Pneumonia Due to Scrub Typhus Infection of Unknown Origin: A Case Report

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Patients typically present with sudden high fever, headache, myalgia, and eschar formation at the site of the bites. Respiratory symptoms, such as cough and shortness of breath, can also occur, especially in severe cases that lead to pneumonia, organ failure, or acute respiratory distress syndrome (ARDS). This report presents a case of scrub typhus pneumonia of unknown origin, diagnosed by metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid. Case Presentation: A 58-year-old woman was admitted with cough, sputum production, and fever. Imaging revealed pneumonia. During hospitalization, bronchoscopy was performed to identify the causative pathogen. mNGS of the bronchoalveolar lavage fluid confirmed Orientia tsutsugamushi infection. the patient's pneumonia was improved after oral administration of doxycycline(100mg, tid) for anti-infection treatment for 1 month. Conclusion: This report highlights the diagnostic challenges of scrub typhus-induced pneumonia and demonstrates the advantages of mNGS in identifying rare pathogens. It also underscores the importance of standardized antibiotic therapy for treating scrub typhus pneumonia. pneumonia scrub typhus case report Figures Figure 1 Introduction Scrub typhus is an acute febrile illness caused by the rickettsial bacterium Orientia tsutsugamushi , which is transmitted to humans through the bite of infected mites. It is primarily found in rural and scrubby regions of Asia, the Pacific Islands, and parts of northern Australia. The disease is endemic in several areas of Southeast Asia, China, India, and Japan[ 1 ]. Scrub typhus can present with a wide range of nonspecific symptoms, often resulting in delayed or missed diagnoses. Patients usually present with a sudden onset of high fever, headache, myalgia, and eschar formation at the site of mite bites[ 2 ]. Additional common features include lymphadenopathy, maculopapular rash, and gastrointestinal symptoms. In rare cases, infection with Rickettsia rickettsii can lead to sensorineural hearing loss and otalgia[ 3 ]. Respiratory involvement, such as cough and shortness of breath, may occur, particularly in severe cases where scrub typhus can lead to complications such as pneumonia, organ failure, or acute respiratory distress syndrome (ARDS)[ 4 – 5 ]. Early diagnosis and prompt antibiotic treatment, such as doxycycline, are essential to prevent severe complications. Case Report A 58-year-old woman with hypertension was admitted to the Affiliated Hospital of Yanbian University on October 30, 2024. She presented with a 10-day history of cough, sputum, and fever, with a maximum temperature of 38°C. Upon admission, her vital signs were: blood pressure 93/58 mmHg, heart rate 68 beats per minute, temperature 37.4°C, and respiratory rate 18 breaths per minute. Laboratory tests revealed a white blood cell count of 11.37 × 10⁹ cells/L, a neutrophil count of 8.72 × 10⁹/L, C-reactive protein of 55.80 mg/L, and procalcitonin of 0.10 ng/mL. Liver function tests were normal. Chest CT showed right lung inflammation, mildly enlarged mediastinal lymph nodes, and a small right pleural effusion(Figure 1 A). A diagnosis of community-acquired pneumonia was made based on clinical and imaging findings. Physical examination showed intact skin with no eschar or scab, and auscultation revealed thickened breath sounds and moist rales in the right lung. The patient had no recent travel history or insect bites. Despite receiving 7 days of cefoxitin treatment at an outside hospital, her symptoms did not improve. Given the lack of response to antibiotics and the potential for atypical pathogens, ciprofloxacin was started, and bronchoscopy was recommended. Bronchoscopy, performed on the second day of admission, revealed sputum obstructing the lumen of the medial segment of the right middle lobe. Bronchoalveolar lavage was conducted for bacterial, fungal culture, and mNGS analysis.While bacterial and fungal cultures showed no growth,mNGS identified Orientia tsutsugamushi、Rhinovirus B and Human gammaherpesvirus 4 .The mNGS process is as follows: 1.Homogenization: BALF samples are mixed with a digestion buffer and briefly vortexed until liquefied.The liquefied BALF is then transferred into an MP Lysing Matrix E tube (containing internal reference beads) and processed using a homogenizer (Jingxin, Shanghai, China).After homogenization, the sample is centrifuged briefly, and the supernatant is collected for subsequent nucleic acid extraction.2.Nucleic Acid Extraction:The supernatant is treated with a nucleic acid extraction/purification reagent (Geneseeq, Beijing, China).Automated extraction of DNA and RNA is performed separately using a fully automated nucleic acid extraction system (Tianlong, Xi’an, China).3.DNA Library Preparation: Library construction is performed using a Universal Sequencing Reaction Preparation Kit (Geneseeq, Beijing, China).The products are purified using magnetic beads (Geneseeq, Beijing, China).The purified DNA library is quantified using a Qubit 4.0 Fluorometer (with the Qubit dsDNA HS Assay Kit), and the concentration is recorded.4.RNA Library Preparation: cDNA library construction is performed using an RNA Library Enrichment Kit (Geneseeq, Beijing, China) and the Universal Sequencing Reaction Preparation Kit (Geneseeq, Beijing, China).The reaction products are purified immediately after completion.5.Library Pooling: The basic information of the libraries to be pooled is recorded in a pooling table.Based on the library concentrations and required sequencing data volume, the sample volumes and theoretical pooled concentration are calculated.To ensure accuracy, the measured pooled concentration should not deviate by more than 15% from the theoretical concentration.6.Sequencing: The pooled libraries are processed into DNA Nanoballs (DNB).Sequencing is performed on the MGI-200 Sequencer (BGI, Shenzhen, China).7.Data Analysis: After sequencing, the Genseq-PM Pathogen Metagenomics Analysis Software automatically processes the raw sequencing data.Quality control (QC) is performed on the raw data, followed by alignment against a custom-built pathogen database for species identification. Table 1 This table illustrates workup that was carried out for diagnosis of community acquired pneumonia in our patient. Test Sputum Specimen Respiratory Nasopharyngeal Swab Bronchoalveolar lavage fluid Cultures Negative - Negative mNGS - - Rhinovirus B (759) Human gammaherpesvirus 4 (24886) Orientia tsutsugamushi (2566) Influenza B - Negative - Adenovirus - Negative - Respiratory Syncytial Virus - Negative - Parainfluenza virus,type1 - Negative - Parainfluenza virus,type2 - Negative - Influenza A - Negative - Historically, scrub typhus has been treated with doxycycline or chloramphenicol, but chloramphenicol has been gradually applied because of its toxic side effects.For severe scrub typhus, doxycycline combined with azithromycin can be used to reduce complications and mortality[ 6 ].Based on these results, ciprofloxacin was discontinued, and doxycycline 0.1 g BID was initiated. After 9 days of doxycycline treatment, the patient showed clinical improvement with reduced fever, cough, and sputum production. Laboratory tests demonstrated a white blood cell count of 8.49 × 10⁹ cells/L, neutrophils at 5.17 × 10⁹/L, and C-reactive protein reduced to 7.90 mg/L(Table 2 ). Chest CT showed no significant change in lung pathology (Fig. 1 B), but the patient 's clinical symptoms and laboratory parameters were improved, and the patient' s subjective symptoms were significantly improved. We recommended oral doxycycline treatment and the patient was discharged after obtaining consent. The patient continued oral doxycycline for 6 weeks. Follow-up chest CT after 6 weeks showed marked resolution of pulmonary lesions(Figure 1 C). Table 2 Illustrates the trend of common laboratory derangement seen in patients with Scrub typhus. Admission Discharge White Blood Cell Count 11.37 8.49 Neutrophils 8.72 5.17 Lymphocytes 1.40 2.41 PCT 0.10 0.10 CRP 55.80 7.90 Hemoglobin 106 96 Platelet Count 300 434 Discussion Scrub typhus is a significant public health concern in the Asia-Pacific region, particularly in the area known as the "Scrub Typhus Triangle." This region includes China, where an estimated 1 million new cases of scrub typhus occur each year, and over 1 billion people globally are at risk. Without appropriate treatment, the disease can have a mortality rate of up to 30% or even higher[ 7 ]. Scrub typhus has long been considered a neglected infectious disease, and many aspects of its diagnosis and prevention remain poorly understood. In China, cases of scrub typhus are most commonly reported in the southwest, southeast coastal, and eastern regions[ 8 ]. A recent study by Yue et al. (2019) divided the prevalence of scrub typhus in China into three regions: northern China (Anhui, Jiangsu, Shandong), southwest China (Yunnan, Sichuan), and southern China (Fujian, Guangdong, Guangxi, Hainan, Hunan, Jiangxi, Zhejiang), with relatively low incidence in Jilin Province[ 9 ]. Scrub typhus presents with a variety of clinical symptoms, with the most common being fever, eschar, rash, and lymphadenopathy. After an incubation period of 4 to 21 days, patients typically develop fever, ranging from 38.5°C to 42°C, which lasts from 1 to 12 days (with an average duration of 4.5 days)[ 10 ]. Eschar formation, a painless necrotic lesion at the bite site, is a hallmark feature of the disease.The results of a meta-analysis study showed that the positive rate of eschar was estimated to be 30.34%(22.54–38.15)[ 11 ], and eschar lesions were mainly present in the chest and abdomen of women(42.3%), whereas it was present in the axilla, groin, and genitalia of men (55.8%)[ 12 ].Scrub typhus may involve the abdominopelvic lymph nodes. Regional lymphadenopathy, characterized by tenderness and enlargement of the draining lymph node around the bite site. This pathologic findings may be influenced not only by O.tsutsugamushi pathogen spread, but also by host immune mechanisms[ 13 ].An imaging study of scrub typhus showed the periportal area was the most common site of lymphadenopathy, the majority of patients had a diffuse pattern of abdominopelvic lymphadenopathy, including the extraperitoneum, perigastric area, and the periportal area. This diffuse pattern of abdominopelvic lymphadenopathy may suggest scrub typhus,especially when physical examination does not reveal eschar[ 14 ].In China, scrub typhus cases may also present with splenomegaly, hepatomegaly, pneumonia, meningitis, multiple organ dysfunction, disseminated intravascular coagulation, and conjunctival congestion[ 15 ]. Zoonotic diseases, including Scrub typhus, are infectious diseases that can be transmitted from animals to humans. These diseases can be caused by bacteria, viruses, parasites, and fungi. Zoonotic diseases can be transmitted to humans through direct contact with infected animals, consumption of contaminated food or water, or through the bite of infected arthropod vectors such as ticks and mosquitoes[ 16 ]. Of note, the role of wildlife in pathogen transmission, amplification, and zoonotic spillover as well as transmission, such as coronavirus causing Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and the recent coronavirus pandemic (COVID-19), are zoonoses characterized by pneumonia[ 17 ].For pulmonary infectious diseases, the most common bacteria and viruses of community-acquired pneumonia should first be considered. In patients with CAP, attention must be paid to patient epidemiological characteristics, including patient work environment, travel history, and contact history, which can provide clinicians with clues to rule out infectious diseases according to local epidemiology, such as in tick-endemic areas, the presence of pneumonia may be caused by ehrlichiosis, anaplasmosis, babesiosis, tularemia, or Rocky Mountain spotted fever[ 18 ].Progress has been made in the field of zoonotic disease research in early detection diagnosis, treatment, prevention and control. For example, the use of polymerase chain reaction (PCR) technology has revolutionized the detection of zoonotic viruses such as Ebola and Zika. In addition, significant progress has been made in the development of vaccines and treatments for zoonotic diseases, such as the development of effective vaccines for Ebola and Nipah viruses. Similarly, the development of new treatments for diseases such as West Nile virus and avian influenza, as well as a recently discovered new antiviral drug, can effectively fight a variety of zoonotic viruses, including Ebola virus, Lassa fever, and COVID-19, and can help save numerous lives. In this case, the patient presented with fever, sputum, and cough as the main symptoms, and a diagnosis of community-acquired pneumonia was initially considered, supported by serological tests and CT findings. Fever is a common symptom in many infectious diseases, including pneumonia, making it easy to overlook the possibility of scrub typhus in the early stages. While typical clinical features such as eschar can aid in diagnosis, serological tests remain the gold standard for confirming scrub typhus. Currently, the indirect immunofluorescence antibody (IFA) test is widely regarded as the diagnostic gold standard for scrub typhus[ 19 ]. However, this test requires specialized fluorescence microscopy and trained personnel, making it unavailable in many non-endemic areas. The Weil–Felix agglutination test has limited sensitivity and specificity due to cross-reactivity with other pathogens like those causing dengue fever, malaria, and typhoid fever. Real-time polymerase chain reaction (Q-PCR) is highly sensitive (97%) and specific (100%) for diagnosing scrub typhus[ 20 ], but many laboratories, including those in China, do not routinely use this test.In this case, we confirmed the etiological detection of pulmonary infection by mNGS, because the patient 's clinical manifestations were common pulmonary symptoms, so we did not obtain samples for PCR detection during bronchoscopic alveolar lavage examination. Without mNGS results, we have also neglected infection with Orientia tsutsugamushi , which may delay early diagnosis, leading to recurrent infections and delayed treatment. Metagenomic next-generation sequencing (mNGS) offers a rapid, non-targeted approach to pathogen detection. It can sequence hundreds of thousands to millions of DNA molecules simultaneously, allowing for the detection of all pathogens present, even in low abundance[ 21 ]. This makes mNGS particularly valuable for diagnosing complex infectious diseases and identifying atypical pathogens[ 22 ]. Broad spectrum microbial coverage leading to interpretation of mNGS results is a huge challenge.mNGS can theoretically detect all currently known pathogens of about 8,000 species or even currently unknown genome sequences. Therefore, in mNGS detection results, microbial contamination in the environment, reagents, and containers, as well as detection signals of a large number of non-pathogenic microorganisms and pathogenic microorganisms such as colonization in the human body are mixed[ 23 ]. The number of microorganisms reported by mNGS is also 5–20, which makes the clinical interpretation of mNGS a great challenge and requires a lot of clinical, pathogenic microorganism diagnosis and professional experience to interpret pathogenic bacteria[ 24 – 25 ].As an unbiased method, mNGS detects all possible pathogens in a clinical sample. It is especially suitable for the early screening of complex infectious diseases, severe infections, and the diagnosis of rare and atypical causes. Although the test is expensive, mNGS always takes less time (< 24h) compared with conventional diagnostic methods and can identify millions of base pairs of non-targeted sequences in a single sample, while traditional culture, PCR and other detection techniques have significant disadvantages, including a long culture cycle and can only detect single pathogens, and many laboratories may not be equipped with corresponding reagents for infectious disease pathogens to perform PCR and other tests except for typical infectious disease endemic areas[ 26 ]. As a rapid microbiological diagnostic method for infectious diseases, mNGS has recently been applied in clinical practice due to its high efficiency, sensitivity, and cost-effectiveness, which has significant benefits for both physician evaluation of pathogenic bacteria and patient disease recovery. In this case, the patient lived in an area with a very low incidence of scrub typhus and had no recent travel history. No evidence of skin lesions or eschar was found during the physical examination, which led to a common initial diagnosis of community-acquired pneumonia. However, during the course of treatment, bronchoscopy was performed, and mNGS eventually identified Orientia tsutsugamushi as the causative pathogen. This allowed for a timely adjustment of the treatment regimen based on the etiology.Doxycycline and chloramphenicol are the main antibiotics used to treat scrub typhus[ 27 ]. In this case, doxycycline treatment effectively controlled the patient's illness. Declarations Authors' Contributions: ZW:Data collection, original draft writing. YP:Data collection,Physical examination.ZA:Performed bronchoscopy.HP:Supervision,review,and editing.All authors contributed to the drafting and final approval of the manuscript. Funding: This work was supported by Health Science and Technology Ability Improvement Program of Jilin Province (Nos.2024A060). Data Availability declaration: The datasets used during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate ： This case report was approved by the Ethics Committee of the Affiliated Hospital of Yanbian University. Consent to Participate and Publish declarations ： Written informed consent was obtained from the patient for publication of images and personal information for this case report. Conflicts of Interest: None. References Xu G, Walker DH, Jupiter D, Melby PC, Arcari CM. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis. 2017 Nov 3;11(11):e0006062. Alam AM, Gillespie CS, Goodall J, Damodar T, Turtle L, Vasanthapuram R, Solomon T, Michael BD. Neurological manifestations of scrub typhus infection: A systematic review and meta-analysis of clinical features and case fatality. PLoS Negl Trop Dis. 2022 Nov 28;16(11):e0010952. Kang JI, Kim DM, Lee J. Acute sensorineural hearing loss and severe otalgia due to scrub typhus. BMC Infect Dis. 2009 Oct 22;9:173. Rajapakse S, Weeratunga P, Sivayoganathan S, Fernando SD. Clinical manifestations of scrub typhus. Trans R Soc Trop Med Hyg. 2017 Feb 1;111(2):43-54. Premaratna R, Ariyaratna N, Botheju WI, Bandara NK, de Silva HJ. Scrub typhus pneumonitis. Int J Infect Dis. 2013 Apr;17(4):e284. Varghese GM, Dayanand D, Gunasekaran K, et al. Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus. N Engl J Med. 2023;388(9):792-803. Kelly DJ, Fuerst PA, Ching W-M, Richards AL. Scrub typhus: the geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi. Clin Infect Dis. 2009;48(Suppl 3):S203–30. doi: 10.1086/596576. Fan MY, Walker DH, Yu SR, Liu QH. Epidemiology and ecology of rickettsial diseases in the People’s Republic of China. Rev Infect Dis. 1987;9:823–40. doi: 10.1093/clinids/9.4.823. Yue Y, Ren D, Liu X, Wang Y, Liu Q, Li G. Spatio-temporal patterns of scrub typhus in mainland China, 2006–2017. PLoS Negl Trop Dis. 2019;13:e0007916. doi: 10.1371/journal.pntd.0007916. Kim DM, Kim SW, Choi SH, Yun NR. Clinical and laboratory findings associated with severe scrub typhus. BMC Infect Dis. 2010;10(108):1–7. doi: 10.1186/1471-2334-10-108. Dasgupta S, Asish PR, Rachel G, Bagepally BS, Chethrapilly Purushothaman GK. Global seroprevalence of scrub typhus: a systematic review and meta-analysis. Sci Rep. 2024;14(1):10895. Lu CT, Wang LS, Hsueh PR. Scrub typhus and antibiotic-resistant Orientia tsutsugamushi. Expert Rev Anti Infect Ther. 2021;19(12):1519-1527. Park MJ, Lee HS, Shim SG, Kim SH. Scrub typhus associated hepatic dysfunction and abdominal CT findings. Pak J Med Sci. 2015;31(2):295-299. Kim KY, Song JS, Park EH, Jin GY. Scrub typhus: radiological and clinical findings in abdominopelvic involvement. Jpn J Radiol. 2017;35(3):101-108. Musa TH, Ahmad T, Wana MN, Li W, Musa HH, Sharun K, Tiwari R, Dhama K, Chaicumpa W, Campbell MC, Wei P. The epidemiology, diagnosis and management of scrub typhus disease in China. Hum Vaccin Immunother. 2021 Oct 3;17(10):3795-3805. Rahman MT, Sobur MA, Islam MS, et al. Zoonotic Diseases: Etiology, Impact, and Control. Microorganisms. 2020;8(9):1405. Elsohaby I, Villa L. Zoonotic diseases: understanding the risks and mitigating the threats. BMC Vet Res. 2023;19(1):186. Dumic I, Person E, Igandan O, et al. Anaplasma phagocytophilum Community-Acquired Pneumonia: Case Report and Literature Review. Microorganisms. 2023;11(6):1483. Janardhanan J, Trowbridge P, Varghese GM. Diagnosis of scrub typhus. Expert Rev Anti Infect Ther. 2014 Dec;12(12):1533-40. Kannan K, John R, Kundu D, Dayanand D, Abhilash K, Mathuram A, Zachariah A, Sathyendra S, Hansdak S, Abraham O, et al. Performance of molecular and serologic tests for the diagnosis of scrub typhus. PLoS Negl Tro Dis. 2020;14(11):e0008747. Miao Q, Ma Y, Wang Q, Pan J, Zhang Y, Jin W, et al. Microbiological diagnostic performance of metagenomic next-generation sequencing when applied to clinical practice. Clin Infect Dis. 2018;67:S231–S240. Li Y, Ma J-M. Expert consensus for the application of metagenomic next generation sequencing in the pathogen diagnosis in clinical moderate and severe infections (first edition) Chin Crit Care Med. 2020;21(5):531–536. Salter SJ, Cox MJ, Turek EM, et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 2014;12:87 Blauwkamp TA, Thair S, Rosen MJ, et al. Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease. Nat Microbiol. 2019;4(4):663-674. Li N, Cai Q, Miao Q, Song Z, Fang Y, Hu B. High-Throughput Metagenomics for Identification of Pathogens in the Clinical Settings. Small Methods. 2021;5(1):2000792. Liu X, Zhang Y, Zhang J, Lou Z, Xia H, Lu Z. The Early Diagnosis of Scrub Typhus by Metagenomic Next-Generation Sequencing. Front Public Health. 2021;9:755228. John R, Varghese GM. Scrub typhus: a reemerging infection. Curr Opin Infect Dis. 2020 Oct;33(5):365-371. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 12 Jul, 2025 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 21 Apr, 2025 Reviews received at journal 16 Apr, 2025 Reviewers agreed at journal 16 Apr, 2025 Reviews received at journal 16 Apr, 2025 Reviewers agreed at journal 16 Apr, 2025 Reviewers invited by journal 15 Apr, 2025 Submission checks completed at journal 15 Apr, 2025 First submitted to journal 15 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6003110","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":443824998,"identity":"29d16a3e-5165-47ac-a7ac-d55cc4ff2b65","order_by":0,"name":"Zhiguang Wang","email":"","orcid":"","institution":"Affiliated Hospital of Yanbian University","correspondingAuthor":false,"prefix":"","firstName":"Zhiguang","middleName":"","lastName":"Wang","suffix":""},{"id":443825001,"identity":"decbaf15-7e77-4d04-ad13-d395b57e469d","order_by":1,"name":"Yuhua Piao","email":"","orcid":"","institution":"Affiliated Hospital of Yanbian University","correspondingAuthor":false,"prefix":"","firstName":"Yuhua","middleName":"","lastName":"Piao","suffix":""},{"id":443825002,"identity":"d68cb871-737e-4e39-b988-31902272cc6f","order_by":2,"name":"Zhongjian An","email":"","orcid":"","institution":"Affiliated Hospital of Yanbian University","correspondingAuthor":false,"prefix":"","firstName":"Zhongjian","middleName":"","lastName":"An","suffix":""},{"id":443825003,"identity":"e4c27afb-6854-423d-9089-60a93d805c06","order_by":3,"name":"Hongmei Piao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYDACZjCSkONnbz5w4EMF8VosjCV7jiUenHGGeIsqEjfMyDE+zNtChHJzduaHjwtzJBI3SOR8OMDbwCDPL3YAvxbLZjZj45nbJIy387zdcEByB4PhzNkJ+LUYHGYwk+bdJiG7sz13wwHDMwwJBrcJamH/BtLCuOFAzoMDiW1EaeEB26K44UQOw4GDxGixbOYpNgZqAQWywcGGMxKE/WLOf3zjY95tdaCofPz5T4WNPL80IYeh8SXwK8emZRSMglEwCkYBJgAAM25G+E48zWgAAAAASUVORK5CYII=","orcid":"","institution":"Affiliated Hospital of Yanbian University","correspondingAuthor":true,"prefix":"","firstName":"Hongmei","middleName":"","lastName":"Piao","suffix":""}],"badges":[],"createdAt":"2025-02-11 03:08:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6003110/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6003110/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-025-03827-2","type":"published","date":"2025-07-12T15:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81009580,"identity":"aca7b647-ca56-4f21-b1d9-ddae99851ae2","added_by":"auto","created_at":"2025-04-21 08:08:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3611408,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging changes of chest CT in patients with pneumonia\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6003110/v1/ff5e8e3ddb1f4265d0452cf3.png"},{"id":86699351,"identity":"8060ab55-0322-4fb2-9498-4033ecbb5cb0","added_by":"auto","created_at":"2025-07-14 16:08:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4484719,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6003110/v1/d340781c-4278-4253-b9d6-f20143e5c618.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pneumonia Due to Scrub Typhus Infection of Unknown Origin: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eScrub typhus is an acute febrile illness caused by the rickettsial bacterium \u003cem\u003eOrientia tsutsugamushi\u003c/em\u003e, which is transmitted to humans through the bite of infected mites. It is primarily found in rural and scrubby regions of Asia, the Pacific Islands, and parts of northern Australia. The disease is endemic in several areas of Southeast Asia, China, India, and Japan[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Scrub typhus can present with a wide range of nonspecific symptoms, often resulting in delayed or missed diagnoses.\u003c/p\u003e \u003cp\u003ePatients usually present with a sudden onset of high fever, headache, myalgia, and eschar formation at the site of mite bites[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Additional common features include lymphadenopathy, maculopapular rash, and gastrointestinal symptoms. In rare cases, infection with Rickettsia rickettsii can lead to sensorineural hearing loss and otalgia[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Respiratory involvement, such as cough and shortness of breath, may occur, particularly in severe cases where scrub typhus can lead to complications such as pneumonia, organ failure, or acute respiratory distress syndrome (ARDS)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Early diagnosis and prompt antibiotic treatment, such as doxycycline, are essential to prevent severe complications.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 58-year-old woman with hypertension was admitted to the Affiliated Hospital of Yanbian University on October 30, 2024. She presented with a 10-day history of cough, sputum, and fever, with a maximum temperature of 38\u0026deg;C. Upon admission, her vital signs were: blood pressure 93/58 mmHg, heart rate 68 beats per minute, temperature 37.4\u0026deg;C, and respiratory rate 18 breaths per minute. Laboratory tests revealed a white blood cell count of 11.37 \u0026times; 10⁹ cells/L, a neutrophil count of 8.72 \u0026times; 10⁹/L, C-reactive protein of 55.80 mg/L, and procalcitonin of 0.10 ng/mL. Liver function tests were normal.\u003c/p\u003e \u003cp\u003eChest CT showed right lung inflammation, mildly enlarged mediastinal lymph nodes, and a small right pleural effusion(Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). A diagnosis of community-acquired pneumonia was made based on clinical and imaging findings.\u003c/p\u003e \u003cp\u003ePhysical examination showed intact skin with no eschar or scab, and auscultation revealed thickened breath sounds and moist rales in the right lung. The patient had no recent travel history or insect bites. Despite receiving 7 days of cefoxitin treatment at an outside hospital, her symptoms did not improve. Given the lack of response to antibiotics and the potential for atypical pathogens, ciprofloxacin was started, and bronchoscopy was recommended.\u003c/p\u003e \u003cp\u003eBronchoscopy, performed on the second day of admission, revealed sputum obstructing the lumen of the medial segment of the right middle lobe. Bronchoalveolar lavage was conducted for bacterial, fungal culture, and mNGS analysis.While bacterial and fungal cultures showed no growth,mNGS identified \u003cem\u003eOrientia tsutsugamushi、Rhinovirus B and Human gammaherpesvirus 4\u003c/em\u003e.The mNGS process is as follows: 1.Homogenization: BALF samples are mixed with a digestion buffer and briefly vortexed until liquefied.The liquefied BALF is then transferred into an MP Lysing Matrix E tube (containing internal reference beads) and processed using a homogenizer (Jingxin, Shanghai, China).After homogenization, the sample is centrifuged briefly, and the supernatant is collected for subsequent nucleic acid extraction.2.Nucleic Acid Extraction:The supernatant is treated with a nucleic acid extraction/purification reagent (Geneseeq, Beijing, China).Automated extraction of DNA and RNA is performed separately using a fully automated nucleic acid extraction system (Tianlong, Xi\u0026rsquo;an, China).3.DNA Library Preparation: Library construction is performed using a Universal Sequencing Reaction Preparation Kit (Geneseeq, Beijing, China).The products are purified using magnetic beads (Geneseeq, Beijing, China).The purified DNA library is quantified using a Qubit 4.0 Fluorometer (with the Qubit dsDNA HS Assay Kit), and the concentration is recorded.4.RNA Library Preparation: cDNA library construction is performed using an RNA Library Enrichment Kit (Geneseeq, Beijing, China) and the Universal Sequencing Reaction Preparation Kit (Geneseeq, Beijing, China).The reaction products are purified immediately after completion.5.Library Pooling: The basic information of the libraries to be pooled is recorded in a pooling table.Based on the library concentrations and required sequencing data volume, the sample volumes and theoretical pooled concentration are calculated.To ensure accuracy, the measured pooled concentration should not deviate by more than 15% from the theoretical concentration.6.Sequencing: The pooled libraries are processed into DNA Nanoballs (DNB).Sequencing is performed on the MGI-200 Sequencer (BGI, Shenzhen, China).7.Data Analysis: After sequencing, the Genseq-PM Pathogen Metagenomics Analysis Software automatically processes the raw sequencing data.Quality control (QC) is performed on the raw data, followed by alignment against a custom-built pathogen database for species identification.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThis table illustrates workup that was carried out for diagnosis of community acquired pneumonia in our patient.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSputum Specimen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRespiratory Nasopharyngeal Swab\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBronchoalveolar lavage fluid\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCultures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emNGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eRhinovirus B\u003c/em\u003e(759)\u003c/p\u003e \u003cp\u003e\u003cem\u003eHuman gammaherpesvirus 4\u003c/em\u003e(24886)\u003c/p\u003e \u003cp\u003e\u003cem\u003eOrientia tsutsugamushi\u003c/em\u003e(2566)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfluenza B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenovirus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory Syncytial Virus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParainfluenza virus,type1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParainfluenza virus,type2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfluenza A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHistorically, scrub typhus has been treated with doxycycline or chloramphenicol, but chloramphenicol has been gradually applied because of its toxic side effects.For severe scrub typhus, doxycycline combined with azithromycin can be used to reduce complications and mortality[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].Based on these results, ciprofloxacin was discontinued, and doxycycline 0.1 g BID was initiated.\u003c/p\u003e \u003cp\u003eAfter 9 days of doxycycline treatment, the patient showed clinical improvement with reduced fever, cough, and sputum production. Laboratory tests demonstrated a white blood cell count of 8.49 \u0026times; 10⁹ cells/L, neutrophils at 5.17 \u0026times; 10⁹/L, and C-reactive protein reduced to 7.90 mg/L(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Chest CT showed no significant change in lung pathology (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB), but the patient 's clinical symptoms and laboratory parameters were improved, and the patient' s subjective symptoms were significantly improved. We recommended oral doxycycline treatment and the patient was discharged after obtaining consent. The patient continued oral doxycycline for 6 weeks. Follow-up chest CT after 6 weeks showed marked resolution of pulmonary lesions(Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIllustrates the trend of common laboratory derangement seen in patients with Scrub typhus.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdmission\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDischarge\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite Blood Cell Count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet Count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e434\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eScrub typhus is a significant public health concern in the Asia-Pacific region, particularly in the area known as the \"Scrub Typhus Triangle.\" This region includes China, where an estimated 1\u0026nbsp;million new cases of scrub typhus occur each year, and over 1\u0026nbsp;billion people globally are at risk. Without appropriate treatment, the disease can have a mortality rate of up to 30% or even higher[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Scrub typhus has long been considered a neglected infectious disease, and many aspects of its diagnosis and prevention remain poorly understood. In China, cases of scrub typhus are most commonly reported in the southwest, southeast coastal, and eastern regions[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. A recent study by Yue et al. (2019) divided the prevalence of scrub typhus in China into three regions: northern China (Anhui, Jiangsu, Shandong), southwest China (Yunnan, Sichuan), and southern China (Fujian, Guangdong, Guangxi, Hainan, Hunan, Jiangxi, Zhejiang), with relatively low incidence in Jilin Province[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eScrub typhus presents with a variety of clinical symptoms, with the most common being fever, eschar, rash, and lymphadenopathy. After an incubation period of 4 to 21 days, patients typically develop fever, ranging from 38.5\u0026deg;C to 42\u0026deg;C, which lasts from 1 to 12 days (with an average duration of 4.5 days)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Eschar formation, a painless necrotic lesion at the bite site, is a hallmark feature of the disease.The results of a meta-analysis study showed that the positive rate of eschar was estimated to be 30.34%(22.54\u0026ndash;38.15)[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and eschar lesions were mainly present in the chest and abdomen of women(42.3%), whereas it was present in the axilla, groin, and genitalia of men (55.8%)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].Scrub typhus may involve the abdominopelvic lymph nodes. Regional lymphadenopathy, characterized by tenderness and enlargement of the draining lymph node around the bite site. This pathologic findings may be influenced not only by \u003cem\u003eO.tsutsugamushi\u003c/em\u003e pathogen spread, but also by host immune mechanisms[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].An imaging study of scrub typhus showed the periportal area was the most common site of lymphadenopathy, the majority of patients had a diffuse pattern of abdominopelvic lymphadenopathy, including the extraperitoneum, perigastric area, and the periportal area. This diffuse pattern of abdominopelvic lymphadenopathy may suggest scrub typhus,especially when physical examination does not reveal eschar[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].In China, scrub typhus cases may also present with splenomegaly, hepatomegaly, pneumonia, meningitis, multiple organ dysfunction, disseminated intravascular coagulation, and conjunctival congestion[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eZoonotic diseases, including Scrub typhus, are infectious diseases that can be transmitted from animals to humans. These diseases can be caused by bacteria, viruses, parasites, and fungi. Zoonotic diseases can be transmitted to humans through direct contact with infected animals, consumption of contaminated food or water, or through the bite of infected arthropod vectors such as ticks and mosquitoes[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Of note, the role of wildlife in pathogen transmission, amplification, and zoonotic spillover as well as transmission, such as coronavirus causing Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and the recent coronavirus pandemic (COVID-19), are zoonoses characterized by pneumonia[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].For pulmonary infectious diseases, the most common bacteria and viruses of community-acquired pneumonia should first be considered. In patients with CAP, attention must be paid to patient epidemiological characteristics, including patient work environment, travel history, and contact history, which can provide clinicians with clues to rule out infectious diseases according to local epidemiology, such as in tick-endemic areas, the presence of pneumonia may be caused by ehrlichiosis, anaplasmosis, babesiosis, tularemia, or Rocky Mountain spotted fever[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].Progress has been made in the field of zoonotic disease research in early detection diagnosis, treatment, prevention and control. For example, the use of polymerase chain reaction (PCR) technology has revolutionized the detection of zoonotic viruses such as Ebola and Zika. In addition, significant progress has been made in the development of vaccines and treatments for zoonotic diseases, such as the development of effective vaccines for Ebola and Nipah viruses. Similarly, the development of new treatments for diseases such as West Nile virus and avian influenza, as well as a recently discovered new antiviral drug, can effectively fight a variety of zoonotic viruses, including Ebola virus, Lassa fever, and COVID-19, and can help save numerous lives.\u003c/p\u003e \u003cp\u003eIn this case, the patient presented with fever, sputum, and cough as the main symptoms, and a diagnosis of community-acquired pneumonia was initially considered, supported by serological tests and CT findings. Fever is a common symptom in many infectious diseases, including pneumonia, making it easy to overlook the possibility of scrub typhus in the early stages. While typical clinical features such as eschar can aid in diagnosis, serological tests remain the gold standard for confirming scrub typhus. Currently, the indirect immunofluorescence antibody (IFA) test is widely regarded as the diagnostic gold standard for scrub typhus[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, this test requires specialized fluorescence microscopy and trained personnel, making it unavailable in many non-endemic areas. The Weil\u0026ndash;Felix agglutination test has limited sensitivity and specificity due to cross-reactivity with other pathogens like those causing dengue fever, malaria, and typhoid fever. Real-time polymerase chain reaction (Q-PCR) is highly sensitive (97%) and specific (100%) for diagnosing scrub typhus[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], but many laboratories, including those in China, do not routinely use this test.In this case, we confirmed the etiological detection of pulmonary infection by mNGS, because the patient 's clinical manifestations were common pulmonary symptoms, so we did not obtain samples for PCR detection during bronchoscopic alveolar lavage examination. Without mNGS results, we have also neglected infection with \u003cem\u003eOrientia tsutsugamushi\u003c/em\u003e, which may delay early diagnosis, leading to recurrent infections and delayed treatment.\u003c/p\u003e \u003cp\u003eMetagenomic next-generation sequencing (mNGS) offers a rapid, non-targeted approach to pathogen detection. It can sequence hundreds of thousands to millions of DNA molecules simultaneously, allowing for the detection of all pathogens present, even in low abundance[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This makes mNGS particularly valuable for diagnosing complex infectious diseases and identifying atypical pathogens[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Broad spectrum microbial coverage leading to interpretation of mNGS results is a huge challenge.mNGS can theoretically detect all currently known pathogens of about 8,000 species or even currently unknown genome sequences. Therefore, in mNGS detection results, microbial contamination in the environment, reagents, and containers, as well as detection signals of a large number of non-pathogenic microorganisms and pathogenic microorganisms such as colonization in the human body are mixed[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The number of microorganisms reported by mNGS is also 5\u0026ndash;20, which makes the clinical interpretation of mNGS a great challenge and requires a lot of clinical, pathogenic microorganism diagnosis and professional experience to interpret pathogenic bacteria[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].As an unbiased method, mNGS detects all possible pathogens in a clinical sample. It is especially suitable for the early screening of complex infectious diseases, severe infections, and the diagnosis of rare and atypical causes. Although the test is expensive, mNGS always takes less time (\u0026lt;\u0026thinsp;24h) compared with conventional diagnostic methods and can identify millions of base pairs of non-targeted sequences in a single sample, while traditional culture, PCR and other detection techniques have significant disadvantages, including a long culture cycle and can only detect single pathogens, and many laboratories may not be equipped with corresponding reagents for infectious disease pathogens to perform PCR and other tests except for typical infectious disease endemic areas[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. As a rapid microbiological diagnostic method for infectious diseases, mNGS has recently been applied in clinical practice due to its high efficiency, sensitivity, and cost-effectiveness, which has significant benefits for both physician evaluation of pathogenic bacteria and patient disease recovery.\u003c/p\u003e \u003cp\u003eIn this case, the patient lived in an area with a very low incidence of scrub typhus and had no recent travel history. No evidence of skin lesions or eschar was found during the physical examination, which led to a common initial diagnosis of community-acquired pneumonia. However, during the course of treatment, bronchoscopy was performed, and mNGS eventually identified \u003cem\u003eOrientia tsutsugamushi\u003c/em\u003e as the causative pathogen. This allowed for a timely adjustment of the treatment regimen based on the etiology.Doxycycline and chloramphenicol are the main antibiotics used to treat scrub typhus[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In this case, doxycycline treatment effectively controlled the patient's illness.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZW:Data collection, original draft writing. YP:Data collection,Physical examination.ZA:Performed bronchoscopy.HP:Supervision,review,and editing.All authors contributed to the drafting and final approval of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Health Science and Technology Ability Improvement Program of Jilin Province (Nos.2024A060).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was approved by the Ethics Committee of the Affiliated Hospital of Yanbian University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate and Publish declarations\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of images and personal information for this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eXu G, Walker DH, Jupiter D, Melby PC, Arcari CM. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis. 2017 Nov 3;11(11):e0006062.\u003c/li\u003e\n\u003cli\u003eAlam AM, Gillespie CS, Goodall J, Damodar T, Turtle L, Vasanthapuram R, Solomon T, Michael BD. Neurological manifestations of scrub typhus infection: A systematic review and meta-analysis of clinical features and case fatality. PLoS Negl Trop Dis. 2022 Nov 28;16(11):e0010952.\u003c/li\u003e\n\u003cli\u003eKang JI, Kim DM, Lee J. Acute sensorineural hearing loss and severe otalgia due to scrub typhus. BMC Infect Dis. 2009 Oct 22;9:173.\u003c/li\u003e\n\u003cli\u003eRajapakse S, Weeratunga P, Sivayoganathan S, Fernando SD. Clinical manifestations of scrub typhus. Trans R Soc Trop Med Hyg. 2017 Feb 1;111(2):43-54.\u003c/li\u003e\n\u003cli\u003ePremaratna R, Ariyaratna N, Botheju WI, Bandara NK, de Silva HJ. Scrub typhus pneumonitis. Int J Infect Dis. 2013 Apr;17(4):e284.\u003c/li\u003e\n\u003cli\u003eVarghese GM, Dayanand D, Gunasekaran K, et al. Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus. N Engl J Med. 2023;388(9):792-803.\u003c/li\u003e\n\u003cli\u003eKelly DJ, Fuerst PA, Ching W-M, Richards AL. Scrub typhus: the geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi. Clin Infect Dis. 2009;48(Suppl 3):S203\u0026ndash;30. doi: 10.1086/596576.\u003c/li\u003e\n\u003cli\u003eFan MY, Walker DH, Yu SR, Liu QH. Epidemiology and ecology of rickettsial diseases in the People\u0026rsquo;s Republic of China. Rev Infect Dis. 1987;9:823\u0026ndash;40. doi: 10.1093/clinids/9.4.823.\u003c/li\u003e\n\u003cli\u003eYue Y, Ren D, Liu X, Wang Y, Liu Q, Li G. Spatio-temporal patterns of scrub typhus in mainland China, 2006\u0026ndash;2017. PLoS Negl Trop Dis. 2019;13:e0007916. doi: 10.1371/journal.pntd.0007916.\u003c/li\u003e\n\u003cli\u003eKim DM, Kim SW, Choi SH, Yun NR. Clinical and laboratory findings associated with severe scrub typhus. BMC Infect Dis. 2010;10(108):1\u0026ndash;7. doi: 10.1186/1471-2334-10-108.\u003c/li\u003e\n\u003cli\u003eDasgupta S, Asish PR, Rachel G, Bagepally BS, Chethrapilly Purushothaman GK. Global seroprevalence of scrub typhus: a systematic review and meta-analysis. Sci Rep. 2024;14(1):10895.\u003c/li\u003e\n\u003cli\u003eLu CT, Wang LS, Hsueh PR. Scrub typhus and antibiotic-resistant Orientia tsutsugamushi. Expert Rev Anti Infect Ther. 2021;19(12):1519-1527.\u003c/li\u003e\n\u003cli\u003ePark MJ, Lee HS, Shim SG, Kim SH. Scrub typhus associated hepatic dysfunction and abdominal CT findings. Pak J Med Sci. 2015;31(2):295-299.\u003c/li\u003e\n\u003cli\u003eKim KY, Song JS, Park EH, Jin GY. Scrub typhus: radiological and clinical findings in abdominopelvic involvement. Jpn J Radiol. 2017;35(3):101-108.\u003c/li\u003e\n\u003cli\u003eMusa TH, Ahmad T, Wana MN, Li W, Musa HH, Sharun K, Tiwari R, Dhama K, Chaicumpa W, Campbell MC, Wei P. The epidemiology, diagnosis and management of scrub typhus disease in China. Hum Vaccin Immunother. 2021 Oct 3;17(10):3795-3805. \u003c/li\u003e\n\u003cli\u003eRahman MT, Sobur MA, Islam MS, et al. Zoonotic Diseases: Etiology, Impact, and Control. Microorganisms. 2020;8(9):1405.\u003c/li\u003e\n\u003cli\u003eElsohaby I, Villa L. Zoonotic diseases: understanding the risks and mitigating the threats. BMC Vet Res. 2023;19(1):186.\u003c/li\u003e\n\u003cli\u003eDumic I, Person E, Igandan O, et al. Anaplasma phagocytophilum Community-Acquired Pneumonia: Case Report and Literature Review. Microorganisms. 2023;11(6):1483.\u003c/li\u003e\n\u003cli\u003eJanardhanan J, Trowbridge P, Varghese GM. Diagnosis of scrub typhus. Expert Rev Anti Infect Ther. 2014 Dec;12(12):1533-40.\u003c/li\u003e\n\u003cli\u003eKannan K, John R, Kundu D, Dayanand D, Abhilash K, Mathuram A, Zachariah A, Sathyendra S, Hansdak S, Abraham O, et al. Performance of molecular and serologic tests for the diagnosis of scrub typhus. PLoS Negl Tro Dis. 2020;14(11):e0008747.\u003c/li\u003e\n\u003cli\u003eMiao Q, Ma Y, Wang Q, Pan J, Zhang Y, Jin W, et al. Microbiological diagnostic performance of metagenomic next-generation sequencing when applied to clinical practice. Clin Infect Dis. 2018;67:S231\u0026ndash;S240.\u003c/li\u003e\n\u003cli\u003eLi Y, Ma J-M. Expert consensus for the application of metagenomic next generation sequencing in the pathogen diagnosis in clinical moderate and severe infections (first edition) Chin Crit Care Med. 2020;21(5):531\u0026ndash;536.\u003c/li\u003e\n\u003cli\u003eSalter SJ, Cox MJ, Turek EM, et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 2014;12:87\u003c/li\u003e\n\u003cli\u003eBlauwkamp TA, Thair S, Rosen MJ, et al. Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease. Nat Microbiol. 2019;4(4):663-674.\u003c/li\u003e\n\u003cli\u003eLi N, Cai Q, Miao Q, Song Z, Fang Y, Hu B. High-Throughput Metagenomics for Identification of Pathogens in the Clinical Settings. Small Methods. 2021;5(1):2000792.\u003c/li\u003e\n\u003cli\u003eLiu X, Zhang Y, Zhang J, Lou Z, Xia H, Lu Z. The Early Diagnosis of Scrub Typhus by Metagenomic Next-Generation Sequencing. Front Public Health. 2021;9:755228.\u003c/li\u003e\n\u003cli\u003eJohn R, Varghese GM. Scrub typhus: a reemerging infection. Curr Opin Infect Dis. 2020 Oct;33(5):365-371.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"pneumonia, scrub typhus, case report","lastPublishedDoi":"10.21203/rs.3.rs-6003110/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6003110/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Scrub typhus is an acute febrile illness caused by the rickettsial bacterium \u003cem\u003eOrientia tsutsugamushi\u003c/em\u003e, transmitted to humans through infected mite bites. Patients typically present with sudden high fever, headache, myalgia, and eschar formation at the site of the bites. Respiratory symptoms, such as cough and shortness of breath, can also occur, especially in severe cases that lead to pneumonia, organ failure, or acute respiratory distress syndrome (ARDS). This report presents a case of scrub typhus pneumonia of unknown origin, diagnosed by metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation: \u003c/strong\u003eA 58-year-old woman was admitted with cough, sputum production, and fever. Imaging revealed pneumonia. During hospitalization, bronchoscopy was performed to identify the causative pathogen. mNGS of the bronchoalveolar lavage fluid confirmed \u003cem\u003eOrientia tsutsugamushi\u003c/em\u003e infection. the patient's pneumonia was improved after oral administration of doxycycline(100mg, tid) for anti-infection treatment for 1 month.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThis report highlights the diagnostic challenges of scrub typhus-induced pneumonia and demonstrates the advantages of mNGS in identifying rare pathogens. It also underscores the importance of standardized antibiotic therapy for treating scrub typhus pneumonia.\u003c/p\u003e","manuscriptTitle":"Pneumonia Due to Scrub Typhus Infection of Unknown Origin: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 08:08:42","doi":"10.21203/rs.3.rs-6003110/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-21T07:19:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-16T12:04:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"106991468819269154722146628425163664030","date":"2025-04-16T11:43:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-16T11:39:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"84302021545123142365443143364492315453","date":"2025-04-16T11:30:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-16T01:14:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-15T12:52:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-04-15T12:46:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3d7940a4-24ac-473f-a407-f8a708b77df4","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:01:07+00:00","versionOfRecord":{"articleIdentity":"rs-6003110","link":"https://doi.org/10.1186/s12890-025-03827-2","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2025-07-12 15:56:59","publishedOnDateReadable":"July 12th, 2025"},"versionCreatedAt":"2025-04-21 08:08:42","video":"","vorDoi":"10.1186/s12890-025-03827-2","vorDoiUrl":"https://doi.org/10.1186/s12890-025-03827-2","workflowStages":[]},"version":"v1","identity":"rs-6003110","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6003110","identity":"rs-6003110","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}