| Domain | Compact knowledge-base summary | Suggested ontology mappings | Key evidence |
|---|---|---|---|
| Identity / identifiers | Scrub typhus is an acute febrile zoonotic infectious disease caused mainly by *Orientia tsutsugamushi*; also called tsutsugamushi disease. Humans are accidental dead-end hosts. ICD-10-CM code reported as **A75.3**. Disease-level information is derived from aggregated literature, surveillance, and clinical studies rather than individual EHRs in the cited sources. | **Suggested mappings:** ICD-10 **A75.3**; MeSH: scrub typhus / tsutsugamushi disease; MONDO: suggest mapping only after external ontology confirmation; NCIT: infectious disease / rickettsial-oriential infection terms if used locally | (pqac-00000003, pqac-00000004, pqac-00000006) |
| Cause and transmission | Primary cause: infection with *O. tsutsugamushi* transmitted by larval trombiculid mites (chiggers), especially *Leptotrombidium* spp. Rodents are maintenance/reservoir hosts; humans acquire infection from mite bites in mite-infested habitats including farming/plantation settings. >20 genotypes reported in India. | **Suggested mappings:** CHEBI not central; UBERON skin for inoculation site; GO: pathogenesis, host cell invasion; CL: endothelial cell, monocyte, macrophage | (pqac-00000003, pqac-00000004, pqac-00000006) |
| Incubation / course | Incubation typically **6–21 days**; illness usually begins as acute undifferentiated febrile illness. Without treatment, systemic manifestations often expand over the first 1–2 weeks and may progress to multiorgan dysfunction. In mouse intradermal model, fever emerged at 11–12 dpi and tissue burden peaked ~14 dpi, supporting acute then persistent phases. | **Suggested mappings:** HPO: Fever; HPO: Acute infectious disease course; UBERON: blood, lung, liver, kidney, brain, skin | (pqac-00000006, pqac-00000007, pqac-00000003, pqac-00000010) |
| Major phenotypes with frequencies | Common phenotype: fever/AUFI pooled prevalence **97%** in India meta-analysis. General symptoms such as headache/chills/myalgia/arthralgia occur in **33–56%**. Eschar pooled prevalence about **26%** in meta-analysis, though reviews note wide observed range **7–80%**. Hepatomegaly **46%** and hepatic dysfunction **44%** were reported in meta-analysis. Severe-trial complications: respiratory **62%**, hepatic **54%**, cardiovascular **42%**, renal **30%**, neurologic **20%**. Reported neurologic manifestations include meningitis/meningoencephalitis, tremor, delirium, hearing loss; respiratory disease includes interstitial pneumonia/ARDS; renal injury and myocarditis/arrhythmia are recognized complications. | **Suggested HPO terms:** Fever; Eschar; Headache; Myalgia; Rash; Lymphadenopathy; Hepatomegaly; Elevated hepatic transaminases; Acute kidney injury; Pneumonia; Acute respiratory distress syndrome; Myocarditis; Arrhythmia; Meningoencephalitis; Hearing impairment | (pqac-00000000, pqac-00000007, pqac-00000020, pqac-00000021) |
| Key cell types and pathways | Targeted/involved cells include **endothelial cells**, **monocytes/macrophages**, dendritic cells, and in CNS disease **microglia**. Human monocytes showed >4,500 altered genes with type I IFN program, interferon-stimulated genes, apoptosis genes, and M1 polarization. Endothelial dual RNA-seq found strain-specific host responses: Karp induced **IL33-NOS3-FAS** anoikis-associated signaling, whereas UT176 induced **IL6**-dominant inflammatory response. Mouse brain RNA-seq showed IFN responses, defense response to bacteria, IL-6/JAK-STAT, TNF/NF-κB, immunoglobulin-mediated immunity, and BBB-disruption programs with microglial activation. | **Suggested GO terms:** inflammatory response; type I interferon signaling pathway; cytokine-mediated signaling pathway; apoptotic process; response to bacterium; IL-6-mediated signaling pathway; JAK-STAT cascade; TNF-mediated signaling pathway; blood-brain barrier maintenance/disruption. **Suggested CL terms:** endothelial cell, monocyte, macrophage, dendritic cell, microglial cell. **Suggested UBERON terms:** vascular endothelium, brain, skin, liver, lung | (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000003) |
| Diagnostics | Diagnosis is difficult when eschar is absent. Serology remains central: IFA is the most widely used reference method, but thresholds and antigen panels vary greatly by region. IgM/IgG serology and ELISA are widely used; immunochromatographic tests have about **~70% sensitivity** in one review context. PCR is most useful early and can be performed on blood/buffy coat and eschar material; editorial summary reported eschar PCR positivity **100%** and buffy-coat positivity **94%** in highlighted work. QuEST (NCT06675110) is evaluating insulated isothermal PCR against qPCR/IFA. | **Suggested mappings:** LOINC/local lab mappings for IgM ELISA, IFA, PCR; HPO/Lab terms: thrombocytopenia, transaminitis, hyperbilirubinemia, elevated creatinine | (pqac-00000003, pqac-00000004, pqac-00000005, pqac-00000017) |
| Treatment | Standard therapy uses anti-rickettsial antibiotics, especially **doxycycline**; **azithromycin** is an important alternative, including in pregnancy. In the 2023 multicenter double-blind RCT for severe disease, IV doxycycline was **200 mg BID day 1 then 100 mg BID for 6 days**; IV azithromycin was **500 mg BID day 1 then 500 mg daily for 6 days**; combination used both. Combination therapy reduced the composite endpoint to **33%** vs **47%** with doxycycline and **48%** with azithromycin (risk differences **−13.3** and **−14.8** percentage points, respectively). Mortality at day 28 was similar (**11–13%**). | **Suggested NCIT terms:** Doxycycline; Azithromycin; Combination anti-infective therapy; Intravenous antibiotic therapy. **Suggested CHEBI:** doxycycline, azithromycin | (pqac-00000020, pqac-00000021, pqac-00000022, pqac-00000024) |
| Epidemiology | Endemic historically in the “tsutsugamushi triangle,” but current literature emphasizes broader geographic concern. About **2 billion** people are at risk and roughly **1 million** cases occur annually. In India, a 2025 systematic review identified **47,650** cumulative cases from 2003–2023 with **5%** case fatality among 35,243 cases analyzed. In South Korea, **95,601** patients were reported from 2013–2019 with spatial clustering associated with rodent suitability and local socioeconomic/environmental factors. | **Suggested mappings:** geographic/endemic disease annotations; One Health/vector-borne disease labels | (pqac-00000003, pqac-00000005, pqac-00000004) |
| Prognosis | Prognosis is highly treatment-sensitive: untreated or delayed diagnosis can progress to severe multiorgan disease. In severe hospitalized disease, 28-day mortality remained around **11–13%** in the 2023 RCT despite therapy. Prognostic burden is driven by respiratory, cardiovascular, renal, hepatic, and neurologic complications; delayed diagnosis and limited diagnostic access are recurring risk amplifiers in reviews. | **Suggested HPO terms:** Multiorgan failure; Shock; ARDS; Acute kidney injury; Encephalopathy. **Suggested NCIT:** Critical care / ICU support | (pqac-00000001, pqac-00000020, pqac-00000021, pqac-00000002) |
| Prevention | No licensed highly effective vaccine is currently available in the cited literature. Prevention focuses on avoiding chigger exposure, vector/reservoir control, environmental risk reduction, and early recognition/treatment. Public-health emphasis is on awareness, region-specific surveillance, and improved rapid diagnostics. | **Suggested NCIT/public health mappings:** Vector control; Health education; Personal protective measures; Early diagnosis | (pqac-00000001, pqac-00000004, pqac-00000003) |
| Animal models / other species | Natural ecology involves rodents and chiggers, with human, rodent, and mite genotype-linkage studied in field cohorts. A C57BL/6 intradermal mouse model reproduces acute disease and persistent infection after ear inoculation, with mixed Th1/Th2 cytokine responses and prolonged tissue persistence to **84 dpi**. Additional model-development work includes nonhuman-primate transmission studies and newer humanized IFN-γ mouse approaches mentioned in the literature context. | **Suggested mappings:** NCBI Taxon for *O. tsutsugamushi* and rodent/chigger hosts; CL/UBERON as above for infected tissues | (pqac-00000016, pqac-00000003, pqac-00000006, pqac-00000010) |
| Genetics fields that are non-applicable or limited | **Mendelian inheritance, causal human disease genes, pathogenic germline variants, carrier frequency, anticipation, consanguinity, CMA/karyotype/FISH-based diagnosis:** generally **not applicable** because scrub typhus is an infectious disease, not a monogenic inherited disorder. **Host susceptibility genetics:** limited candidate-gene evidence only; an unobtainable 2013 study is noted in retrieved metadata for TLR2/TLR4/HSP70 SNPs, but this was not directly available for full evidence extraction here. Pathogen genomics, not host Mendelian genetics, is the main molecular genetics domain of relevance. | **Suggested mappings:** mark as “Not applicable” for inheritance fields; use pathogen-genomics annotations instead of human Mendelian fields | (pqac-00000009, pqac-00000011) |


*Table: This table condenses the most actionable scrub typhus facts for a disease knowledge base, including clinical, epidemiologic, mechanistic, diagnostic, and treatment domains. It also flags which classical human genetics fields are not applicable for this infectious disease and suggests ontology mappings without inventing uncertain IDs.*