or chestnuts in the forest. Her medical history indicated that the patient had been taking medications for 10 years after being diagnosed with hypertension and diabetes, but she had no history of hepatitis or tuberculosis. Her symptoms started on October 13.

Vital signs at the time of visit were as follows: blood pressure, 110/70 mmHg; pulse rate, 98 beats/minutes; breathing rate, 22 times/minutes; and body temperature, 38.4°C. Despite her drowsy state, there were no abnormal findings on neurologic examination, although cervical lymphadenopathy was observed. Results of heart and lung auscultation were normal, and abdominal examination revealed no hepatomegaly, splenomegaly, or abdominal pain. There was an erythematous macular rash, and the scalp had eschar (Figure 1).

Figure 1.
Figure 1.

A 75-year-old woman was admitted with chills and rash as the primary complaints. (A) Eschar lesion identified on the head. (B) Erythematous rash on the face. (C) Conjunctival suffusion in both the eyes. (D) Maculopapular rash on the abdomen. (E) Phylogenetic tree for Rickettsia spp. based on the partial outer membrane protein A (ompA) gene (521 nucleotides). The number at the node represents the bootstrap confidence levels for 1,000 replicates. The black triangles represent the isolates obtained in our study. (F) Phylogenetic tree for Orientia tsutsugamushi based on the partial 56-kDa protein gene (435 nucleotides). The number at the node represents bootstrap confidence levels for 1,000 replicates. The black triangles represent the isolates obtained in our study. This figure appears in color at www.ajtmh.org.

Citation: The American Journal of Tropical Medicine and Hygiene 101, 2; 10.4269/ajtmh.18-0631

Test results of peripheral blood collected on October 21 and those of blood collected on admission were as follows: leukocyte count, 7,200/mm3; hemoglobin, 11.6 g/dL; platelet count, 232,000/mm3; and erythrocyte sedimentation rate, 31 mm/hours. C-reactive protein and procalcitonin levels were elevated at 9.26 mg/dL and 0.836 ng/mL (0–0.5 ng/mL), respectively. Levels of blood electrolytes (Na/K/Cl) were 129/4.1/95 mEq/L. Biochemical examination of the serum revealed a ratio of 59.1:62.9 (mg/dL) for aspartate transaminase:alanine aminotransferase; total bilirubin, 0.78 mg/dL; blood urea nitrogen/creatinine, 14.1/1.0 mg/dL); serum lactate dehydrogenase, 584 U/L; and adenosine deaminase, 54.4 U/L; there were no abnormal urinalysis findings. Arterial blood test results at the time of visit revealed pH, 7.533; pCO2/pO2, 27.4/89.3 mmHg; HCO3, 26.3 mmol/L; and O2 saturation 98.5%, indicating metabolic alkalosis. Cardiac enzyme levels were within normal ranges with creatine kinase MB of 4.9 ng/mL and high-sensitivity troponin T of 0.011 ng/mL. Brain computed tomography was conducted because of her drowsiness, but showed no abnormal results. Cerebrospinal fluid (CSF) examination revealed two white blood cells (WBCs), zero red blood cells (RBCs), protein 47.3 mg/dL, and glucose 91.6 mg/dL (serum 208 mg/dL).

The patient was involved in outdoor activities and displayed characteristic eschar findings. Using the patient’s buffy coat from the blood sample, polymerase chain reaction (PCR) test was positive for a 56-kDa target gene of O. tsutsugamushi4; subsequent sequencing analysis confirmed the Boryong genotype (accession no. MK613928). Immunofluorescence antibody assay (IFA) examination for O. tsutsugamushi5 revealed an IgM ratio of 1:16 and an IgG ratio of 1:128, whereas total Ig antibody titer examined by Green Cross Laboratories (Youngin, Korea) was elevated at 1:640; IFA testing for R. conorii by the Korea Centers for Disease Control and Prevention (KCDC) revealed values of < 1:32 for both IgM and IgG antibodies on admission (October 21) and at follow-up (December 18). IFA testing for R. japonica revealed an IgM ratio of < 1:16 and an IgG ratio of 1:32 on admission (October 21) and an IgM ratio of 1:16 and an IgG ratio of 1:128 at follow-up (December 18). The patient was diagnosed with scrub typhus infection and was administered 200 mg doxycycline daily. From the second day of hospitalization, her fever subsided, and her symptoms improved; although the weakness remained, she was discharged.

To detect Rickettsia species, pan-rickettsial real-time PCR that targeted the 23S rRNA was performed using blood collected at the time of hospitalization; as the results were positive,6 the real-time PCR amplicon was subjected to sequencing analysis, which confirmed the presence of R. monacensis. To reconfirm the result using an additional target gene, nested-PCR testing using Rickettsia-specific rOmpA was performed and was positive; subsequent sequencing analysis reconfirmed the presence of R. monacensis (accession no. MK613926). Using CSF, a N-PCR test for the Rickettsia-specific partial outer membrane protein A (rOmpA) also confirmed R. monacensis (Figure 1) (accession no. MK613927). Homology was tested based on sequence alignment, in which R. monacensis identified in the buffy coat showed 99.6% homology with R. monacensis identified in CSF. The buffy coat isolate showed 96.9% homology with the Korea R. monacensis isolate CN45kr (accession no. KC993862), 98.3% homology with the Chinese R. monacensis isolate (accession no. EU665232), and 98.7% homology with Rickettsia sp. ZJ42/2007 (accession no. EU258734). Finally, coinfection with O. tsutsugamushi and R. monacensis was confirmed.

DISCUSSION

Korea is an endemic region of scrub typhus, with about 10,000 cases reported to the KCDC every year. Most incidences occur from late October to early November.7 Rickettsia monacensis distribution is widely prevalent in European regions such as Spain, Slovakia, Germany, and Italy810; R. monacensis was first characterized and isolated from Ixodes ricinus ticks collected in Munich, Germany, in 2002.8 In 2005, R. monacensis was reported as the causative human pathogen in Mediterranean spotted fever-like illness (MSF-like illness) in Spain, where the patient had maculopapular rash but no eschar. Moreover, R. monacensis was isolated from the same species of ticks in Portugal and Hungary.9 In addition, there was a case report in Italy of a 28-year-old man who had eschar without rash; the organism detected was similar to R. monacensis isolate N72 (accession no. FJ919650.1), the causative agent of MSF-like illness.10

In Korea, R. monacensis was isolated from I. nippiness ticks collected from rats.11 In addition, it was reported in Korea that a patient presented with a main complaint of fever, along with eschar and rash; R. monacensis was isolated from the patient.3 The patient also had eschar and rash similar to that of the scrub typhus patient, and testing for antibodies against O. tsutsugamushi was positive. However, they failed to exclude the possibility that the patient could also be coinfected with O. tsutsugamushi.

The present report provides the first reported confirmation of coinfection with R. monacensis and O. tsutsugamushi based on molecular testing in a patient who was treated for typical scrub typhus. The clinical manifestations of the present case are similar to those of other scrub typhus patients. However, it is not easy to differentiate between scrub typhus and spotted fever due to R. monacensis. Until now, there was no report of coinfection of O. tsutsugamushi and R. monacensis; therefore, further study is needed to examine the implications of coinfection.

Rickettsia monacensis is a relatively common coinfective pathogen. Coinfection with R. monacensis and Borrelia afzelii was reported in the Netherlands,12 where the patient had only rash and erythema migrans lesions, in which 47 skin tissue samples from 67 patients with erythema migrans were positive for B. burgdorferi and one patient was positive for R. monacensis with a Borrelia genotype of B. afzelii. The patient showed no Rickettsia-related symptoms; thus, the pathogenic role of R. monacensis was unclear. Interestingly, CSF from the patient in the present case was negative for O. tsutsugamushi using PCR, whereas it was positive for R. monacensis. Thus, further studies on the pathogenicity of R. monacensis are required.

In a study conducted in southwestern Slovakia using rodents and ectoparasitic mites, 112 of 345 mite pool samples after mite pooling (32.46%) and 46 of 487 rodent blood samples (9.44%) were positive for Rickettsia DNA, and sequencing analysis confirmed the presence of R. helvetica and R. monacensis.13 Another study from China revealed a unique Rickettsia species that was detected in Leptotrombidium scutellare; this study expanded the knowledge on the vector distribution of Rickettsia spp.14 These findings suggested that mites per se act as a vector and a reservoir of R. monacensis. In Korea, scrub typhus caused by O. tsutsugamushi is the most common rickettsial infection, for which the vector and reservoir are larval trombiculid mites, a Leptotrombidium spp. Because there are various mites in Korea, coinfection is theoretically possible, and the roles of mites in Korea as a cause of coinfection and a vector of R. monacensis should be further studied.

In conclusion, the present study reports the first confirmation of coinfection with O. tsutsugamushi and R. monacensis based on molecular testing in a patient suspected of having scrub typhus due to the presence of fever, rash, and eschar. Thus, clinicians should note that patients diagnosed with scrub typhus in an endemic region may be coinfected with R. monacensis.

REFERENCES

  • 1.

    Pretorius AM, Jensenius M, Birtles RJ, 2004. Update on spotted fever group Rickettsiae in South Africa. Vector Borne Zoonotic Dis 4: 249260.

  • 2.

    Lee HJ, Park CY, Park SG, Yoon NR, Kim DM, Chung CH, 2017. Activation of the coagulation cascade in patients with scrub typhus. Diagn Microbiol Infect Dis 89: 16.

    • Search Google Scholar
    • Export Citation
  • 3.

    Kim YS, Choi YJ, Lee KM, Ahn KJ, Kim HC, Klein T, Jiang J, Richards A, Park KH, Jang WJ, 2017. First isolation of Rickettsia monacensis from a patient in South Korea. Microbiol Immunol 61: 258263.

    • Search Google Scholar
    • Export Citation
  • 4.

    Choi SH, Kim DM, Lee J, Yun NR, 2017. Endoscopic characteristics of infection-associated peptic ulcers. Helicobacter 2017 Dec;22(6). doi: 10.1111/hel.12427.

    • Search Google Scholar
    • Export Citation
  • 5.

    Park JW 2018. Molecular epidemiology of an Orientia tsutsugamushi gene encoding a 56-kDa type-specific antigen in chiggers, small mammals, and patients from the southwest region of Korea. Am J Trop Med Hyg 98: 616624.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kato CY, Chung IH, Robinson LK, Austin AL, Dasch GA, Massung RF, 2013. Assessment of real-time PCR assay for detection of Rickettsia spp. and Rickettsia rickettsii in banked clinical samples. J Clin Microbiol 51: 314317.

    • Search Google Scholar
    • Export Citation
  • 7.

    Jeung YS, Kim CM, Yun NR, Kim SW, Han MA, Kim DM, 2016. Effect of latitude and seasonal variation on scrub typhus, South Korea, 2001-2013. Am J Trop Med Hyg 94: 2225.

    • Search Google Scholar
    • Export Citation
  • 8.

    Simser JA, Palmer AT, Fingerle V, Wilske B, Kurtti TJ, Munderloh UG, 2002. Rickettsia monacensis sp. nov., a spotted fever group Rickettsia, from ticks (Ixodes ricinus) collected in a European city park. Appl Environ Microbiol 68: 4 5594566.

    • Search Google Scholar
    • Export Citation
  • 9.

    Jado I 2007. Rickettsia monacensis and human disease, Spain. Emerg Infect Dis 13: 1405140 7.

  • 10.

    Madeddu G, Mancini F, Caddeo A, Ciervo A, Babudieri S, Maida I, Fiori ML, Rezza G, Mura MS, 2012. Rickettsia monacensis as cause of Mediterranean spotted fever-like illness, Italy. Emerg Infect Dis 18: 702704.

    • Search Google Scholar
    • Export Citation
  • 11.

    Lee KM, Choi YJ, Shin SH, Choi MK, Song HJ, Kim HC, Klein TA, Richards AL, Park KH, Jang WJ, 2013. Spotted fever group rickettsia closely related to Rickettsia monacensis isolated from ticks in South Jeolla Province, Korea. Microbiol Immunol 57: 487495.

    • Search Google Scholar
    • Export Citation
  • 12.

    Tijsse-Klasen E, Sprong H, Pandak N, 2013. Co-infection of Borrelia burgdorferi sensu lato and Rickettsia species in ticks and in an erythema migrans patient. Parasit Vectors 6: 347.

    • Search Google Scholar
    • Export Citation
  • 13.

    Miťková K, Berthová L, Kalúz S, Kazimírová M, Burdová L, Kocianová E, 2015. First detections of Rickettsia helvetica and R. monacensis in ectoparasitic mites (Laelapidae and Trombiculidae) infesting rodents in south-western Slovakia. Parasitol Res 114: 24652472.

    • Search Google Scholar
    • Export Citation
  • 14.

    Huang Y 2017. Detection of a novel Rickettsia from Leptotrombidium scutellare mites (Acari: Trombiculidae) from Shandong of China. J Med Entomol 54: 544549.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Dong-Min Kim, Department of Internal Medicine, School of Medicine, Chosun University, 588 Seosuk-dong, Dong-gu, Gwangju 501-717, Republic of Korea. E-mail: drongkim@chosun.ac.kr

Financial support: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03930956).

Disclosure: The authors do not have any commercial interests or other associations that might pose a conflict of interest.

Authors’ addresses: Seok Won Kim, Chosun University College of Medicine, Departments of Neurosurgery Chosun University College of Medicine, Gwangju, Republic of Korea, E-mail: chosunns@chosun.ac.kr. Choon-Mee Kim, College of Medicine, Premedical Science, Gwangju, Republic of Korea, E-mail: choonmee@chosun.ac.kr. Dong-Min Kim and Na Ra Yun, Chosun University College of Medicine, Departments of Internal Medicine Chosun University College of Medicine, Gwang-Ju, Republic of Korea, E-mails: drongkim@chosun.ac.kr and shine@chosun.ac.kr.

These authors contributed equally to this work.

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