Emergence of Astrakhan Rickettsial Fever in China

•Human cases of Astrakhan Rickettsial Fever were first documented in China.•A high seroprevalence of R. conorii infections occurred in the local population.•The expanding spread of rickettsial pathogens is posing threats to public health. Dear Editor, Four laboratory-confirmed Astrakhan rickettsial fever (ARF) cases were identified in the Xinjiang Uygur Autonomous Region (XUAR) of China in July 2023, which is the first documented R. conorii subsp. caspia infections in East Asia. The agent was found to cause ARF in regions endemic in Astrakhan and Kalmykia by the Caspian Sea, and has limited distribution in some regions of Europe and Africa, such as southern France, Kosovo, Chad, and Zambia1Chitimia-Dobler L. Dobler G. Schaper S. Küpper T. Kattner S. Wölfel S. First detection of Rickettsia conorii ssp. caspia in Rhipicephalus sanguineus in Zambia.Parasitology research. 2017 Nov; 116 (PubMed PMID: 28986641. Epub 2017/10/08.eng): 3249-3251Google Scholar. Infection with ARF may range in severity from mild, to moderate, to severe, and the first death due to infection was reported in 2013. In Russia, severe ARF cases have accounted for 5.3% of all those infected and the mortality rate approximates 1-2%2Rudakov N.V. Shpynov S.N. Pen`evskaya N.A. Trankvilevsky D.V. Blokh A.I.J.Po.P.D.I. Epidemiological Situation on Tick-Borne Rickettsioses in the Russian Federation in 2010–2019 and Prognosis for 2020. 2020; : 61-68Google Scholar. For the four ASF cases, all of the rickettsial targeted genes (ompA, ompB, and the 17kD gene) were amplified from the blood genomic DNA samples of the patients by polymerase-chain-reaction amplification (PCR). The DNA sequences of each targeted gene amplified showed 100% homology and phylogenetic analysis revealed that the causative agent of the four patients was R. conorii subsp. caspia through 100% identification of ompA and ompB genes and 99.7% identification of the 17kD gene from those of R. conorii subsp. caspia A-167, previously isolated in Russia (Fig. 1). According to the immunofluorescence assay, the patients were confirmed as current infections of R. conorii based on a 4-fold increase in IgG titer between acute and convalescent sera and a positive IgM titer in acute sera. The main clinical features of the patients in this study included pink-red rashes (all cases), fever (all cases), headaches (2 of 4 cases), muscle pain (2 of 4 cases), chills (3 of 4 cases), and anorexia (3 of 4 cases) as shown in Table 1, which is consistent with the reports of ARF patients in Russia3Tarasevich I.V. Makarova V.A. Fetisova N.F. Stepanov A.V. Miskarova E.D. Balayeva N. et al.Astrakhan fever, a spotted-fever rickettsiosis.Lancet (London, England). 1991 Jan 19; 337 (PubMed PMID: 1670806. Epub 1991/01/19.eng): 172-173Google Scholar. The increase in liver enzymes and pleural effusions in some of the patients indicated hepatic and pulmonary damage caused by R. conorii subsp. caspia infection (Supplementary Table 1). Eschar at the site of tick attachment is considered as a cutaneous hallmark of spotted fever. However, an inoculation eschar at the site of the tick bite is present in only 23% of ASF patients from previous reports3Tarasevich I.V. Makarova V.A. Fetisova N.F. Stepanov A.V. Miskarova E.D. Balayeva N. et al.Astrakhan fever, a spotted-fever rickettsiosis.Lancet (London, England). 1991 Jan 19; 337 (PubMed PMID: 1670806. Epub 1991/01/19.eng): 172-173Google Scholar. In the present study, only one of the four patients displayed an eschar upon physical examination. The low rates of eschar in ASF patients make primary diagnosis more difficult, especially in areas where clinical awareness of this tick-borne disease is low but where vectors are increasingly prevalent. For rickettsial infection, any delay in making a definitive diagnosis and giving appropriate antibiotics can lead to more severe disease, and even death if left untreated. The patient in case 1 was diagnosed as having sepsis with electrolyte disturbances and high serum levels of IL-6 by the time she was admitted to our hospital. A timely diagnosis and corresponding anti-rickettsial treatment prevented the progression of the disease and the patient made a good recovery.Table 1Clinical characteristics and laboratory test results of the ARF patients.Clinical signsCase 1Case 2Case 3Case 4SexFemaleMaleMaleFemaleAge63556650Month of admissionJul.Jul.Jul.Jul.OccupationFarmerFarmerHerdsmanFarmerRegionsAltaiWujiaquWujiaquWujiaquTick bitesPresentPresentPresentPresentPrevious illnessHealthyHealthytype 2 diabetesHealthyFirst day of fevera. The day of the patient bite by tick was defined as Day 0Day 5 a. The day of the patient bite by tick was defined as Day 0Day 10Day 7Day 7Highest temperature, °C39.039.039.040.0HeadachePresent (Day 7)AbsentAbsentPresent (Day 7)MalaisePresentPresentPresentPresentMyalgiaAbsentPresentAbsentPresentChillsPresentPresentAbsentPresentAnorexiaPresentPresentPresentAbsentEscharPresentAbsentAbsentAbsentRashPresent (Day 7)Present (Day 12)Present (Day 7)Present (Day 8)HypotensionPresent (Day 9)AbsentAbsentAbsentNauseaPresent (Day 7)Present (Day13)AbsentAbsentVomitingPresent (Day 7)Present (Day13)AbsentAbsentProteinuria--+-Occult blood in urine--+--Pleural effusionAbsentPresentAbsentPresenta . The day of the patient bite by tick was defined as Day 0 Open table in a new tab XUAR is located on the northwestern border of China and adjacent to Central Asia. About a million birds migrate here each year, while more than 130 wildlife species migrate across the border. It serves as an important land port for trade between China and Europe. There have been 10 SFG rickettsial species identified and 3 of the 10 species have been confirmed as human pathogens in the region4Yang M. Jia Y. Dong Z. Zhang Y. Xie S. Liu Q. et al.Rickettsia aeschlimannii Infection in a Woman from Xingjiang, Northwestern China.Vector borne and zoonotic diseases (Larchmont, NY). 2022 Jan; 22 (PubMed PMID: 35030047. Epub 2022/01/15.eng): 55-57Google Scholar. Though R. conorii was demonstrated to be carried by Rh. turanicus in Yecheng City, southern XUAR, the isolates were identified as R. conorii indica subspecies5Guo L.P. Jiang S.H. Liu D. Wang S.W. Chen C.F. Wang Y.Z. Emerging spotted fever group rickettsiae in ticks, northwestern China.Ticks and tick-borne diseases. 2016 Oct; 7 (PubMed PMID: 27554852. Epub 2016/08/25.eng): 1146-1150Google Scholar. In this study, the patients were not from the same region in the XUAR; one was from the Altai region and the other three were from Wujiaqu City. The two regions are 400 kilometers apart and are split by two mountain ranges, the Aertai Mountains and Tian Mountains, respectively (Supplementary Fig. 1). The patient's habitat was an alluvial, plain landscape at the edge of the desert. Previously, ARF patients were concentrated in the Volga delta and the desert areas of the river's left bank in regions of Russia6Malkhazova S. Pestina P. Prasolova A. Orlov D. Emerging Natural Focal Infectious Diseases in Russia: A Medical-Geographical Study.International journal of environmental research and public health. 2020 Oct 30; 17 (PubMed PMID: 33143199. PubMed Central PMCID: PMC7663368. Epub 2020/11/05.eng)Google Scholar. Approximately 25.5% (51/200) of IgG antibodies against R. conorii were found in serum samples from the local population of the patients' surrounding community. This indicated that residents of the XUAR and neighboring provinces are at high risk for R. conorii subsp. caspia infection, as these areas have similar geomorphologic and climatic conditions. In Europe and Africa, the vectors for R. conorii subsp. caspia are Rhipicephalus ticks, namely Rh. sanguineus and Rh. pumilio. The two tick species have also been found to exist in XUAR with a prevalence of 1.7% and 0.6%, respectively7Li Y. Wen X. Li M. Moumouni P.F.A. Galon E.M. Guo Q. et al.Molecular detection of tick-borne pathogens harbored by ticks collected from livestock in the Xinjiang Uygur Autonomous Region, China.Ticks and tick-borne diseases. 2020 Sep; 11 (PubMed PMID: 32723638. Epub 2020/07/30.eng)101478Google Scholar. The patients in our study all experienced onset of disease in July, which is consistent with the seasonality of ARF in Astrakhan, Russia. ARF outbreaks, peaking from July to August in summer, may be due to larval development to nymph and the increased aggression towards humans of Rhipicephalus ticks in higher temperatures8Parola P. Paddock C.D. Raoult D. Tick-borne rickettsioses around the world: emerging diseases challenging old concepts.Clinical microbiology reviews. 2005 Oct; 18 (PubMed PMID: 16223955. Pubmed Central PMCID: PMC1265907. Epub 2005/10/15.eng): 719-756Google Scholar, 9Backus L.H. López Pérez A.M. Foley J.E. Effect of Temperature on Host Preference in Two Lineages of the Brown Dog Tick, Rhipicephalus sanguineus.The American journal of tropical medicine and hygiene. 2021 Apr 5; 104 (PubMed PMID: 33819179. Pubmed Central PMCID: PMC8176482. Epub 2021/04/06.eng): 2305-2311Google Scholar. In recent decades, geographic distributions of many ticks and consequently tick-borne diseases have expanded beyond locations previously known, including rickettsial infections. Notably, the ASF patients in this study were infected without a history of sojourn, suggesting that R. conorii subsp. caspia and its vectors have expanded beyond the traditional endemic areas. The emergence of ASF in the XUAR may be the result of climate change, international trade, and wildlife migration. The climate warming in the area increasing human bites and subsequent pathogen transmission by Rhipicephalus ticks as previous reports in Europe8Parola P. Paddock C.D. Raoult D. Tick-borne rickettsioses around the world: emerging diseases challenging old concepts.Clinical microbiology reviews. 2005 Oct; 18 (PubMed PMID: 16223955. Pubmed Central PMCID: PMC1265907. Epub 2005/10/15.eng): 719-756Google Scholar, 9Backus L.H. López Pérez A.M. Foley J.E. Effect of Temperature on Host Preference in Two Lineages of the Brown Dog Tick, Rhipicephalus sanguineus.The American journal of tropical medicine and hygiene. 2021 Apr 5; 104 (PubMed PMID: 33819179. Pubmed Central PMCID: PMC8176482. Epub 2021/04/06.eng): 2305-2311Google Scholar. In 2019, the first human infection of R. conorii subsp. indica (Indian tick typhus) in China was reported in Qingdao, an international port city on the eastern coast of China10Xu N. Gai W. Zhang Y. Wang W. Wang G. Dasch G.A. et al.Confirmation of Rickettsia conorii Subspecies indica Infection by Next-Generation Sequencing, Shandong, China.Emerging infectious diseases. 2021 Oct; 27 (PubMed PMID: 34545782. Pubmed Central PMCID: PMC8462315. Epub 2021/09/22.eng): 2691-2694Google Scholar. We suspect that international trade may play a role in the expansion of rickettsiosis distribution. The findings highlight the potential expansion of rickettsial pathogens to previously non-endemic regions, and warrant increased public health awareness for ARF, in northwest China and neighboring countries. Further environmental surveillance and investigation of the local hosts and vectors of R. conorii subsp. caspia is required to improve the prevention of the disease. Experimental protocols were approved by the Ethical Review Committee of the First Affiliated Hospital of Xinjiang Medical University (No. 20220802-04). All patients provided written informed consent. This work was supported by grants from Science Foundation for the State Key Laboratory for Infectious Disease Prevention and Control from China (grant nos. 2022SKLID302 and 2019SKLID403), and the Public Health Service Capability Improvement Project of the National Health Commission of the People's Republic of China (grant no. 2100409031), Key R&D projects (2022B03014), Natural Science Foundation (2022D01D19), and Tianshan Talent Training Program (2022TSYCLJ0024) from the Science and Technology Department of Xinjiang Uygur Autonomous Region.