Relapsing epidemic typhus (Brill-Zinsser disease) in China

Dear Editor, Rickettsia prowazekii, the agent of louse-borne epidemic typhus1Warrell C.E. Osborne J. Nabarro L. et al.Imported rickettsial infections to the United Kingdom, 2015-2020.J Infect. 2023; 86 (PMID: 36948252): 446-452https://doi.org/10.1016/j.jinf.2023.03.015Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, is considered a biological warfare and terrorism agent with a mortality of as high as 30%2Bechah Y. El Karkouri K. Mediannikov O. et al.Genomic, proteomic, and transcriptomic analysis of virulent and avirulent Rickettsia prowazekii reveals its adaptive mutation capabilities.Genome Res. 2010; 20 (PMID: 20368341): 655-663https://doi.org/10.1101/gr.103564.109Crossref PubMed Scopus (53) Google Scholar. Historically, numerous outbreaks of epidemic typhus have occurred worldwide, resulting in millions of deaths3Ge H. Chuang Y.Y. Zhao S. et al.Comparative genomics of Rickettsia prowazekii Madrid E and Breinl strains.J Bacteriol. 2004; 186 (PMID: 14702324): 556-565https://doi.org/10.1128/JB.186.2.556-565.2004Crossref PubMed Scopus (31) Google Scholar. With the improvements in hygiene, epidemic typhus cases have been rare in recent years. However, infection of R. prowazekii could be life-long. Brill-Zinsser disease, a recurrent form of epidemic typhus that may occur up to 40 years after the initial infection, was still sporadically reported4Stein A. Purgus R. Olmer M. Raoult D. Brill-Zinsser disease in France.Lancet. 1999; 353 (PMID: 10371575): 1936https://doi.org/10.1016/S0140-6736(99)01995-9Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 5Faucher J.F. Socolovschi C. Aubry C. et al.Brill-Zinsser disease in Moroccan man, France, 2011.Emerg Infect Dis. 2012; 18 (PMID: 22261378): 171-172https://doi.org/10.3201/eid1801.111057Crossref PubMed Scopus (18) Google Scholar, 6Lutwick L.I. Brill-Zinsser disease.Lancet. 2001; 357 (PMID: 11323068): 1198-1200https://doi.org/10.1016/s0140-6736(00)04339-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. Herein we reported the first case of Brill-Zinsser disease in China. On Aug 27, 2023, a 73-year-old woman living in Northeast China presented to the hospital after four days of fever (39 oC), malaise, and dyspnea. She has been treated with ceftriaxone sodium for two days in a county-level hospital but the symptoms were not alleviated. On admission, she was diagnosed with pneumonia, type I respiratory failure, hypoproteinemia, electrolyte disturbance (hyponatremia, hypokalemia, and hypochloremia), liver dysfunction, and Grade-Ⅱ hypertension. No rash was observed. She was suspected to be infected with severe fever with thrombocytopenia syndrome virus (SFTSV), but the laboratory test was negative. She was then hospitalized and antibiotic treatment was applied by intravenous cefmetazole sodium and levofloxacin sodium chloride. Diprophylline, compound amino acid, sodium chloride, potassium chloride, rosatidine acetate, and nifedipine were used for supportive treatment. On the third day of hospitalization, the temperature became normal, but a routine blood test still showed thrombocytopenia, and computed tomography (CT) demonstrated pleural effusion and pneumonia involving both lungs (Fig S1). In addition, she was diagnosed with cardiac insufficiency. Subsequently, furosemide and nicotinamide were used. The symptoms were alleviated in the next few days, and she was discharged from the hospital on the 11th day (Table S1). In a retrospective study, the blood sample of this patient was screened for vector-borne pathogens. Out of our expectation, the partial 16 S rRNA and groESL sequences of R. prowazekii were amplified by hemi-nested PCR using Rickettsia-specific primers. The result was then confirmed by meta-genomic and meta-transcriptomic sequencing, yielding 7 and 227 contigs, respectively. For further genotyping, 37 genes and intergenic regions were selected for analysis. DNA comparison shows that this strain (Yingkou20) differs from all sequenced strains elsewhere worldwide (Table S2-3). An epidemiological investigation was then carried out (Fig S2). The patient was living in a clean environment. She denied both the presence of lice and contact with wild animals. After careful inspection, no lice were found in her living environment. Besides, no epidemic typhus case has been reported in this region (Yingkou City) in recent years. However, the patient claimed that she had been infested with lice in the 1980s. Although the patient has never received a diagnosis of R. prowazekii infection previously, she was determined as a case of Brill-Zinsser disease based on current evidence. In China, outbreaks of epidemic typhus have been recorded since the 19th century7Fan M.Y. Walker D.H. Yu S.R. Liu Q.H. Epidemiology and ecology of rickettsial diseases in the People's Republic of China.Rev Infect Dis. 1987; 9 (PMID: 3326129): 823-840Crossref PubMed Google Scholar. However, almost all the cases were diagnosed only based on clinical manifestations or preliminary immunological tests such as the Weil-Felix test. Until today, no patient was molecularly diagnosed and no DNA sequence was published. Therefore, nothing is known about the genetic features of R. prowazekii in China as well as in Asia. The current results suggest that an evolutionary-independent R. prowazekii strain may have been circulating in China. Besides, since the 1970s, only 8 cases of Brill-Zinsser disease have been reported worldwide, all of which were in Europe and America5Faucher J.F. Socolovschi C. Aubry C. et al.Brill-Zinsser disease in Moroccan man, France, 2011.Emerg Infect Dis. 2012; 18 (PMID: 22261378): 171-172https://doi.org/10.3201/eid1801.111057Crossref PubMed Scopus (18) Google Scholar. This may be the first report of Brill-Zinsser disease in Asia. Patients of Brill-Zinsser disease can act as the source of an outbreak of epidemic typhus8Raoult D. Ndihokubwayo J.B. Tissot-Dupont H. et al.Outbreak of epidemic typhus associated with trench fever in Burundi.Lancet. 1998; 352 (PMID: 9717922): 353-358https://doi.org/10.1016/s0140-6736(97)12433-3Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. In the presence of lice, it spreads fast and fiercely. Our results suggest that the risk of the re-emergence of epidemic typhus still exists in China, especially in historical endemic areas. Sustainable surveillance of patients and vector control measures are still needed. The study was designed and conducted following the Helsinki Declaration and approved by the Ethics Committee of the National Institute for Communicable Disease Control and Prevention, the Chinese CDC. An informed consent was signed by the patient as part of the hospital's routine activity. This work was funded by the National Key Research and Development Program (Grant No. 2021YFC2301202) and the National Natural Science Foundation of China (Grant No. 82102390).