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325-bp ompA sequences revealed that the agent Qiu-Bo Huo, M.S. clustered with other R. sibirica subspecies and Mudanjiang Forestry Central Hospital was most closely related to R. sibirica subspecies Mudanjiang, China sibirica 246, which had been isolated from Derma- Bao-Gui Jiang, M.D. centor nuttalli in Russia (Fig. 1). In serum samples Beijing Institute of Microbiology and Epidemiology obtained from the patient, the titers of IgM and Beijing, China IgG antibodies against R. sibirica on indirect immunofluorescence assay increased from 1:32 and Wu-Chun Cao, M.D., Ph.D. Key Laboratory of Pathogen and Biosecurity 1:64, respectively, in the acute phase to 1:4096 State Beijing, China for IgM and for IgG in the convalescent phase.
[email protected] The study of this case was approved by the Drs. Jia and Jiang contributed equally to this letter. institutional review board of the Chinese AcadSupported by grants (81290344 and 81130086) from the Naemy of Military Medical Sciences. The patient tional Natural Science Foundation of China. Disclosure forms provided by the authors are available with provided written informed consent. the full text of this letter at NEJM.org. R. sibirica subspecies sibirica BJ-90 was initially isolated from D. sinicus in China in 1990,2,3 and it 1. Pacheco RC, Moraes-Filho J, Marcili A, et al. Rickettsia monwas detected in D. silvarum in Russia.4 Our case teiroi sp. nov., infecting the tick Amblyomma incisum in Brazil. Appl Environ Microbiol 2011;77:5207-11. shows that this organism can cause human dis- 2. Yu XJ, Jin Y, Fan MY, Xu G, Liu Q, Raoult D. Genotypic and ease. Unlike patients infected with R. sibirica and antigenic identification of two new strains of spotted fever R. heilongjiangensis in the same geographic re- group rickettsiae isolated from China. J Clin Microbiol 1993;31:83-8. gion,5 this patient was severely ill with multior- 3. Zhang LJ, Jin JL, Fu XP, Raoult D, Fournier PE. Genetic difgan dysfunction. Further investigation of the ferentiation of Chinese isolates of Rickettsia sibirica by partial epidemiologic and clinical features of R. sibirica ompA gene sequencing and multispacer typing. J Clin Microbiol 2006;44:2465-7. subspecies sibirica BJ-90 is required to distin- 4. Shpynov SN, Fournier PE, Rudakov NV, et al. Molecular idenguish it from other known tickborne infections. tification of a collection of spotted fever group rickettsiae obtained from patients and ticks from Russia. Am J Trop Med Hyg Na Jia, M.D. 2006;74:440-3. State Key Laboratory of Pathogen and Biosecurity Beijing, China
5. Fan MY, Zhang JZ, Chen M, Yu XJ. Spotted fever group rick-
Jia-Fu Jiang, M.D.
ettsioses in China. In: Raoult D, Broqui P, eds. Rickettsiae and rickettsial diseases at the turn of the third millennium. Paris: Elsevier, 1999:247-57.
Beijing Institute of Microbiology and Epidemiology Beijing, China
DOI: 10.1056/NEJMc1303625
Human Infection with Candidatus Rickettsia tarasevichiae To the Editor: From May through August 2012, a total of 251 patients who had recent tick bites sought treatment at Mudanjiang Forestry Central Hospital in northeastern China and were tested for tickborne infections. Polymerase-chain-reaction testing followed by sequencing of eschar and blood samples showed that 5 patients were infected with Candidatus Rickettsia tarasevichiae, a new species of rickettsiae of the spotted fever group. Phylogenetic analysis based on either the citrate synthase gene or the outer-membrane protein A gene showed that the agent was genetically close to R. canadensis (see Fig. 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org), one of several “ancestral” rickettsiae that are suspected to be 1178
endosymbionts and nonpathogens.1 In an indirect immunofluorescence assay, IgM or IgG antibodies reacted to two endemic species of rickettsiae of the spotted fever group, R. heilongjiangensis and R. sibirica.2 The study of these cases was approved by the institutional review board of the Chinese Academy of Military Medical Sciences. All patients provided written informed consent. Characteristics of the five patients are shown in Table 1. All five patients had a recent tick bite and no documented immunocompromised conditions. Their ages ranged from 12 to 56 years (median, 30 years), and three were women. They were hospitalized with fever (in two patients), asthenia (in three patients), anorexia (in three
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correspondence
Table 1. Clinical Characteristics and Laboratory Test Results of the Five Patients with Candidatus Rickettsia tarasevichiae Infections on Admission.* Patient 1
Characteristics Age — yr Sex Days between known tick bite and illness onset Specimen source for PCR amplification
Patient 2
Patient 3
Patient 4
Patient 5
12
56
30
29
40
Female
Female
Female
Male
Male
9
10
2
13
17
Eschar
Blood
Blood
Blood
Blood
Elevated temperature (°C)
No
No
No
Yes (39)
Yes (39)
Asthenia
No
Yes
Yes
No
Yes
Anorexia
No
Yes
Yes
No
Yes
Nausea
No
Yes
Yes
No
Yes
Headache
No
No
Yes
Yes
Yes
Rash
No
No
No
No
No
Eschar
Yes
Yes
Yes
No
No
Lymphadenopathy
Yes
No
Yes
No
No
Vomiting
No
No
Yes
No
Yes
Neck stiffness
No
No
Yes
No
Yes
Kernig’s sign
No
No
No
No
Yes
Hospitalization — days
20
20
17
22
4
Hematologic test Leukocyte count — ×10−9/liter
10.5
5.4
9.8
11.6
11.8
Lymphocyte count — ×10−9/liter
4.0
2.7
2.2
1.4
1.6
−9
Neutrophil count — ×10 /liter
6.3
2.6
7.3
9.9
9.9
Hemoglobin — g/liter
143
143
122
163
143
Platelet count — ×10−9/liter
305
244
221
203
163
AST — U/liter
9.6
18.4
8.9
75.9
15.3
ALT — U/liter
15.5
34.3
14.4
44.4
19.9
No
No
No
No
Yes
Leukocytes — per mm3
NA
NA
0
NA
80
Lymphocytes — %
NA
NA
0
NA
60
Protein — g/liter
NA
NA
0.3
NA
0.6
Glucose — mmol/liter
NA
NA
3.8
NA
4.5
Biochemical test
Urinalysis Proteinuria Cerebrospinal fluid measurements
* ALT denotes alanine aminotransferase, AST aspartate aminotransferase, NA not available (not performed or not reported), and PCR polymerase chain reaction.
patients), nausea (in three patients), headache (in three patients), eschar (in three patients) (Fig. 2 in the Supplementary Appendix), and lymphadenopathy (in two patients). Patient 5 had meningitis-like manifestations such as vomiting, neck stiffness, and Kernig’s sign. Coma, renal dysfunction, and respiratory acidosis then developed, and the patient died 4 days after ad-
mission to the hospital. Laboratory tests showed a slight increase in the leukocyte count (in three patients), an elevated level of aspartate aminotransferase (in one patient), proteinuria (in one patient), and an increase in the level of cerebrospinal fluid protein and leukocyte count in Patient 5 (Table 1). Since none of the patients presented with rash, which is considered to be a
n engl j med 369;12 nejm.org september 19, 2013
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1179
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The
typical sign of infections with species of rickettsiae of the spotted fever group in China,3 their conditions were initially misdiagnosed, and they received penicillin G, leading to a prolonged hospitalization for approximately 20 days. To identify local natural foci, host-seeking ticks were collected around the patients’ residences. A total of 46 of 453 Ixodes persulcatus ticks (10%) were positive for Candidatus R. tarasevichiae. Candidatus R. tarasevichiae was initially detected in I. persulcatus ticks in various regions of Russia.4 We identified the agent as an emerging pathogen causing human infection. These findings underscore the concept that rickettsioses are more common than previously realized and may be associated with misdiagnosed causes of fever globally.5 Careful attention to clinical features and the use of molecular diagnostic tools could be helpful in establishing an etiologic diagnosis that may facilitate appropriate treatment and public health measures. Na Jia, M.D. State Key Laboratory of Pathogen and Biosecurity Beijing, China
Yuan-Chun Zheng, M.D. Mudanjiang Forestry Central Hospital Mudanjiang, China
Jia-Fu Jiang, M.D. Lan Ma, M.D. Beijing Institute of Microbiology and Epidemiology Beijing, China
Wu-Chun Cao, M.D., Ph.D. State Key Laboratory of Pathogen and Biosecurity Beijing, China
[email protected] Drs. Jia and Zheng contributed equally to this letter. Supported by grants (81290344 and 81130086) from the National Natural Science Foundation of China. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Walker DH, Ismail N. Emerging and re-emerging rickettsio-
ses: endothelial cell infection and early disease events. Nat Rev Microbiol 2008;6:375-86. 2. La Scola B, Raoult D. Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol 1997;35:2715-27. 3. Fan MY, Zhang JZ, Chen M, Yu XJ. Spotted fever group rickettsioses in China. In: Raoult D, Broqui P, eds. Rickettsiae and rickettsial diseases at the turn of the third millennium. Paris: Elsevier, 1999:247-57. 4. Shpynov S, Fournier PE, Rudakov N, Raoult D. “Candidatus Rickettsia tarasevichiae” in Ixodes persulcatus ticks collected in Russia. Ann N Y Acad Sci 2003;990:162-72. 5. Walker DH, Paddock CD, Dumler JS. Emerging and reemerging tick-transmitted rickettsial and ehrlichial infections. Med Clin North Am 2008;92:1345-61. DOI: 10.1056/NEJMc1303004 Correspondence Copyright © 2013 Massachusetts Medical Society.
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correction Global Health: Response to the AIDS Pandemic — A Global Health Model (June 6, 2013;368:2210-8). In Figure 1 (page 2212), the estimated HIV prevalence in Gabon should have been shown as 5.0 to
