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Classifications

Harrison's Part

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Discussions and Knowledge Gaps

4

Does Orientia tsutsugamushi possess a peptidoglycan layer capable of serving as a beta-lactam target? The 1987 chemical analysis that underpinned the reclassification out of Rickettsia found no detectable muramic acid or glucosamine and concluded the organism has little or no peptidoglycan; a 2017 structural study reported evidence for a peptidoglycan-like structure alongside a cross-linked outer-membrane protein network. The two results have not been reconciled.

KNOWLEDGE GAP OPEN orientia-peptidoglycan-status

Attached to

pathophysiology#Peptidoglycan-Poor Atypical Cell Envelope pathophysiology#Requirement for Cell-Penetrant Antimicrobials

The answer determines how beta-lactam inactivity in scrub typhus should be modelled. If peptidoglycan is genuinely absent, the correct model is target absence and this entry should conform to `bacterial_cell_wall_synthesis_inhibition#Intrinsic Resistance in Cell-Wall-Deficient Organisms` alongside the Mollicutes. If a functional peptidoglycan-like layer exists, the exclusion of beta-lactams is purely pharmacokinetic - they cannot reach a cytosolic organism - and belongs entirely to `intracellular_pathogen_persistence`. This entry currently declares only the latter, because asserting target absence on contested evidence would be the stronger and less defensible claim. The distinction is not merely taxonomic: it bears on whether any cell-wall-active agent could ever be made to work if delivery were solved.

Proposed experiments

Direct muropeptide analysis of purified Orientia

orientia-pg-muropeptide-analysis

Apply quantitative muropeptide profiling (LC-MS of mutanolysin digests) and D-amino-acid metabolic labelling to highly purified Orientia tsutsugamushi from several strains, with Chlamydia and a Mollicute as positive and negative controls, to determine whether cross-linked peptidoglycan is present and at what abundance.

Readouts

Cross-linked muropeptide abundance

pathophysiology#Peptidoglycan-Poor Atypical Cell Envelope

Would support

pathophysiology#Peptidoglycan-Poor Atypical Cell Envelope

Do clinically significant doxycycline-resistant strains of Orientia tsutsugamushi exist, and if so what is the molecular basis? Poor clinical response to doxycycline has been reported from parts of northern Thailand and has motivated dedicated trials, but the organism is genetically intractable and cannot be susceptibility tested by routine methods, so the phenotype has not been tied to a ribosomal target mutation, an efflux mechanism, or to host and pharmacokinetic factors instead.

KNOWLEDGE GAP OPEN orientia-doxycycline-susceptibility

Attached to

pathophysiology#Orientia Ribosomal Translation (Tetracycline and Macrolide Target)

The module `bacterial_protein_synthesis_inhibition` models ribosomal target resistance as a distinct node, and whether scrub typhus conforms to it is currently unanswerable. Because every agent with established activity in scrub typhus acts on the same ribosome, a true target-level resistance mechanism would threaten the entire therapeutic repertoire at once, which is why the question matters more here than in infections with several independent drug targets. Until it is resolved this entry does not curate a resistance node.

Proposed experiments

Genotype-phenotype study of poor doxycycline responders

orientia-resistance-genotype-phenotype

Couple a prospective treatment-response cohort in a reported low-response area with whole-genome sequencing of infecting strains and measurement of plasma and intracellular doxycycline exposure, to separate ribosomal or efflux-mediated bacterial resistance from inadequate drug exposure.

Readouts

Association of ribosomal or efflux variants with delayed defervescence

pathophysiology#Orientia Ribosomal Translation (Tetracycline and Macrolide Target)

Would support

pathophysiology#Orientia Ribosomal Translation (Tetracycline and Macrolide Target)

The mechanistic account of scrub typhus neuroinflammation - excessive interferon responses, microglial activation and blood-brain-barrier disruption - rests on brain RNA-seq and immunostaining in a murine model of severe infection. Do these pathways operate the same way in human scrub typhus encephalitis, where the CNS is rarely sampled?

HUMAN MODEL MISMATCH OPEN scrub-typhus-neuroinflammation-model-fidelity

Attached to

pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response pathophysiology#Multi-Organ Vascular Leak and End-Organ Dysfunction

Evidence for the CNS arm exists and is internally coherent, but it is predominantly murine, so its translational validity rather than its existence is the open question - which is what distinguishes this from a plain knowledge gap. The monocyte arm of this entry is anchored partly in patient mononuclear cells and so is on firmer human ground; the brain-specific mechanism is not. Human CNS validation matters because interferon-directed or barrier-directed adjunctive therapy would be prescribed on the strength of exactly these pathways.

Proposed experiments

Human CSF and neuroimaging validation of the murine neuroinflammation programme

scrub-typhus-human-csf-validation

In patients with scrub typhus-associated acute encephalitis syndrome, measure CSF interferon-stimulated protein signatures, microglial activation markers and barrier-integrity indices, and compare the pattern against the murine brain transcriptome programme.

Readouts

Concordance of human CSF interferon and barrier markers with the murine programme

pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response

Would support

pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response

Show evidence (2 references)

PMID:37426673 SUPPORT Model Organism

"This study provides new insights into neuroinflammation in scrub typhus, highlighting the impact of excessive IFN responses, microglial activation, and BBB dysregulation on disease pathogenesis."

The murine brain RNA-seq study that is the source of the interferon, microglial and blood-brain-barrier mechanism whose human validity this discussion questions. Evidence source is MODEL_ORGANISM, which is precisely the mismatch at issue.

PMID:37426673 SUPPORT Model Organism

"By using a well-established murine model of severe scrub typhus and brain RNA-seq, we studied the brain transcriptome dynamics and identified the activated neuroinflammation pathways."

States explicitly that the evidence base for this mechanism is a murine model and mouse brain transcriptomics, establishing the model-to-human gap.

Orientia tsutsugamushi is antigenically extremely diverse - Karp-like, Kato-like, Gilliam-like and JG-like strains circulate in different proportions across India alone, and the diversity is defined by the very TSA56 protein this entry models as the adhesin. Two strain-dependent observations are unexplained: it is postulated that some strains produce eschars less commonly than other antigenic types, and dual RNA-seq of two clinical isolates found them driving divergent host programmes, with the Karp strain associated with IL33-linked responses and UT176 with IL6-mediated inflammation, differences that tracked relative virulence in mice. Does strain genotype determine eschar formation, host inflammatory programme, and severity in humans?

KNOWLEDGE GAP OPEN orientia-strain-variation

Attached to

pathophysiology#TSA56-Fibronectin Binding and Integrin-Mediated Host Cell Entry pathophysiology#Eschar Formation at the Inoculation Site pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response

This bears directly on three curated nodes. If TSA56 variation alters adhesion or entry, that is a property of this entry's molecular node, not a bystander observation. If it determines whether an eschar forms, then eschar frequency is not a single number at all - which would explain the wide geographic variation this entry already records (under 12% to over 46% between Indian states) as strain composition rather than examination technique, and would change how the diagnostic sign should be weighted regionally. And if strains drive different cytokine programmes, the interferon/M1 node is strain-conditioned rather than uniform. The practical obstacle is that most surveillance genotyping is done on the same TSA56 gene used for diagnosis, so genotype and detection are not independent.

Proposed experiments

Strain genotype versus eschar, cytokine programme and severity

orientia-genotype-phenotype-cohort

A prospective multi-site cohort in regions with differing circulating genotypes, in which infecting strain is typed by whole-genome sequencing rather than TSA56 alone, and correlated with eschar presence, host cytokine profile and severity - separating strain effects from examination technique and from host factors.

Readouts

Eschar presence and host cytokine programme by infecting strain genotype

pathophysiology#Eschar Formation at the Inoculation Site

Would support

pathophysiology#Eschar Formation at the Inoculation Site pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response

Show evidence (2 references)

PMID:40754340 SUPPORT Human Clinical

"It is postulated that some strains produce eschars less commonly than other antigenic types."

The eschar-strain link is stated as a postulate rather than a finding, which is the gap. Recorded as PARTIAL for that reason.

PMID:32620750 SUPPORT Model Organism

"Comparing the host response to two clinical isolates, we identify distinct immune response networks for each strain, leading to predictions of relative virulence that are validated in a mouse infection model."

Establishes that different clinical isolates drive distinct host immune programmes with differing virulence. Evidence source is MODEL_ORGANISM because the virulence prediction was validated in mice.

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Pathophysiology

13

Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi

A feeding Leptotrombidium larva deposits Orientia tsutsugamushi into the dermis at its attachment site. This is the initiating event of the disease and the only natural route of human infection; the mite feeds once, so a single attachment is sufficient. Bacteraemia becomes detectable roughly a week after attachment, one to three days before clinical illness begins.

dermal fibroblast at the inoculation site CL:0000057

Downstream

TSA56-Fibronectin Binding and Integrin-Mediated Host Cell Entry Inoculated organisms encounter and attach to resident dermal cells, which is the first molecular step of infection.

Show evidence (1 reference)

PMID:6808205 SUPPORT Human Clinical

"Rickettsemias were detected in all three volunteers beginning on day 7 PCA, 1-3 days before the onset of clinical disease."

Establishes chigger attachment as the initiating event and quantifies the delay to detectable bacteraemia in deliberately infected human volunteers.

TSA56-Fibronectin Binding and Integrin-Mediated Host Cell Entry

The 56-kDa type-specific antigen (TSA56), the major outer membrane protein of O. tsutsugamushi, binds host fibronectin. Fibronectin bridges the bacterium to integrin alpha5beta1, and the bacterium then activates the integrin signalling machinery - focal adhesion kinase, Src kinase and RhoA GTPase, with recruitment of talin and paxillin - to drive actin reorganisation and membrane protrusion that engulfs it. This is an induced uptake: the organism forces its own entry into cells that are not professional phagocytes. Blocking tyrosine kinases or RhoA, or competing with the fibronectin-binding region of TSA56, reduces invasion, which is what makes this a causal step rather than a correlate.

integrin-mediated signaling pathway GO:0007229 ↑ INCREASED actin cytoskeleton organization GO:0030036 ↑ INCREASED symbiont entry into host GO:0044409

Downstream

Cytosolic Replication in an Obligate Intracellular Niche Induced endocytosis delivers the organism into the host cell, the prerequisite for its intracellular replication.

Show evidence (2 references)

PMID:20160019 SUPPORT In Vitro

"the 56-kDa type-specific antigen (TSA56), a major outer membrane protein of O. tsutsugamushi, binds to fibronectin and facilitates bacterial entry into the host cell"

Identifies TSA56-fibronectin binding as the adhesion event that initiates host cell entry.

PMID:20160019 SUPPORT In Vitro

"these results clearly indicate that O. tsutsugamushi exploits integrin-mediated signaling and the actin cytoskeleton for invasion of eukaryotic host cells"

States the paper's conclusion that integrin signalling and actin remodelling are the mechanism of invasion, which is the molecular content of this node.

Cytosolic Replication in an Obligate Intracellular Niche

Having entered the cell, Orientia escapes the endocytic vacuole into the cytosol and replicates free in the cytoplasm. It cannot replicate outside a host cell at all. This niche is simultaneously the engine of the disease and the constraint on its treatment: an antibiotic must cross the host plasma membrane and accumulate intracellularly to reach the organism, which excludes the poorly cell-penetrant beta-lactams.

biological process involved in interaction with host GO:0051701

Downstream

Eschar Formation at the Inoculation Site Local replication and the ensuing inflammatory and necrotic response at the bite site produce the eschar.

Lymphatic and Haematogenous Dissemination Replication at the inoculation site seeds draining lymphatics and then the bloodstream.

Requirement for Cell-Penetrant Antimicrobials Because the replicating organism sits in the host cytosol, only agents that accumulate intracellularly can reach it.

Show evidence (1 reference)

PMID:21610853 SUPPORT In Vitro

"O. tsutsugamushi is an obligate intracellular bacterium that mainly infects endothelial cells."

Establishes the obligately intracellular lifestyle that this node represents and that gates drug choice.

Ank13-Mediated p53 Suppression and Host Cell Cycle Arrest

Orientia does not merely occupy the host cell, it reconfigures it. The nucleomodulatory effector Ank13 blocks transcription of TP53, nearly depleting p53 and disabling the DNA-damage-triggered apoptosis that would otherwise destroy the infected cell and with it the bacterial niche. Rather than releasing the cell into unrestricted proliferation, the organism arrests the cycle at S phase in a way that favours its own replication, and delays genotoxic apoptosis until a high bacterial load has accumulated. This is niche maintenance, and it explains why infected endothelium survives long enough to support the bacterial burden that drives systemic disease.

biological process involved in interaction with host GO:0051701 ↑ INCREASED

Downstream

Cytosolic Replication in an Obligate Intracellular Niche Suppressing host apoptosis and arresting the cell cycle preserves and extends the intracellular niche in which the organism replicates.

Show evidence (2 references)

PMID:40830139 SUPPORT In Vitro

"the endotheliotropic obligate intracellular bacterium Orientia tsutsugamushi blocks transcription of TP53 to nearly deplete p53 levels"

Establishes the molecular event of this node - transcriptional blockade of TP53 by the organism in host endothelial cells.

PMID:40830139 SUPPORT In Vitro

"Orientia arrests the cell cycle at S phase to promote bacterial replication."

States that the cell-cycle arrest is directed at promoting bacterial replication, which is the causal claim of the downstream edge to the replication node.

Eschar Formation at the Inoculation Site

Replication at the chigger attachment site produces a localised necrotic papule that ulcerates and forms a black crust surrounded by an erythematous halo - the eschar - typically with regional lymphadenopathy in the draining basin. It is the single most useful diagnostic sign, but it is not universal, is frequently concealed in the axilla, groin or under clothing, and is easily missed on darker skin, which is a recurring cause of delayed diagnosis. The eschar is the visible correlate of the initiating focus rather than a cause of the systemic disease, so it is deliberately a terminal node carrying no outgoing causal edge.

Show evidence (1 reference)

PMID:6808205 SUPPORT Human Clinical

"these included fever, severe headache, myalgia, regional lymphadenopathy, and eschar"

Human volunteer infections produced eschar together with regional lymphadenopathy, tying the local lesion to the inoculation site.

Lymphatic and Haematogenous Dissemination

From the inoculation site the organism travels through draining lymphatics to regional nodes and then into the bloodstream, producing the rickettsaemia that precedes clinical illness by one to three days. Dissemination is what converts a localised skin lesion into a systemic vasculotropic disease, and it is why the organ complications of scrub typhus are simultaneous rather than sequential.

Downstream

Endothelial and Mononuclear Phagocyte Infection Blood-borne organisms reach and infect vascular endothelium and circulating mononuclear phagocytes throughout the body.

Show evidence (1 reference)

PMID:40747630 SUPPORT Other

"with Orientia tsutsugamushi selectively targeting dermal and endothelial cells, facilitating systemic dissemination and subsequent neurological implications"

States the progression from dermal infection to systemic dissemination and thence to distant organ involvement. Evidence source is OTHER as this is a review article.

Endothelial and Mononuclear Phagocyte Infection

Orientia is endotheliotropic: vascular endothelial cells are its principal target throughout the body, and infection of the endothelium is the anatomical basis of the disease's small-vessel character. Monocytes, macrophages and dendritic cells are also productively infected - monocytes support bacterial replication, not merely uptake - which supplies the second, immunological arm of the lesion.

blood vessel endothelial cell CL:0000071 monocyte CL:0000576 macrophage CL:0000235 dendritic cell CL:0000451

Downstream

Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response Infection of monocytes and macrophages triggers the interferon-dominated transcriptional programme that drives systemic inflammation.

Disseminated Small-Vessel Vasculitis and Endothelial Barrier Failure Direct infection of endothelium injures the vessel wall and initiates the vasculitic lesion.

Show evidence (1 reference)

PMID:21610853 SUPPORT In Vitro

"We demonstrated here that O. tsutsugamushi also replicated in monocytes isolated from healthy donors."

Shows the organism replicates in monocytes as well as endothelium, establishing the mononuclear phagocyte arm of this node.

Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response

Infection reprogrammes the mononuclear phagocyte compartment on a large scale: more than 4,500 genes change in infected healthy-donor monocytes, with upregulation of type I interferon and interferon-stimulated genes, M1 macrophage-polarisation genes, and apoptosis-related genes. Live organisms are required for the interferon response, so this is an active host response to replicating bacteria rather than a reaction to bacterial debris. Critically, the same interferon-dominated signature is recovered from the mononuclear cells of patients with scrub typhus, so this is not a cell-culture artefact.

monocyte CL:0000576 M1-polarised macrophage CL:0000235

Downstream

Disseminated Small-Vessel Vasculitis and Endothelial Barrier Failure The cytokine and interferon response amplifies endothelial activation and permeability beyond the injury caused by direct infection alone.

Show evidence (2 references)

PMID:21610853 SUPPORT In Vitro

"The expression of type I interferon, interferon-stimulated genes and genes associated with the M1 polarization of macrophages was significantly upregulated."

Establishes the interferon-dominated, M1-polarising transcriptional programme that defines this node.

PMID:21610853 SUPPORT Human Clinical

"the microarray analyses revealed the upregulation of 613 genes, which included interferon-related genes, and some features of M1 polarization were observed in these patients"

Recovers the same signature from patients with scrub typhus, which is what makes the in-vitro programme relevant to human disease rather than a culture artefact.

Disseminated Small-Vessel Vasculitis and Endothelial Barrier Failure

Direct endothelial infection plus the interferon- and cytokine-rich inflammatory response produce a disseminated small-vessel vasculitis with perivascular mononuclear infiltration and loss of endothelial barrier integrity. This is the single unifying lesion of scrub typhus. Because the vascular bed is everywhere, one lesion expressed in different organs generates the entire severe phenotype, which is why respiratory, hepatic, cardiac, renal and neurological complications appear together rather than in sequence.

blood vessel endothelial cell CL:0000071

Downstream

Multi-Organ Vascular Leak and End-Organ Dysfunction Loss of endothelial barrier function permits the capillary leak and tissue hypoperfusion that manifest as organ dysfunction.

Show evidence (1 reference)

PMID:42126901 SUPPORT Human Clinical

"rapidly progressive multiorgan dysfunction driven by smallvessel vasculitis, including pneumonitis, acute kidney injury, hepatitis, encephalitis and circulatory shock"

Names small-vessel vasculitis as the driver of the multi-organ syndrome and enumerates the organ manifestations that follow from it.

Multi-Organ Vascular Leak and End-Organ Dysfunction

Capillary leak and microvascular injury across multiple beds produce the severe end of the disease: pneumonitis and acute respiratory distress syndrome, hepatitis, myocarditis and circulatory shock, acute kidney injury, and meningoencephalitis. In the INTREST trial of severe scrub typhus - a hospitalised cohort selected for having at least one organ involved, so these proportions describe severe disease and are not population frequencies - complications were respiratory in 62%, hepatic in 54%, cardiovascular in 42%, renal in 30% and neurologic in 20% of patients.

Show evidence (2 references)

PMID:36856615 SUPPORT Human Clinical

"complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%)"

Quantifies the organ-system distribution of severe scrub typhus in a 794-patient randomised trial cohort, showing the simultaneous multi-organ pattern this node represents.

PMID:40747630 SUPPORT Other

"Neurological complications, notably encephalitis and meningitis, have emerged as significant clinical manifestations, considerably affecting morbidity and mortality rates among affected individuals."

Supports the neurological arm of the end-organ node and its contribution to mortality. Evidence source is OTHER as this is a review article.

Orientia Ribosomal Translation (Tetracycline and Macrolide Target)

Like other bacteria, Orientia tsutsugamushi depends on translation of its mRNA by the 70S ribosome, and that ribosome is the target of every antibiotic with established activity in scrub typhus. Doxycycline binds the 30S subunit and blocks aminoacyl-tRNA delivery to the A site; azithromycin binds the 50S subunit and blocks nascent-chain elongation. The target is the ribosome and not the cell wall, which - together with the intracellular niche - is why a tetracycline or macrolide rather than a beta-lactam is used.

translation GO:0006412

Downstream

Cytosolic Replication in an Obligate Intracellular Niche Bacterial protein synthesis sustains intracellular replication, so inhibiting translation arrests the replicating organism.

Show evidence (2 references)

PMID:24336183 SUPPORT Other

"The ribosome is one of the main antibiotic targets in the bacterial cell."

Review establishing the bacterial ribosome as the target of tetracyclines and macrolides, the step this node represents. Evidence source is OTHER as this is a review article.

PMID:36856615 SUPPORT Human Clinical

"we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus"

Confirms that the agents used in scrub typhus are a tetracycline and a macrolide, both of which act on the bacterial ribosome represented by this node.

Requirement for Cell-Penetrant Antimicrobials

Because the organism replicates free in the host cytosol, effective therapy requires an antibiotic that crosses the host plasma membrane and accumulates intracellularly. Doxycycline and azithromycin do; beta-lactams do not reach the cytosolic organism regardless of dose. This is pharmacokinetic gating rather than a molecular target, and it operates alongside - not instead of - the ribosomal target node. The clinical urgency of the constraint follows from the multi-organ node, since untreated disease progresses to organ failure - but that is a statement about why the constraint matters, not a causal relationship, so it is recorded here rather than encoded as an edge.

response to antibiotic GO:0046677

Show evidence (1 reference)

PMID:18611821 SUPPORT Other

"The intracellular location of some microorganisms allow them to resist antibiotics with poor ability to penetrate eukaryotic cell membranes, such as the beta-lactam compounds."

States the gating principle this node represents: an intracellular niche excludes poorly cell-penetrant antibiotics. Evidence source is OTHER as this is a review article.

Peptidoglycan-Poor Atypical Cell Envelope

Orientia's envelope chemistry diverges sharply from that of the rickettsiae it was once classified with, and this divergence was the basis for erecting the genus Orientia. Chemical analysis found no detectable muramic acid, glucosamine, heptose or KDO and no lipopolysaccharide bands, concluding the organism has little or no peptidoglycan or LPS. A later structural study qualified this: it found evidence for a peptidoglycan-LIKE structure together with a cross-linked outer-membrane protein network that confers envelope stability. The two results are curated here together, unresolved, because the difference matters mechanistically - it determines whether beta-lactam inactivity in scrub typhus is target absence or only drug exclusion. See the `orientia-peptidoglycan-status` discussion; this entry deliberately does NOT declare conformance to `bacterial_cell_wall_synthesis_inhibition#Intrinsic Resistance in Cell-Wall-Deficient Organisms` while that question is open.

Downstream

Requirement for Cell-Penetrant Antimicrobials Whatever the residual peptidoglycan status, the envelope offers no validated cell-wall target in this organism, leaving cell-penetrant ribosome-active agents as the therapeutic route.

Show evidence (2 references)

PMID:3114150 SUPPORT In Vitro

"It is concluded that R. tsutsugamushi has little or no peptidoglycan or lipopolysaccharide."

The original chemical analysis concluding the organism lacks the classical Gram-negative envelope components, including the peptidoglycan that is the beta-lactam target.

PMID:28513097 SUPPORT In Vitro

"This bacterium was previously reported to completely lack peptidoglycan, but here we present evidence supporting the existence of a peptidoglycan-like structure in Orientia"

Directly qualifies the earlier conclusion by presenting structural evidence for a peptidoglycan-like layer. Recorded as PARTIAL because it supports an atypical, peptidoglycan-poor envelope while contradicting the stronger claim of complete absence.

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Pathograph

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Phenotypes

25

Blood 1

Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:42126901 SUPPORT Human Clinical

"Thrombocytopenia and acute kidney injury occurred in 50%, while 75% demonstrated transaminitis."

Reports thrombocytopenia in half of a confirmed scrub typhus case series.

Cardiovascular 6

Regional lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:6808205 SUPPORT Human Clinical

"these included fever, severe headache, myalgia, regional lymphadenopathy, and eschar"

Regional lymphadenopathy in the basin draining the eschar was reproduced in human volunteer infection, supporting lymphatic spread from the inoculation site.

Circulatory shock HP:0031273

Temporal: ACUTE

Show evidence (1 reference)

PMID:42126901 SUPPORT Human Clinical

"rapidly progressive multiorgan dysfunction driven by smallvessel vasculitis, including pneumonitis, acute kidney injury, hepatitis, encephalitis and circulatory shock"

Lists circulatory shock among the multiorgan manifestations driven by the small-vessel vasculitis.

Splenomegaly FREQUENT HP:0001744

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Inflammation (31%) in scrub typhus affects the spleen (34%), lymph nodes (33%), meninges (24%) and pancreas (6%)"

Pooled prevalence of 34% for splenic involvement places it in the FREQUENT band (30-79%).

Tachycardia FREQUENT HP:0001649

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Cardiac-associated symptoms (24%) included hypotension (22%) and tachycardia (65%) only, with cardiac complications such as myocarditis (4%), cardiac dysfunction (16%) and disseminated intravascular coagulation (7%) also reported in some studies"

Pooled prevalence of 65% for tachycardia places it in the FREQUENT band (30-79%).

Hypotension OCCASIONAL HP:0002615

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Cardiac-associated symptoms (24%) included hypotension (22%) and tachycardia (65%) only, with cardiac complications such as myocarditis (4%), cardiac dysfunction (16%) and disseminated intravascular coagulation (7%) also reported in some studies"

Pooled prevalence of 22% for hypotension places it in the OCCASIONAL band (5-29%).

Myocarditis VERY_RARE HP:0012819

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Cardiac-associated symptoms (24%) included hypotension (22%) and tachycardia (65%) only, with cardiac complications such as myocarditis (4%), cardiac dysfunction (16%) and disseminated intravascular coagulation (7%) also reported in some studies"

Pooled prevalence of 4% for myocarditis across a systematic review places it in the VERY_RARE band (<5%), in deliberate contrast with the 42% cardiovascular complication rate of the severity-selected INTREST cohort.

Digestive 5

Hepatomegaly FREQUENT HP:0002240

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"O. tsutsugamushi parasite invades the hepatocyte cells, leading to hepatic symptoms like hepatomegaly and hepatic dysfunction, with an overall pooled prevalence rate of 44% (figure 6). Hepatomegaly was the most common liver-related symptom (46%)"

Pooled prevalence of 46% for hepatomegaly across a systematic review places it in the FREQUENT band (30-79%) and is the quantitative basis for the band asserted here.

Nausea FREQUENT HP:0002018

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%), abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other gastric abnormalities (43%)"

Pooled prevalence of 43% for nausea places it in the FREQUENT band (30-79%).

Vomiting FREQUENT HP:0002013

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%), abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other gastric abnormalities (43%)"

Pooled prevalence of 35% for vomiting places it in the FREQUENT band (30-79%).

Diarrhea OCCASIONAL HP:0002014

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%), abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other gastric abnormalities (43%)"

Pooled prevalence of 11% for diarrhoea places it in the OCCASIONAL band (5-29%).

Jaundice OCCASIONAL HP:0000952

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%), abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other gastric abnormalities (43%)"

Pooled prevalence of 18% for jaundice/icterus places it in the OCCASIONAL band (5-29%).

Genitourinary 1

Acute kidney injury HP:0001919

Temporal: ACUTE

Show evidence (1 reference)

PMID:36856615 SUPPORT Human Clinical

"complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%)"

Quantifies renal involvement in a 794-patient severe scrub typhus trial cohort. No frequency band is asserted because the cohort was selected for severity.

Immune 2

Maculopapular rash Maculopapular exanthema HP:0040186

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:6808205 SUPPORT Human Clinical

"The two L. fletcheri subjects developed a transient generalized rash on days 3-4 after the onset of fever"

Documents the rash, its transient character, and its timing relative to fever onset in controlled human infection.

Meningitis HP:0001287

Show evidence (1 reference)

PMID:40747630 SUPPORT Other

"Neurological complications, notably encephalitis and meningitis, have emerged as significant clinical manifestations, considerably affecting morbidity and mortality rates among affected individuals."

Names meningitis alongside encephalitis as a significant neurological manifestation. Evidence source is OTHER as this is a review article.

Metabolism 2

Fever HP:0001945

Temporal: ACUTE

Show evidence (1 reference)

PMID:6808205 SUPPORT Human Clinical

"these included fever, severe headache, myalgia, regional lymphadenopathy, and eschar"

Fever was part of the syndrome reproduced in deliberately infected human volunteers.

Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:42126901 SUPPORT Human Clinical

"Thrombocytopenia and acute kidney injury occurred in 50%, while 75% demonstrated transaminitis."

Reports transaminitis as the commonest laboratory abnormality in a confirmed scrub typhus case series.

Nervous System 1

Headache HP:0002315

Severity: SEVERE

Show evidence (1 reference)

PMID:6808205 SUPPORT Human Clinical

"these included fever, severe headache, myalgia, regional lymphadenopathy, and eschar"

Severe headache was among the signs produced by controlled chigger transmission in human volunteers.

Respiratory 3

Acute respiratory distress syndrome HP:0033677

Temporal: ACUTE

Show evidence (1 reference)

PMID:36856615 SUPPORT Human Clinical

"complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%)"

Respiratory complications were the most frequent organ involvement in the severe-disease trial cohort. No frequency band is asserted because the cohort was selected for severity.

Cough FREQUENT HP:0012735

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Pulmonary symptoms (35%) include cough and sore throat (34%), breathing problems like tachypnoea and dyspnoea (37%), crepitations (26%) and haemoptysis"

Pooled prevalence of 34% for cough and sore throat places it in the FREQUENT band (30-79%).

Dyspnea FREQUENT HP:0002094

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Pulmonary symptoms (35%) include cough and sore throat (34%), breathing problems like tachypnoea and dyspnoea (37%), crepitations (26%) and haemoptysis"

Pooled prevalence of 37% for tachypnoea and dyspnoea places it in the FREQUENT band (30-79%).

Constitutional 2

Myalgia HP:0003326

Show evidence (1 reference)

PMID:6808205 SUPPORT Human Clinical

"these included fever, severe headache, myalgia, regional lymphadenopathy, and eschar"

Myalgia was among the signs produced by controlled chigger transmission in human volunteers.

Abdominal pain OCCASIONAL HP:0002027

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%), abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other gastric abnormalities (43%)"

Pooled prevalence of 26% for abdominal pain places it in the OCCASIONAL band (5-29%).

Other 2

Eschar OCCASIONAL HP:6000793

Show evidence (2 references)

PMID:39282546 SUPPORT Human Clinical

"The overall pooled proportion of eschar positivity was 28.5% (95% CI: 24.1 to 32.9%)."

Pooled proportion across 34,002 cases; 28.5% falls in the OCCASIONAL band (5-29%) and is the quantitative basis for the frequency asserted here.

PMID:39282546 SUPPORT Human Clinical

"The pooled proportion of eschar positivity in the 'trunk' (39.3%), 'groin' (23.8%), and 'axilla' (16.5%) was higher than in the 'limbs' (9.9%) and 'head' (11.3%)."

Documents the anatomical distribution that explains why the eschar is so often overlooked on routine examination.

Meningoencephalitis Bacterial encephalitis HP:0034387

Temporal: ACUTE

Show evidence (1 reference)

PMID:40747630 SUPPORT Other

"Neurological complications, notably encephalitis and meningitis, have emerged as significant clinical manifestations, considerably affecting morbidity and mortality rates among affected individuals."

Establishes encephalitis and meningitis as significant manifestations affecting outcome. Evidence source is OTHER as this is a review article.

💊

Medical Actions

4

Doxycycline

Action: Pharmacotherapy NCIT:C15986

Agent: doxycycline CHEBI:50845

A tetracycline and the standard first-line agent for scrub typhus in adults and children. It satisfies both mechanistic constraints simultaneously: it binds the 30S ribosomal subunit, which is the drug target in this organism, and it accumulates intracellularly, so it reaches an organism replicating free in the host cytosol. Because laboratory confirmation is usually retrospective, treatment is started empirically on clinical suspicion.

Mechanism Target:

INHIBITS Orientia Ribosomal Translation (Tetracycline and Macrolide Target) — Doxycycline binds the 30S ribosomal subunit and arrests bacterial protein synthesis, the molecular target that makes a tetracycline first-line.

Requirement for Cell-Penetrant Antimicrobials — Doxycycline accumulates intracellularly and therefore reaches the cytosolic organism that beta-lactams cannot.

Show evidence (2 references)

PMID:36856615 SUPPORT Human Clinical

"we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus"

Establishes doxycycline as one of the two standard agents evaluated in the definitive randomised trial of severe scrub typhus.

PMID:42126901 SUPPORT Human Clinical

"All patients achieved clinical defervescence and symptomatic improvement within 24-48 hours of doxycycline initiation, consistent with the characteristic brisk antimicrobial response."

Documents the rapid defervescence on doxycycline that is characteristic of treated scrub typhus.

Azithromycin

Action: Pharmacotherapy NCIT:C15986

Agent: azithromycin CHEBI:2955

A macrolide with efficacy equivalent to doxycycline in adults and in children, and the preferred agent in pregnancy where tetracyclines are avoided. It acts on the 50S ribosomal subunit - a different site on the same target - and, like doxycycline, concentrates intracellularly.

Mechanism Target:

INHIBITS Orientia Ribosomal Translation (Tetracycline and Macrolide Target) — Azithromycin binds the 50S ribosomal subunit and blocks nascent-chain elongation, acting on the same ribosomal target as doxycycline by a different mechanism.

Requirement for Cell-Penetrant Antimicrobials — Azithromycin achieves high intracellular concentrations, satisfying the cell-penetration requirement imposed by the cytosolic niche.

Show evidence (2 references)

PMID:37773623 SUPPORT Human Clinical

"AZ and DX had comparable rates of defervescence among children with scrub typhus."

Randomised comparison establishing azithromycin as equivalent to doxycycline in paediatric scrub typhus.

PMID:37773623 SUPPORT Human Clinical

"Macrolides, especially azithromycin (AZ), have been found to be equally efficacious as DX for treating scrub typhus in adults."

States the prior adult equivalence that motivates azithromycin as an alternative first-line agent.

Combination intravenous doxycycline plus azithromycin for severe disease

Action: Pharmacotherapy NCIT:C15986

Agent: doxycycline CHEBI:50845 azithromycin CHEBI:2955

In severe scrub typhus with organ involvement, combining the two ribosome-active agents outperformed either alone. In a 794-patient double-blind randomised trial the composite outcome of death, persistent complications or persistent fever occurred in 33% with combination therapy versus 47% with doxycycline and 48% with azithromycin, with no difference between the two monotherapies and no excess of adverse events. This is the current evidence-based regimen for severe disease.

Mechanism Target:

INHIBITS Orientia Ribosomal Translation (Tetracycline and Macrolide Target) — Both agents inhibit the same bacterial ribosome at different subunits, which is the mechanistic rationale for combining them.

Multi-Organ Vascular Leak and End-Organ Dysfunction — Faster and more complete bacterial clearance limits progression of the vasculitic organ injury that defines severe disease.

Show evidence (2 references)

PMID:36856615 SUPPORT Human Clinical

"Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone."

The trial's primary conclusion, establishing combination therapy as superior in severe scrub typhus.

PMID:36856615 SUPPORT Human Clinical

"The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively)"

Quantifies the benefit of combination therapy over doxycycline monotherapy on the composite primary outcome.

Chloramphenicol

Action: Pharmacotherapy NCIT:C15986

Agent: chloramphenicol CHEBI:17698

The historical treatment for scrub typhus and still an option where the first-line agents cannot be used. Its role is now limited by toxicity in exactly the groups that most need an alternative: it is avoided in pregnancy and not prescribed to neonates. That constraint, together with the teratogenicity of tetracyclines in pregnancy and their effect on children's teeth, is what makes azithromycin the agent of choice in pregnancy rather than a mere alternative.

Mechanism Target:

INHIBITS Orientia Ribosomal Translation (Tetracycline and Macrolide Target) — Chloramphenicol binds the 50S ribosomal subunit and blocks peptidyl transferase, acting on the same bacterial ribosome as the first-line agents.

Show evidence (2 references)

PMID:40754340 SUPPORT Human Clinical

"Historically, scrub typhus has been treated with chloramphenicol. However, its use in pregnant women and infants is fraught with complications, due to which it is avoided in pregnancy and not prescribed to neonates."

Establishes chloramphenicol as an effective historical agent while stating the toxicity constraints that limit it. Recorded as PARTIAL because the same sentence both supports and restricts the treatment.

PMID:40754340 SUPPORT Human Clinical

"At the same time, tetracycline is contraindicated during pregnancy due to teratogenicity, and it can discolour children's teeth."

Supplies the counterpart constraint on tetracyclines that jointly determines agent choice in pregnancy and childhood.

🌍

Environmental Factors

3

Agricultural and forest-dependent occupational exposure to chigger habitat

Deliberately left unbound to an ontology term. ECTO was searched for arthropod-vector, agricultural and occupational exposure concepts and no adequate match was found; per the project rule that no term beats a bad one, a free-text preferred_term is retained rather than forcing an approximate CURIE.

Scrub typhus is fundamentally an exposure disease: risk is set by contact with the vegetation where infected Leptotrombidium larvae wait for a host. Agricultural practice and work in or near forested land are the dominant behavioural determinants, and Indian states with agricultural and forest-dependent lifestyles show correspondingly high prevalence. This is why the disease clusters occupationally and seasonally rather than person-to-person - there is no human-to-human transmission at all.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"possibly due to agricultural and forest-dependent lifestyles, which increase exposure to vector habitats"

Links high regional prevalence to agricultural and forest-dependent lifestyles through increased vector-habitat exposure.

Mechanism Target:

TRIGGERS Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi — Entering chigger habitat is the route by which a larval mite reaches human skin and inoculates the organism; without that contact the initiating event cannot occur.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Behavioural aspects of human activities that are linked to the danger of chigger infestation include agricultural practices and exposure to forested regions."

Names agricultural practice and forest exposure as the behavioural determinants of chigger contact, which is the initiating event of this entry's pathograph.

Peridomestic exposure through firewood storage and livestock proximity

Unbound for the same reason as the occupational exposure above; ECTO has no adequate peridomestic-vector-habitat concept.

Beyond occupational exposure, domestic living conditions that bring rodent and mite habitat up against the house - stored firewood, close proximity to livestock - are associated with moderate regional prevalence. This matters practically because it is the arm of exposure that is modifiable by household measures rather than by changing someone's occupation.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Moderate prevalence in Odisha-30%, Haryana-23% and Uttar Pradesh-16% links scrub typhus to living conditions such as firewood storage and proximity to livestock."

Documents the peridomestic exposure association at population level.

Mechanism Target:

PREDISPOSES Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi — Peridomestic mite habitat raises the probability of chigger contact at home rather than at work, but the intermediate step - mite population density around the dwelling - is inferred rather than measured in the cited source.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"Moderate prevalence in Odisha-30%, Haryana-23% and Uttar Pradesh-16% links scrub typhus to living conditions such as firewood storage and proximity to livestock."

Associates regional prevalence with specific peridomestic living conditions.

Ecological amplification of mite populations by bamboo flowering

Unbound; ECTO has no concept for a vector-population ecological event of this kind.

Mass bamboo flowering is followed by a rodent population surge and a corresponding increase in chigger abundance, and has been invoked to explain outbreak surges in north-east India. It is an unusually clean illustration of how the disease's epidemiology is driven by vector ecology rather than by anything about human immunity.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"This surge may be linked to ecological changes like bamboo flowering, which boost mite populations."

Hedged in the source as a possible link, and recorded as PARTIAL for that reason.

Mechanism Target:

EXACERBATES Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi — A larger infected-mite population raises the community-level probability of inoculation; the intermediate rodent-host amplification step is described in the source as a link rather than demonstrated.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"This surge may be linked to ecological changes like bamboo flowering, which boost mite populations."

The source states the bamboo-flowering link as a possible explanation for a case surge. Recorded as PARTIAL because it is offered as a hypothesis rather than a demonstrated association.

🔬

Diagnosis

5

Indirect immunofluorescence assay (reference standard serology)

IFA for anti-Orientia antibodies is the CDC reference standard. Its practical problem is an availability inversion that shapes the whole diagnostic landscape of this disease: the reference test is rarely available in exactly the developing-country settings where scrub typhus is most prevalent. Paired acute and convalescent sera are needed for a definitive serological diagnosis, so IFA rarely informs the decision to treat.

serology testing NCIT:C25294

Results: Seroconversion or a fourfold rise in anti-Orientia tsutsugamushi antibody titre between paired acute and convalescent samples supports the diagnosis.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"As per the Centre for Disease Control and Prevention, indirect immunofluorescence assay (IFA) is the reference standard, though it is rarely available in developing nations where prevalence is high."

Establishes IFA as the reference standard and states the availability inversion that limits its practical use.

Immunochromatographic rapid antibody tests

Rapid ICTs using pooled Orientia cell lysates or recombinant p56 outer-membrane protein as antigen detect IgG, IgM and IgA with better sensitivity and specificity than IFA in field conditions and may eventually replace it. Sensitivity is only moderate at around 70% and rises with fever duration, so a negative test early in illness carries a substantial false-negative rate - which is precisely when the treatment decision has to be made.

serology testing NCIT:C25294

Results: Detection of IgM, IgG or IgA against O. tsutsugamushi supports the diagnosis; a negative result early in the febrile course does not exclude it.

Show evidence (1 reference)

PMID:40754340 SUPPORT Human Clinical

"ICTs detect IgG, IgM and IgA antibodies against O. tsutsugamushi with moderate sensitivity (~70%). Sensitivity increases with fever duration but has a substantial number of false negative results."

Quantifies ICT sensitivity and states the time-dependence and false-negative rate that bound its clinical use.

PCR detection of Orientia tsutsugamushi DNA

PCR assays usually target outer-membrane-protein genes and may be more sensitive than serology, detecting Orientia DNA in blood even during persistent phases of infection without obvious clinical symptoms. PCR is best early, during the rickettsaemic phase that precedes seroconversion, which makes it complementary to serology rather than an alternative to it. It accounted for only 4.6% of diagnoses in the reviewed Indian literature.

molecular diagnostic procedure NCIT:C18020

Results: Detection of O. tsutsugamushi DNA, commonly by amplification of the 56-kDa type-specific antigen gene, confirms infection.

Show evidence (2 references)

PMID:40754340 SUPPORT Human Clinical

"PCRs usually target the genes of outer membrane proteins. They may be more sensitive than serological tests detecting Orientia DNA in blood even during persistent phases of infection with no obvious clinical symptoms."

Establishes the molecular target and the sensitivity advantage of PCR over serology.

PMID:27645781 SUPPORT Human Clinical

"confirmed by indirect immunofluorescence assay or nested polymerase chain reaction on the 56-kDa type-specific antigen gene of Orientia tsutsugamushi"

Documents the 56-kDa type-specific antigen gene as the routine nested-PCR target, the same TSA56 gene that this entry models as the adhesin.

Weil-Felix agglutination test

An old, cheap OXK-antigen agglutination test with poor sensitivity of about 15% and specificity of about 96%, which is therefore not the preferred method. It is recorded here because of an implementation gap that is itself a finding: despite being the least reliable option, Weil-Felix was the primary diagnostic method in about 61% of cases across two decades of Indian literature, while PCR accounted for 4.6%. Any epidemiological figure drawn from that literature inherits the misclassification of a 15%-sensitivity test, which is a reason to treat reported case counts as underestimates.

serology testing NCIT:C25294

Results: Agglutination against Proteus OXK antigen; a positive result is suggestive but a negative result excludes very little given approximately 15% sensitivity.

Show evidence (2 references)

PMID:40754340 SUPPORT Human Clinical

"While providing a cheap option for identifying rickettsial infections in resource-poor settings, the Weil-Felix agglutination test has poor sensitivity (~15%) and specificity (~96%) and is thus not preferred."

Quantifies the poor performance of the Weil-Felix test and states that it is not the preferred method.

PMID:40754340 SUPPORT Human Clinical

"The primary choice of diagnosis in the reviewed studies was the Weil-Felix test, based on ~61% of the cases"

Documents the implementation gap - the least reliable test was the most used - which is why reported case counts from this literature should be read as underestimates.

Clinical recognition of the eschar

Careful whole-body examination for an eschar remains a decisive bedside step because the lesion is pathognomonic when found. It is present in only a minority of patients and concentrates on the trunk, groin and axilla, so it is missed unless covered areas are deliberately examined; eliciting it by directed history and examination is associated with correct diagnosis at the first visit.

physical examination NCIT:C18020

Results: A necrotic, black-crusted ulcer with an erythematous halo at a chigger attachment site is pathognomonic; its absence does not exclude the diagnosis.

Show evidence (2 references)

PMID:42160320 SUPPORT Human Clinical

"In endemic settings, patients correctly diagnosed at the first visit to a participating site more often had rash and eschar brought to clinical attention in specific ways. Directed inquiry about skin symptoms and careful examination for eschar may help recognition in routine care."

States the study's finding that deliberately eliciting rash and eschar is associated with correct diagnosis at the first visit, and the practice recommendation that follows.

PMID:39282546 SUPPORT Human Clinical

"There is a need to create awareness amongst physicians of the need for thorough physical examination."

States the practical conclusion that follows from eschars concentrating on covered body areas.

📊

Prevalence

2

India (pooled published case reports and series, 2003-2023)

Cases In Literature Unknown

A systematic review of two decades of Indian literature accumulated 47,650 reported cases with a 5% case-fatality rate across the 35,243 cases for which outcome was evaluable, and found infections rising since 2010. This is a count of cases appearing in the literature, not a rate against a population denominator, so no prevalence class or normalised rate is asserted.

Show evidence (2 references)

PMID:40754340 SUPPORT Human Clinical

"The case fatality rate was 5% out of 35 243 cases."

Pooled case-fatality across the Indian literature. Recorded as a literature case count rather than a population prevalence because the review has no denominator.

PMID:40754340 SUPPORT Human Clinical

"there has been a notable increase in infections since 2010, peaking in 2019 and 2022"

Documents the rising trend in reported scrub typhus in India over the review window.

Asia-Pacific region (population at risk)

Unknown Unknown

More than one billion people live in the Asia-Pacific area where scrub typhus is endemic. This is a population-at-risk figure, not an occurrence measure, and is recorded here only to scale the public-health importance of the disease.

Show evidence (1 reference)

PMID:36339235 SUPPORT Human Clinical

"Scrub typhus, caused by Orientia tsutsugamushi, is a serious public health problem in the Asia-Pacific region, threatening the health of more than one billion people."

Supports the scale of the at-risk population. Explicitly not curated as a prevalence or incidence measure.

🦠

Infectious Agent

1

Orientia tsutsugamushi

Obligately intracellular, cytosol-dwelling bacterium of the family Rickettsiaceae, reclassified out of the genus Rickettsia into its own genus on the basis of its divergent envelope chemistry and genome. Its major outer membrane protein, the 56-kDa type-specific antigen (TSA56), is both the principal adhesin and the antigen on which strain typing is based.

Orientia tsutsugamushi NCBITaxon:784

Show evidence (2 references)

PMID:21610853 SUPPORT In Vitro

"O. tsutsugamushi is an obligate intracellular bacterium that mainly infects endothelial cells."

Identifies the causative organism and its obligately intracellular, endotheliotropic lifestyle.

PMID:32620750 SUPPORT In Vitro

"Orientia tsutsugamushi (Ot), an obligate intracellular bacterium that causes the vector-borne human disease scrub typhus"

Names O. tsutsugamushi as the agent of scrub typhus and confirms the obligately intracellular, vector-borne character of the infection.

↔️

Transmission

1

Chigger-borne (trombiculid mite larva) transmission

Orientia tsutsugamushi is transmitted by the larval stage - the chigger - of trombiculid mites of the genus Leptotrombidium, which is the only stage of the mite life cycle that feeds on a vertebrate. The mite is both vector and reservoir, maintaining the organism transovarially, so humans are incidental hosts. Human volunteer studies with laboratory-reared infected chiggers reproduce the full syndrome, establishing the route causally rather than by association.

Show evidence (2 references)

PMID:6808205 SUPPORT Human Clinical

"these included fever, severe headache, myalgia, regional lymphadenopathy, and eschar"

Human volunteers fed on laboratory-reared infected chiggers developed the complete scrub typhus syndrome, establishing chigger attachment as a sufficient route of transmission.

PMID:6808205 SUPPORT Human Clinical

"Rickettsemias were detected in all three volunteers beginning on day 7 PCA, 1-3 days before the onset of clinical disease."

Documents the incubation interval between chigger attachment and detectable bacteraemia, which precedes symptom onset - the temporal basis of the dissemination node.

🔬

Clinical Trials

4

NCT03083197 NOT_APPLICABLE UNKNOWN

The Scrub Typhus Antibiotic Resistance Trial (START): an open-label randomised comparison of 7 days of oral doxycycline, 3 days of oral doxycycline and 3 days of oral azithromycin in patients with acute scrub typhus, conducted in an area of reported antimicrobial resistance. It is the trial that directly addresses the reduced-susceptibility question recorded in the `orientia-doxycycline-susceptibility` discussion.

Target Phenotypes: Fever HP:0001945

Show evidence (1 reference)

clinicaltrials:NCT03083197 SUPPORT Human Clinical

"Primary Objective: To evaluate the clinical and microbiological responses in scrub typhus patients to three oral treatment regimens: 7 days of doxycycline, 3 days of doxycycline, and 3 days of azithromycin"

States the trial's objective, which is to compare the two ribosome-active first-line agents and duration in an area of reported resistance.

NCT00351182 PHASE_III UNKNOWN

A controlled trial of a 5-day course of telithromycin versus doxycycline for mild to moderate scrub typhus, motivated by the need for agents usable in pregnancy and childhood and active against strains with reduced doxycycline susceptibility. Telithromycin is a ketolide and therefore also acts on the bacterial ribosome.

Target Phenotypes: Fever HP:0001945

Show evidence (1 reference)

clinicaltrials:NCT00351182 SUPPORT Human Clinical

"Our study was designed to prove the clinical usefulness of telithromycin by comparing it with doxycycline for treating mild or moderate scrub typhus."

States the trial's design and comparator, supporting telithromycin as an investigational ribosome-active alternative.

CTRI/2018/08/015159 NOT_APPLICABLE COMPLETED

INTREST (Intravenous Treatment for Scrub Typhus), the multicentre double-blind randomised controlled trial of intravenous doxycycline versus azithromycin versus both in severe scrub typhus, reported in PMID:36856615. It has no ClinicalTrials.gov record and is registered instead on the Clinical Trials Registry - India, so it is keyed on its WHO ICTRP identifier.

Show evidence (1 reference)

ICTRP:CTRI/2018/08/015159 SUPPORT Other

"Public title: Optimal treatment for a potentially life threatening infection called scrub typhus"

WHO ICTRP registration record establishing the trial's identity and registry of record. Evidence source is OTHER because a registration document is not itself study evidence.

NCT06675110 NOT_APPLICABLE UNKNOWN

QuEST - Quick and Easy Scrub Typhus diagnostic tools. Evaluates insulated isothermal PCR (iiPCR) for direct detection of Orientia tsutsugamushi in Chiang Rai Province, Thailand. It targets precisely the gap this entry's `diagnosis:` section documents: a field-deployable molecular test able to detect the organism during the early rickettsaemic window, in the resource-limited settings where the IFA reference standard is unavailable and the low-sensitivity Weil-Felix test is still the commonest method used.

Target Phenotypes: Fever HP:0001945

Show evidence (1 reference)

clinicaltrials:NCT06675110 SUPPORT Human Clinical

"Evaluate the performance of insulated isothermal polymerase chain reaction (iiPCR) in the diagnosis of scrub typhus in Chiang Rai Province"

States the trial's objective, which is direct molecular detection of the organism in a field setting.

{ }

Source YAML

click to show

name: Scrub typhus
creation_date: '2026-08-19T22:40:00Z'
category: Infectious Disease
description: >-
  Scrub typhus is an acute, mite-borne rickettsial illness caused by Orientia
  tsutsugamushi, an obligately intracellular bacterium transmitted by the larval
  stage (chigger) of trombiculid mites of the genus Leptotrombidium. It is one of
  the commonest causes of non-malarial undifferentiated febrile illness across the
  Asia-Pacific "tsutsugamushi triangle", and its reported range is expanding.

  The mechanism is a single lesion with systemic consequences. A feeding chigger
  inoculates Orientia into the dermis; the organism uses its major outer-membrane
  protein TSA56 to bind host fibronectin and co-opt integrin alpha5beta1 signalling
  and the actin cytoskeleton to force its own uptake into non-phagocytic cells. It
  then escapes into the cytosol and replicates there, remodelling the host cell to
  protect its niche. Local replication produces the diagnostic eschar; lymphatic and
  haematogenous spread carries the organism to vascular endothelium and to monocytes,
  macrophages and dendritic cells throughout the body. The resulting type I
  interferon-dominated, M1-polarised inflammatory response together with direct
  endothelial infection produces a disseminated small-vessel vasculitis and loss of
  endothelial barrier function. That one lesion, expressed in different organs,
  accounts for the whole severe phenotype - pneumonitis and ARDS, hepatitis,
  myocarditis and shock, acute kidney injury, and meningoencephalitis.

  Two features of the organism gate treatment and are curated here as explicit
  mechanism nodes rather than as prose. Orientia is obligately intracellular and
  cytosolic, so only cell-penetrant agents reach it; and its drug target is the
  bacterial ribosome, not the cell wall. Doxycycline and azithromycin therefore work
  and beta-lactams do not. The entry conforms to
  `intracellular_pathogen_persistence` (both nodes) and to
  `bacterial_protein_synthesis_inhibition`, the same multi-module shape used by
  `Murine_Typhus` and `Oroya_Fever`.
disease_term:
  preferred_term: scrub typhus
  term:
    id: MONDO:0019365
    label: scrub typhus
synonyms:
- Tsutsugamushi disease
- Tsutsugamushi fever
- Japanese river fever
- Kedani fever
- Scrub mite-borne typhus
- Chigger-borne typhus
parents:
- Typhus
- Rickettsiaceae infectious disease
- Vector-borne disease
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:40747630
      reference_title: Neurological complications of scrub typhus.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        with Orientia tsutsugamushi selectively targeting dermal and endothelial
        cells, facilitating systemic dissemination and subsequent neurological
        implications
      explanation: >-
        Scrub typhus is an acute bacterial infection acquired from an arthropod
        vector and disseminating systemically, placing it in Harrison's Infectious
        Diseases Part. Evidence source is OTHER as this is a review article.

infectious_agent:
- name: Orientia tsutsugamushi
  description: >-
    Obligately intracellular, cytosol-dwelling bacterium of the family
    Rickettsiaceae, reclassified out of the genus Rickettsia into its own genus on
    the basis of its divergent envelope chemistry and genome. Its major outer
    membrane protein, the 56-kDa type-specific antigen (TSA56), is both the principal
    adhesin and the antigen on which strain typing is based.
  infectious_agent_term:
    preferred_term: Orientia tsutsugamushi
    term:
      id: NCBITaxon:784
      label: Orientia tsutsugamushi
  evidence:
  - reference: PMID:21610853
    reference_title: >-
      Orientia tsutsugamushi stimulates an original gene expression program in
      monocytes: relationship with gene expression in patients with scrub typhus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      O. tsutsugamushi is an obligate intracellular bacterium that mainly infects
      endothelial cells.
    explanation: >-
      Identifies the causative organism and its obligately intracellular,
      endotheliotropic lifestyle.
  - reference: PMID:32620750
    reference_title: >-
      Dual RNA-seq of Orientia tsutsugamushi informs on host-pathogen interactions
      for this neglected intracellular human pathogen.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Orientia tsutsugamushi (Ot), an obligate intracellular bacterium that causes
      the vector-borne human disease scrub typhus
    explanation: >-
      Names O. tsutsugamushi as the agent of scrub typhus and confirms the obligately
      intracellular, vector-borne character of the infection.

transmission:
- name: Chigger-borne (trombiculid mite larva) transmission
  description: >-
    Orientia tsutsugamushi is transmitted by the larval stage - the chigger - of
    trombiculid mites of the genus Leptotrombidium, which is the only stage of the
    mite life cycle that feeds on a vertebrate. The mite is both vector and reservoir,
    maintaining the organism transovarially, so humans are incidental hosts. Human
    volunteer studies with laboratory-reared infected chiggers reproduce the full
    syndrome, establishing the route causally rather than by association.
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these included fever, severe headache, myalgia, regional lymphadenopathy, and
      eschar
    explanation: >-
      Human volunteers fed on laboratory-reared infected chiggers developed the
      complete scrub typhus syndrome, establishing chigger attachment as a sufficient
      route of transmission.
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rickettsemias were detected in all three volunteers beginning on day 7 PCA, 1-3
      days before the onset of clinical disease.
    explanation: >-
      Documents the incubation interval between chigger attachment and detectable
      bacteraemia, which precedes symptom onset - the temporal basis of the
      dissemination node.

pathophysiology:
- name: Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi
  biological_scale: ORGANISM
  role: trigger
  description: >-
    A feeding Leptotrombidium larva deposits Orientia tsutsugamushi into the dermis
    at its attachment site. This is the initiating event of the disease and the only
    natural route of human infection; the mite feeds once, so a single attachment is
    sufficient. Bacteraemia becomes detectable roughly a week after attachment, one to
    three days before clinical illness begins.
  cell_types:
  - preferred_term: dermal fibroblast at the inoculation site
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: TSA56-Fibronectin Binding and Integrin-Mediated Host Cell Entry
    causal_link_type: DIRECT
    description: >-
      Inoculated organisms encounter and attach to resident dermal cells, which is
      the first molecular step of infection.
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rickettsemias were detected in all three volunteers beginning on day 7 PCA, 1-3
      days before the onset of clinical disease.
    explanation: >-
      Establishes chigger attachment as the initiating event and quantifies the delay
      to detectable bacteraemia in deliberately infected human volunteers.

- name: TSA56-Fibronectin Binding and Integrin-Mediated Host Cell Entry
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    The 56-kDa type-specific antigen (TSA56), the major outer membrane protein of
    O. tsutsugamushi, binds host fibronectin. Fibronectin bridges the bacterium to
    integrin alpha5beta1, and the bacterium then activates the integrin signalling
    machinery - focal adhesion kinase, Src kinase and RhoA GTPase, with recruitment of
    talin and paxillin - to drive actin reorganisation and membrane protrusion that
    engulfs it. This is an induced uptake: the organism forces its own entry into
    cells that are not professional phagocytes. Blocking tyrosine kinases or RhoA, or
    competing with the fibronectin-binding region of TSA56, reduces invasion, which is
    what makes this a causal step rather than a correlate.
  biological_processes:
  - preferred_term: integrin-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
  - preferred_term: actin cytoskeleton organization
    modifier: INCREASED
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  - preferred_term: symbiont entry into host
    term:
      id: GO:0044409
      label: symbiont entry into host
  downstream:
  - target: Cytosolic Replication in an Obligate Intracellular Niche
    causal_link_type: DIRECT
    description: >-
      Induced endocytosis delivers the organism into the host cell, the prerequisite
      for its intracellular replication.
  evidence:
  - reference: PMID:20160019
    reference_title: >-
      Intracellular invasion by Orientia tsutsugamushi is mediated by integrin
      signaling and actin cytoskeleton rearrangements.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the 56-kDa type-specific antigen (TSA56), a major outer membrane protein of O.
      tsutsugamushi, binds to fibronectin and facilitates bacterial entry into the
      host cell
    explanation: >-
      Identifies TSA56-fibronectin binding as the adhesion event that initiates host
      cell entry.
  - reference: PMID:20160019
    reference_title: >-
      Intracellular invasion by Orientia tsutsugamushi is mediated by integrin
      signaling and actin cytoskeleton rearrangements.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      these results clearly indicate that O. tsutsugamushi exploits integrin-mediated
      signaling and the actin cytoskeleton for invasion of eukaryotic host cells
    explanation: >-
      States the paper's conclusion that integrin signalling and actin remodelling are
      the mechanism of invasion, which is the molecular content of this node.

- name: Cytosolic Replication in an Obligate Intracellular Niche
  biological_scale: CELLULAR
  role: central_effector
  conforms_to: intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion
  description: >-
    Having entered the cell, Orientia escapes the endocytic vacuole into the cytosol
    and replicates free in the cytoplasm. It cannot replicate outside a host cell at
    all. This niche is simultaneously the engine of the disease and the constraint on
    its treatment: an antibiotic must cross the host plasma membrane and accumulate
    intracellularly to reach the organism, which excludes the poorly cell-penetrant
    beta-lactams.
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  downstream:
  - target: Eschar Formation at the Inoculation Site
    causal_link_type: DIRECT
    description: >-
      Local replication and the ensuing inflammatory and necrotic response at the bite
      site produce the eschar.
  - target: Lymphatic and Haematogenous Dissemination
    causal_link_type: DIRECT
    description: >-
      Replication at the inoculation site seeds draining lymphatics and then the
      bloodstream.
  - target: Requirement for Cell-Penetrant Antimicrobials
    causal_link_type: DIRECT
    description: >-
      Because the replicating organism sits in the host cytosol, only agents that
      accumulate intracellularly can reach it.
  evidence:
  - reference: PMID:21610853
    reference_title: >-
      Orientia tsutsugamushi stimulates an original gene expression program in
      monocytes: relationship with gene expression in patients with scrub typhus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      O. tsutsugamushi is an obligate intracellular bacterium that mainly infects
      endothelial cells.
    explanation: >-
      Establishes the obligately intracellular lifestyle that this node represents and
      that gates drug choice.

- name: Ank13-Mediated p53 Suppression and Host Cell Cycle Arrest
  biological_scale: MOLECULAR
  role: modifier
  description: >-
    Orientia does not merely occupy the host cell, it reconfigures it. The
    nucleomodulatory effector Ank13 blocks transcription of TP53, nearly depleting p53
    and disabling the DNA-damage-triggered apoptosis that would otherwise destroy the
    infected cell and with it the bacterial niche. Rather than releasing the cell into
    unrestricted proliferation, the organism arrests the cycle at S phase in a way that
    favours its own replication, and delays genotoxic apoptosis until a high bacterial
    load has accumulated. This is niche maintenance, and it explains why infected
    endothelium survives long enough to support the bacterial burden that drives
    systemic disease.
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    modifier: INCREASED
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  downstream:
  - target: Cytosolic Replication in an Obligate Intracellular Niche
    causal_link_type: DIRECT
    description: >-
      Suppressing host apoptosis and arresting the cell cycle preserves and extends the
      intracellular niche in which the organism replicates.
  evidence:
  - reference: PMID:40830139
    reference_title: >-
      Orientia tsutsugamushi modulates p53, the cell cycle, and genotoxicity to
      maintain its intracellular niche.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the endotheliotropic obligate intracellular bacterium Orientia tsutsugamushi
      blocks transcription of TP53 to nearly deplete p53 levels
    explanation: >-
      Establishes the molecular event of this node - transcriptional blockade of TP53
      by the organism in host endothelial cells.
  - reference: PMID:40830139
    reference_title: >-
      Orientia tsutsugamushi modulates p53, the cell cycle, and genotoxicity to
      maintain its intracellular niche.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Orientia arrests the cell cycle at S phase to promote bacterial replication.
    explanation: >-
      States that the cell-cycle arrest is directed at promoting bacterial replication,
      which is the causal claim of the downstream edge to the replication node.

- name: Eschar Formation at the Inoculation Site
  biological_scale: TISSUE
  role: consequence
  description: >-
    Replication at the chigger attachment site produces a localised necrotic papule
    that ulcerates and forms a black crust surrounded by an erythematous halo - the
    eschar - typically with regional lymphadenopathy in the draining basin. It is the
    single most useful diagnostic sign, but it is not universal, is frequently
    concealed in the axilla, groin or under clothing, and is easily missed on darker
    skin, which is a recurring cause of delayed diagnosis. The eschar is the visible
    correlate of the initiating focus rather than a cause of the systemic disease, so it
    is deliberately a terminal node carrying no outgoing causal edge.
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these included fever, severe headache, myalgia, regional lymphadenopathy, and
      eschar
    explanation: >-
      Human volunteer infections produced eschar together with regional
      lymphadenopathy, tying the local lesion to the inoculation site.

- name: Lymphatic and Haematogenous Dissemination
  biological_scale: ORGANISM
  role: consequence
  description: >-
    From the inoculation site the organism travels through draining lymphatics to
    regional nodes and then into the bloodstream, producing the rickettsaemia that
    precedes clinical illness by one to three days. Dissemination is what converts a
    localised skin lesion into a systemic vasculotropic disease, and it is why the
    organ complications of scrub typhus are simultaneous rather than sequential.
  downstream:
  - target: Endothelial and Mononuclear Phagocyte Infection
    causal_link_type: DIRECT
    description: >-
      Blood-borne organisms reach and infect vascular endothelium and circulating
      mononuclear phagocytes throughout the body.
  evidence:
  - reference: PMID:40747630
    reference_title: Neurological complications of scrub typhus.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with Orientia tsutsugamushi selectively targeting dermal and endothelial cells,
      facilitating systemic dissemination and subsequent neurological implications
    explanation: >-
      States the progression from dermal infection to systemic dissemination and
      thence to distant organ involvement. Evidence source is OTHER as this is a
      review article.

- name: Endothelial and Mononuclear Phagocyte Infection
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Orientia is endotheliotropic: vascular endothelial cells are its principal target
    throughout the body, and infection of the endothelium is the anatomical basis of
    the disease's small-vessel character. Monocytes, macrophages and dendritic cells
    are also productively infected - monocytes support bacterial replication, not
    merely uptake - which supplies the second, immunological arm of the lesion.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  downstream:
  - target: Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response
    causal_link_type: DIRECT
    description: >-
      Infection of monocytes and macrophages triggers the interferon-dominated
      transcriptional programme that drives systemic inflammation.
  - target: Disseminated Small-Vessel Vasculitis and Endothelial Barrier Failure
    causal_link_type: DIRECT
    description: >-
      Direct infection of endothelium injures the vessel wall and initiates the
      vasculitic lesion.
  evidence:
  - reference: PMID:21610853
    reference_title: >-
      Orientia tsutsugamushi stimulates an original gene expression program in
      monocytes: relationship with gene expression in patients with scrub typhus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrated here that O. tsutsugamushi also replicated in monocytes isolated
      from healthy donors.
    explanation: >-
      Shows the organism replicates in monocytes as well as endothelium, establishing
      the mononuclear phagocyte arm of this node.

- name: Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Infection reprogrammes the mononuclear phagocyte compartment on a large scale:
    more than 4,500 genes change in infected healthy-donor monocytes, with
    upregulation of type I interferon and interferon-stimulated genes, M1
    macrophage-polarisation genes, and apoptosis-related genes. Live organisms are
    required for the interferon response, so this is an active host response to
    replicating bacteria rather than a reaction to bacterial debris. Critically, the
    same interferon-dominated signature is recovered from the mononuclear cells of
    patients with scrub typhus, so this is not a cell-culture artefact.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: M1-polarised macrophage
    term:
      id: CL:0000235
      label: macrophage
  downstream:
  - target: Disseminated Small-Vessel Vasculitis and Endothelial Barrier Failure
    causal_link_type: DIRECT
    description: >-
      The cytokine and interferon response amplifies endothelial activation and
      permeability beyond the injury caused by direct infection alone.
  evidence:
  - reference: PMID:21610853
    reference_title: >-
      Orientia tsutsugamushi stimulates an original gene expression program in
      monocytes: relationship with gene expression in patients with scrub typhus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The expression of type I interferon, interferon-stimulated genes and genes
      associated with the M1 polarization of macrophages was significantly upregulated.
    explanation: >-
      Establishes the interferon-dominated, M1-polarising transcriptional programme
      that defines this node.
  - reference: PMID:21610853
    reference_title: >-
      Orientia tsutsugamushi stimulates an original gene expression program in
      monocytes: relationship with gene expression in patients with scrub typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the microarray analyses revealed the upregulation of 613 genes, which included
      interferon-related genes, and some features of M1 polarization were observed in
      these patients
    explanation: >-
      Recovers the same signature from patients with scrub typhus, which is what makes
      the in-vitro programme relevant to human disease rather than a culture artefact.

- name: Disseminated Small-Vessel Vasculitis and Endothelial Barrier Failure
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Direct endothelial infection plus the interferon- and cytokine-rich inflammatory
    response produce a disseminated small-vessel vasculitis with perivascular
    mononuclear infiltration and loss of endothelial barrier integrity. This is the
    single unifying lesion of scrub typhus. Because the vascular bed is everywhere,
    one lesion expressed in different organs generates the entire severe phenotype,
    which is why respiratory, hepatic, cardiac, renal and neurological complications
    appear together rather than in sequence.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  downstream:
  - target: Multi-Organ Vascular Leak and End-Organ Dysfunction
    causal_link_type: DIRECT
    description: >-
      Loss of endothelial barrier function permits the capillary leak and tissue
      hypoperfusion that manifest as organ dysfunction.
  evidence:
  - reference: PMID:42126901
    reference_title: >-
      Eschars and estate fever: A case series from the Johorean oil palm heartland
      highlighting the changing face of scrub typhus in Malaysia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      rapidly progressive multiorgan dysfunction driven by smallvessel vasculitis,
      including pneumonitis, acute kidney injury, hepatitis, encephalitis and
      circulatory shock
    explanation: >-
      Names small-vessel vasculitis as the driver of the multi-organ syndrome and
      enumerates the organ manifestations that follow from it.

- name: Multi-Organ Vascular Leak and End-Organ Dysfunction
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Capillary leak and microvascular injury across multiple beds produce the severe
    end of the disease: pneumonitis and acute respiratory distress syndrome,
    hepatitis, myocarditis and circulatory shock, acute kidney injury, and
    meningoencephalitis. In the INTREST trial of severe scrub typhus - a hospitalised
    cohort selected for having at least one organ involved, so these proportions
    describe severe disease and are not population frequencies - complications were
    respiratory in 62%, hepatic in 54%, cardiovascular in 42%, renal in 30% and
    neurologic in 20% of patients.
  evidence:
  - reference: PMID:36856615
    reference_title: Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      complications included those that were respiratory (in 62%), hepatic (in 54%),
      cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%)
    explanation: >-
      Quantifies the organ-system distribution of severe scrub typhus in a
      794-patient randomised trial cohort, showing the simultaneous multi-organ
      pattern this node represents.
  - reference: PMID:40747630
    reference_title: Neurological complications of scrub typhus.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neurological complications, notably encephalitis and meningitis, have emerged as
      significant clinical manifestations, considerably affecting morbidity and
      mortality rates among affected individuals.
    explanation: >-
      Supports the neurological arm of the end-organ node and its contribution to
      mortality. Evidence source is OTHER as this is a review article.

- name: Orientia Ribosomal Translation (Tetracycline and Macrolide Target)
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome
  description: >-
    Like other bacteria, Orientia tsutsugamushi depends on translation of its mRNA by
    the 70S ribosome, and that ribosome is the target of every antibiotic with
    established activity in scrub typhus. Doxycycline binds the 30S subunit and blocks
    aminoacyl-tRNA delivery to the A site; azithromycin binds the 50S subunit and
    blocks nascent-chain elongation. The target is the ribosome and not the cell wall,
    which - together with the intracellular niche - is why a tetracycline or macrolide
    rather than a beta-lactam is used.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
  downstream:
  - target: Cytosolic Replication in an Obligate Intracellular Niche
    causal_link_type: DIRECT
    description: >-
      Bacterial protein synthesis sustains intracellular replication, so inhibiting
      translation arrests the replicating organism.
  evidence:
  - reference: PMID:24336183
    reference_title: Ribosome-targeting antibiotics and mechanisms of bacterial resistance.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The ribosome is one of the main antibiotic targets in the bacterial cell.
    explanation: >-
      Review establishing the bacterial ribosome as the target of tetracyclines and
      macrolides, the step this node represents. Evidence source is OTHER as this is a
      review article.
  - reference: PMID:36856615
    reference_title: Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we compared the efficacy of intravenous doxycycline, azithromycin, or a
      combination of both in treating severe scrub typhus
    explanation: >-
      Confirms that the agents used in scrub typhus are a tetracycline and a macrolide,
      both of which act on the bacterial ribosome represented by this node.

- name: Requirement for Cell-Penetrant Antimicrobials
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: intracellular_pathogen_persistence#Requirement for Cell-Penetrant Antimicrobials
  description: >-
    Because the organism replicates free in the host cytosol, effective therapy
    requires an antibiotic that crosses the host plasma membrane and accumulates
    intracellularly. Doxycycline and azithromycin do; beta-lactams do not reach the
    cytosolic organism regardless of dose. This is pharmacokinetic gating rather than
    a molecular target, and it operates alongside - not instead of - the ribosomal
    target node. The clinical urgency of the constraint follows from the multi-organ node,
    since untreated disease progresses to organ failure - but that is a statement about why
    the constraint matters, not a causal relationship, so it is recorded here rather than
    encoded as an edge.
  biological_processes:
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:18611821
    reference_title: Intracellular organisms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The intracellular location of some microorganisms allow them to resist
      antibiotics with poor ability to penetrate eukaryotic cell membranes, such as the
      beta-lactam compounds.
    explanation: >-
      States the gating principle this node represents: an intracellular niche excludes
      poorly cell-penetrant antibiotics. Evidence source is OTHER as this is a review
      article.

- name: Peptidoglycan-Poor Atypical Cell Envelope
  biological_scale: MOLECULAR
  role: modifier
  description: >-
    Orientia's envelope chemistry diverges sharply from that of the rickettsiae it was
    once classified with, and this divergence was the basis for erecting the genus
    Orientia. Chemical analysis found no detectable muramic acid, glucosamine, heptose
    or KDO and no lipopolysaccharide bands, concluding the organism has little or no
    peptidoglycan or LPS. A later structural study qualified this: it found evidence
    for a peptidoglycan-LIKE structure together with a cross-linked outer-membrane
    protein network that confers envelope stability. The two results are curated here
    together, unresolved, because the difference matters mechanistically - it
    determines whether beta-lactam inactivity in scrub typhus is target absence or
    only drug exclusion. See the `orientia-peptidoglycan-status` discussion; this entry
    deliberately does NOT declare conformance to
    `bacterial_cell_wall_synthesis_inhibition#Intrinsic Resistance in Cell-Wall-Deficient
    Organisms` while that question is open.
  downstream:
  - target: Requirement for Cell-Penetrant Antimicrobials
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Whatever the residual peptidoglycan status, the envelope offers no validated
      cell-wall target in this organism, leaving cell-penetrant ribosome-active agents
      as the therapeutic route.
  evidence:
  - reference: PMID:3114150
    reference_title: >-
      Deficiency of peptidoglycan and lipopolysaccharide components in Rickettsia
      tsutsugamushi.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It is concluded that R. tsutsugamushi has little or no peptidoglycan or
      lipopolysaccharide.
    explanation: >-
      The original chemical analysis concluding the organism lacks the classical
      Gram-negative envelope components, including the peptidoglycan that is the
      beta-lactam target.
  - reference: PMID:28513097
    reference_title: Evidence for a peptidoglycan-like structure in Orientia tsutsugamushi.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This bacterium was previously reported to completely lack peptidoglycan, but here
      we present evidence supporting the existence of a peptidoglycan-like structure in
      Orientia
    explanation: >-
      Directly qualifies the earlier conclusion by presenting structural evidence for a
      peptidoglycan-like layer. Recorded as PARTIAL because it supports an atypical,
      peptidoglycan-poor envelope while contradicting the stronger claim of complete
      absence.

phenotypes:
- category: Clinical
  name: Fever
  description: >-
    Acute fever is the presenting feature and the reason scrub typhus is a leading
    cause of undifferentiated febrile illness in endemic areas. Onset follows chigger
    attachment by roughly 8-10 days. No frequency band is asserted: the sources
    available here are a three-volunteer challenge study and a four-patient case
    series, neither of which supports a population estimate.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
    temporality: ACUTE
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these included fever, severe headache, myalgia, regional lymphadenopathy, and
      eschar
    explanation: >-
      Fever was part of the syndrome reproduced in deliberately infected human
      volunteers.

- category: Clinical
  name: Eschar
  frequency: OCCASIONAL
  description: >-
    A necrotic, black-crusted ulcer with an erythematous halo at the chigger
    attachment site. It is pathognomonic when present, but present in a minority of
    patients: a meta-analysis of 107 studies and 34,002 Indian cases pooled eschar
    positivity at 28.5% (95% CI 24.1-32.9%), which places it in the OCCASIONAL band.
    The band should be read as region-specific rather than global - the same
    meta-analysis found pooled positivity ranging from under 12% in some Indian states
    to 46% or more in others, and series from elsewhere in the endemic zone report
    higher rates still. Eschars concentrate on the trunk, groin and axilla, which is
    why they are missed without deliberate examination of covered areas.
  phenotype_term:
    preferred_term: Eschar
    term:
      id: HP:6000793
      label: Eschar
  evidence:
  - reference: PMID:39282546
    reference_title: >-
      Frequency and distribution of eschar in patients with scrub typhus in India:
      systematic review of literature and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall pooled proportion of eschar positivity was 28.5% (95% CI: 24.1 to
      32.9%).
    explanation: >-
      Pooled proportion across 34,002 cases; 28.5% falls in the OCCASIONAL band (5-29%)
      and is the quantitative basis for the frequency asserted here.
  - reference: PMID:39282546
    reference_title: >-
      Frequency and distribution of eschar in patients with scrub typhus in India:
      systematic review of literature and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled proportion of eschar positivity in the 'trunk' (39.3%), 'groin'
      (23.8%), and 'axilla' (16.5%) was higher than in the 'limbs' (9.9%) and 'head'
      (11.3%).
    explanation: >-
      Documents the anatomical distribution that explains why the eschar is so often
      overlooked on routine examination.

- category: Clinical
  name: Headache
  description: >-
    Severe headache accompanies the febrile onset and is one of the features
    reproduced in human challenge infection.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
    severity: SEVERE
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these included fever, severe headache, myalgia, regional lymphadenopathy, and
      eschar
    explanation: >-
      Severe headache was among the signs produced by controlled chigger transmission
      in human volunteers.

- category: Clinical
  name: Myalgia
  description: >-
    Diffuse muscle pain is part of the early nonspecific syndrome that makes scrub
    typhus difficult to distinguish clinically from dengue and other tropical febrile
    illnesses.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these included fever, severe headache, myalgia, regional lymphadenopathy, and
      eschar
    explanation: >-
      Myalgia was among the signs produced by controlled chigger transmission in human
      volunteers.

- category: Clinical
  name: Regional lymphadenopathy
  description: >-
    Enlargement of the lymph nodes draining the eschar, reflecting lymphatic spread
    from the inoculation site; generalised lymphadenopathy may follow dissemination.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these included fever, severe headache, myalgia, regional lymphadenopathy, and
      eschar
    explanation: >-
      Regional lymphadenopathy in the basin draining the eschar was reproduced in human
      volunteer infection, supporting lymphatic spread from the inoculation site.

- category: Clinical
  name: Maculopapular rash
  description: >-
    A transient generalised maculopapular eruption appearing a few days after fever
    onset, typically beginning on the trunk. It is inconstant and short-lived, which
    limits its diagnostic value.
  phenotype_term:
    preferred_term: Maculopapular exanthema
    term:
      id: HP:0040186
      label: Maculopapular exanthema
    temporality: TRANSIENT
  evidence:
  - reference: PMID:6808205
    reference_title: Transmission of scrub typhus to human volunteers by laboratory-reared chiggers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two L. fletcheri subjects developed a transient generalized rash on days 3-4
      after the onset of fever
    explanation: >-
      Documents the rash, its transient character, and its timing relative to fever
      onset in controlled human infection.

- category: Laboratory
  name: Elevated hepatic transaminases
  description: >-
    Transaminitis reflects the hepatic arm of the disseminated vasculitic lesion and is
    among the commonest laboratory abnormalities; hepatic complications occurred in 54%
    of patients in a severe-disease trial cohort.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:42126901
    reference_title: >-
      Eschars and estate fever: A case series from the Johorean oil palm heartland
      highlighting the changing face of scrub typhus in Malaysia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia and acute kidney injury occurred in 50%, while 75% demonstrated
      transaminitis.
    explanation: >-
      Reports transaminitis as the commonest laboratory abnormality in a confirmed
      scrub typhus case series.

- category: Laboratory
  name: Thrombocytopenia
  description: >-
    Platelet consumption and marrow suppression accompany the systemic infection;
    thrombocytopenia is one of the features that leads to scrub typhus being mistaken
    for dengue in co-endemic areas.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:42126901
    reference_title: >-
      Eschars and estate fever: A case series from the Johorean oil palm heartland
      highlighting the changing face of scrub typhus in Malaysia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia and acute kidney injury occurred in 50%, while 75% demonstrated
      transaminitis.
    explanation: >-
      Reports thrombocytopenia in half of a confirmed scrub typhus case series.

- category: Clinical
  name: Acute kidney injury
  description: >-
    Renal involvement follows microvascular injury and hypoperfusion; renal
    complications were present in 30% of patients in a randomised trial cohort of
    severe scrub typhus.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
    temporality: ACUTE
  evidence:
  - reference: PMID:36856615
    reference_title: Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      complications included those that were respiratory (in 62%), hepatic (in 54%),
      cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%)
    explanation: >-
      Quantifies renal involvement in a 794-patient severe scrub typhus trial cohort.
      No frequency band is asserted because the cohort was selected for severity.

- category: Clinical
  name: Acute respiratory distress syndrome
  description: >-
    Pulmonary capillary leak produces interstitial pneumonitis progressing to ARDS, the
    commonest organ complication of severe scrub typhus and a major contributor to
    mortality; respiratory complications affected 62% of a severe-disease trial cohort.
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
    temporality: ACUTE
  evidence:
  - reference: PMID:36856615
    reference_title: Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      complications included those that were respiratory (in 62%), hepatic (in 54%),
      cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%)
    explanation: >-
      Respiratory complications were the most frequent organ involvement in the
      severe-disease trial cohort. No frequency band is asserted because the cohort was
      selected for severity.

- category: Clinical
  name: Meningoencephalitis
  description: >-
    Central nervous system involvement presents as encephalitis or meningitis and is a
    recognised cause of acute encephalitis syndrome in endemic areas. Neurologic
    complications affected 20% of a severe-disease trial cohort and contribute
    substantially to morbidity and mortality.
  phenotype_term:
    preferred_term: Bacterial encephalitis
    term:
      id: HP:0034387
      label: Bacterial encephalitis
    temporality: ACUTE
  evidence:
  - reference: PMID:40747630
    reference_title: Neurological complications of scrub typhus.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neurological complications, notably encephalitis and meningitis, have emerged as
      significant clinical manifestations, considerably affecting morbidity and
      mortality rates among affected individuals.
    explanation: >-
      Establishes encephalitis and meningitis as significant manifestations affecting
      outcome. Evidence source is OTHER as this is a review article.

- category: Clinical
  name: Meningitis
  description: >-
    Meningeal inflammation, typically with a lymphocytic cerebrospinal fluid picture,
    occurring alone or with encephalitis as part of the CNS arm of the vasculitic
    lesion.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:40747630
    reference_title: Neurological complications of scrub typhus.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neurological complications, notably encephalitis and meningitis, have emerged as
      significant clinical manifestations, considerably affecting morbidity and
      mortality rates among affected individuals.
    explanation: >-
      Names meningitis alongside encephalitis as a significant neurological
      manifestation. Evidence source is OTHER as this is a review article.

- category: Clinical
  name: Circulatory shock
  description: >-
    Distributive and cardiogenic shock at the severe end of the spectrum, arising from
    capillary leak, myocardial involvement and systemic inflammation; cardiovascular
    complications affected 42% of a severe-disease trial cohort.
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
    temporality: ACUTE
  evidence:
  - reference: PMID:42126901
    reference_title: >-
      Eschars and estate fever: A case series from the Johorean oil palm heartland
      highlighting the changing face of scrub typhus in Malaysia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      rapidly progressive multiorgan dysfunction driven by smallvessel vasculitis,
      including pneumonitis, acute kidney injury, hepatitis, encephalitis and
      circulatory shock
    explanation: >-
      Lists circulatory shock among the multiorgan manifestations driven by the
      small-vessel vasculitis.

- category: Clinical
  name: Hepatomegaly
  frequency: FREQUENT
  description: >-
    Liver enlargement, the commonest liver-related finding at 46% pooled prevalence and the
    clinical counterpart of the hepatic arm of the disseminated vasculitis. Hepatic symptoms
    overall pool at 44%. These are meta-analytic prevalences across the Indian literature
    rather than severity-selected cohort figures, so they support a frequency band directly.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      O. tsutsugamushi parasite invades the hepatocyte cells, leading to hepatic symptoms like
      hepatomegaly and hepatic dysfunction, with an overall pooled prevalence rate of 44%
      (figure 6). Hepatomegaly was the most common liver-related symptom (46%)
    explanation: >-
      Pooled prevalence of 46% for hepatomegaly across a systematic review places it in the
      FREQUENT band (30-79%) and is the quantitative basis for the band asserted here.

- category: Clinical
  name: Splenomegaly
  frequency: FREQUENT
  description: >-
    Splenic involvement at 34% pooled prevalence, part of the reticuloendothelial response to
    disseminated infection. Hepatosplenomegaly together with fever and thrombocytopenia is a
    recognised presenting pattern, including in neonates.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inflammation (31%) in scrub typhus affects the spleen (34%), lymph nodes (33%), meninges
      (24%) and pancreas (6%)
    explanation: >-
      Pooled prevalence of 34% for splenic involvement places it in the FREQUENT band (30-79%).

- category: Clinical
  name: Nausea
  frequency: FREQUENT
  description: >-
    Nausea at 43% pooled prevalence, part of the gastrointestinal symptom cluster that
    contributes to scrub typhus being mistaken for other tropical febrile illnesses.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%),
      abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other
      gastric abnormalities (43%)
    explanation: >-
      Pooled prevalence of 43% for nausea places it in the FREQUENT band (30-79%).

- category: Clinical
  name: Vomiting
  frequency: FREQUENT
  description: >-
    Vomiting at 35% pooled prevalence, part of the gastrointestinal symptom cluster.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%),
      abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other
      gastric abnormalities (43%)
    explanation: >-
      Pooled prevalence of 35% for vomiting places it in the FREQUENT band (30-79%).

- category: Clinical
  name: Abdominal pain
  frequency: OCCASIONAL
  description: >-
    Abdominal pain at 26% pooled prevalence.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%),
      abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other
      gastric abnormalities (43%)
    explanation: >-
      Pooled prevalence of 26% for abdominal pain places it in the OCCASIONAL band (5-29%).

- category: Clinical
  name: Diarrhea
  frequency: OCCASIONAL
  description: >-
    Diarrhoea at 11% pooled prevalence - notably the least common of the gastrointestinal
    features, which is worth recording because it distinguishes the pattern from enteric fever.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%),
      abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other
      gastric abnormalities (43%)
    explanation: >-
      Pooled prevalence of 11% for diarrhoea places it in the OCCASIONAL band (5-29%).

- category: Clinical
  name: Jaundice
  frequency: OCCASIONAL
  description: >-
    Jaundice or icterus at 18% pooled prevalence, reflecting hepatic involvement severe enough
    to impair bilirubin handling.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal symptoms noted were nausea (43%), diarrhoea (11%), vomiting (35%),
      abdominal pain (26%), jaundice/icterus (18%), gastrointestinal bleeding (15%) and other
      gastric abnormalities (43%)
    explanation: >-
      Pooled prevalence of 18% for jaundice/icterus places it in the OCCASIONAL band (5-29%).

- category: Clinical
  name: Cough
  frequency: FREQUENT
  description: >-
    Cough at 34% pooled prevalence, within an overall pulmonary symptom prevalence of 35%.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary symptoms (35%) include cough and sore throat (34%), breathing problems like
      tachypnoea and dyspnoea (37%), crepitations (26%) and haemoptysis
    explanation: >-
      Pooled prevalence of 34% for cough and sore throat places it in the FREQUENT band (30-79%).

- category: Clinical
  name: Dyspnea
  frequency: FREQUENT
  description: >-
    Breathlessness and tachypnoea at 37% pooled prevalence, the symptomatic expression of the
    pulmonary capillary leak that at its severe end becomes ARDS.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary symptoms (35%) include cough and sore throat (34%), breathing problems like
      tachypnoea and dyspnoea (37%), crepitations (26%) and haemoptysis
    explanation: >-
      Pooled prevalence of 37% for tachypnoea and dyspnoea places it in the FREQUENT band (30-79%).

- category: Clinical
  name: Tachycardia
  frequency: FREQUENT
  description: >-
    Tachycardia at 65% pooled prevalence, the commonest cardiac-associated finding and largely a
    non-specific response to fever and vasodilation rather than evidence of myocardial injury.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac-associated symptoms (24%) included hypotension (22%) and tachycardia (65%) only,
      with cardiac complications such as myocarditis (4%), cardiac dysfunction (16%) and
      disseminated intravascular coagulation (7%) also reported in some studies
    explanation: >-
      Pooled prevalence of 65% for tachycardia places it in the FREQUENT band (30-79%).

- category: Clinical
  name: Hypotension
  frequency: OCCASIONAL
  description: >-
    Hypotension at 22% pooled prevalence. This is the population-representative figure; the
    circulatory shock recorded separately in this entry is the severe-disease endpoint.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac-associated symptoms (24%) included hypotension (22%) and tachycardia (65%) only,
      with cardiac complications such as myocarditis (4%), cardiac dysfunction (16%) and
      disseminated intravascular coagulation (7%) also reported in some studies
    explanation: >-
      Pooled prevalence of 22% for hypotension places it in the OCCASIONAL band (5-29%).

- category: Clinical
  name: Myocarditis
  frequency: VERY_RARE
  description: >-
    Myocarditis at only 4% pooled prevalence, with cardiac dysfunction at 16%. This is the
    important number to band from: the 42% cardiovascular figure quoted elsewhere in this entry
    comes from a trial cohort selected for severe disease with organ involvement, and using it
    as a population frequency would overstate cardiac involvement roughly tenfold. Recording
    both, with their provenance, is the point.
  phenotype_term:
    preferred_term: Myocarditis
    term:
      id: HP:0012819
      label: Myocarditis
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac-associated symptoms (24%) included hypotension (22%) and tachycardia (65%) only,
      with cardiac complications such as myocarditis (4%), cardiac dysfunction (16%) and
      disseminated intravascular coagulation (7%) also reported in some studies
    explanation: >-
      Pooled prevalence of 4% for myocarditis across a systematic review places it in the
      VERY_RARE band (<5%), in deliberate contrast with the 42% cardiovascular complication
      rate of the severity-selected INTREST cohort.

prevalence:
- population: India (pooled published case reports and series, 2003-2023)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    A systematic review of two decades of Indian literature accumulated 47,650
    reported cases with a 5% case-fatality rate across the 35,243 cases for which
    outcome was evaluable, and found infections rising since 2010. This is a count of
    cases appearing in the literature, not a rate against a population denominator, so
    no prevalence class or normalised rate is asserted.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The case fatality rate was 5% out of 35 243 cases.
    explanation: >-
      Pooled case-fatality across the Indian literature. Recorded as a literature case
      count rather than a population prevalence because the review has no denominator.
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub
      typhus in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there has been a notable increase in infections since 2010, peaking in 2019 and
      2022
    explanation: >-
      Documents the rising trend in reported scrub typhus in India over the review
      window.
- population: Asia-Pacific region (population at risk)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    More than one billion people live in the Asia-Pacific area where scrub typhus is
    endemic. This is a population-at-risk figure, not an occurrence measure, and is
    recorded here only to scale the public-health importance of the disease.
  evidence:
  - reference: PMID:36339235
    reference_title: >-
      How meteorological factors impacting on scrub typhus incidences in the main
      epidemic areas of 10 provinces, China, 2006-2018.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scrub typhus, caused by Orientia tsutsugamushi, is a serious public health
      problem in the Asia-Pacific region, threatening the health of more than one
      billion people.
    explanation: >-
      Supports the scale of the at-risk population. Explicitly not curated as a
      prevalence or incidence measure.

environmental:
- name: Agricultural and forest-dependent occupational exposure to chigger habitat
  description: >-
    Scrub typhus is fundamentally an exposure disease: risk is set by contact with the
    vegetation where infected Leptotrombidium larvae wait for a host. Agricultural practice
    and work in or near forested land are the dominant behavioural determinants, and Indian
    states with agricultural and forest-dependent lifestyles show correspondingly high
    prevalence. This is why the disease clusters occupationally and seasonally rather than
    person-to-person - there is no human-to-human transmission at all.
  exposure_term:
    preferred_term: occupational exposure to chigger-infested vegetation through agricultural
      and forest work
  notes: >-
    Deliberately left unbound to an ontology term. ECTO was searched for arthropod-vector,
    agricultural and occupational exposure concepts and no adequate match was found; per the
    project rule that no term beats a bad one, a free-text preferred_term is retained rather
    than forcing an approximate CURIE.
  influences_mechanisms:
  - target: Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Entering chigger habitat is the route by which a larval mite reaches human skin and
      inoculates the organism; without that contact the initiating event cannot occur.
    evidence:
    - reference: PMID:40754340
      reference_title: >-
        Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
        in India: a systematic review and meta-analysis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioural aspects of human activities that are linked to the danger of chigger
        infestation include agricultural practices and exposure to forested regions.
      explanation: >-
        Names agricultural practice and forest exposure as the behavioural determinants of
        chigger contact, which is the initiating event of this entry's pathograph.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      possibly due to agricultural and forest-dependent lifestyles, which increase exposure to
      vector habitats
    explanation: >-
      Links high regional prevalence to agricultural and forest-dependent lifestyles through
      increased vector-habitat exposure.

- name: Peridomestic exposure through firewood storage and livestock proximity
  description: >-
    Beyond occupational exposure, domestic living conditions that bring rodent and mite
    habitat up against the house - stored firewood, close proximity to livestock - are
    associated with moderate regional prevalence. This matters practically because it is the
    arm of exposure that is modifiable by household measures rather than by changing
    someone's occupation.
  exposure_term:
    preferred_term: peridomestic exposure to chigger habitat through firewood storage and
      livestock proximity
  notes: >-
    Unbound for the same reason as the occupational exposure above; ECTO has no adequate
    peridomestic-vector-habitat concept.
  influences_mechanisms:
  - target: Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Peridomestic mite habitat raises the probability of chigger contact at home rather than
      at work, but the intermediate step - mite population density around the dwelling - is
      inferred rather than measured in the cited source.
    evidence:
    - reference: PMID:40754340
      reference_title: >-
        Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
        in India: a systematic review and meta-analysis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Moderate prevalence in Odisha-30%, Haryana-23% and Uttar Pradesh-16% links scrub typhus
        to living conditions such as firewood storage and proximity to livestock.
      explanation: >-
        Associates regional prevalence with specific peridomestic living conditions.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moderate prevalence in Odisha-30%, Haryana-23% and Uttar Pradesh-16% links scrub typhus
      to living conditions such as firewood storage and proximity to livestock.
    explanation: >-
      Documents the peridomestic exposure association at population level.

- name: Ecological amplification of mite populations by bamboo flowering
  description: >-
    Mass bamboo flowering is followed by a rodent population surge and a corresponding
    increase in chigger abundance, and has been invoked to explain outbreak surges in
    north-east India. It is an unusually clean illustration of how the disease's epidemiology
    is driven by vector ecology rather than by anything about human immunity.
  exposure_term:
    preferred_term: ecological amplification of Leptotrombidium mite populations following
      bamboo flowering
  notes: >-
    Unbound; ECTO has no concept for a vector-population ecological event of this kind.
  influences_mechanisms:
  - target: Chigger-Borne Dermal Inoculation of Orientia tsutsugamushi
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A larger infected-mite population raises the community-level probability of inoculation;
      the intermediate rodent-host amplification step is described in the source as a link
      rather than demonstrated.
    evidence:
    - reference: PMID:40754340
      reference_title: >-
        Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
        in India: a systematic review and meta-analysis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This surge may be linked to ecological changes like bamboo flowering, which boost mite
        populations.
      explanation: >-
        The source states the bamboo-flowering link as a possible explanation for a case surge.
        Recorded as PARTIAL because it is offered as a hypothesis rather than a demonstrated
        association.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This surge may be linked to ecological changes like bamboo flowering, which boost mite
      populations.
    explanation: >-
      Hedged in the source as a possible link, and recorded as PARTIAL for that reason.

diagnosis:
- name: Indirect immunofluorescence assay (reference standard serology)
  description: >-
    IFA for anti-Orientia antibodies is the CDC reference standard. Its practical problem is
    an availability inversion that shapes the whole diagnostic landscape of this disease: the
    reference test is rarely available in exactly the developing-country settings where scrub
    typhus is most prevalent. Paired acute and convalescent sera are needed for a definitive
    serological diagnosis, so IFA rarely informs the decision to treat.
  diagnosis_term:
    preferred_term: serology testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: >-
    Seroconversion or a fourfold rise in anti-Orientia tsutsugamushi antibody titre between
    paired acute and convalescent samples supports the diagnosis.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As per the Centre for Disease Control and Prevention, indirect immunofluorescence assay
      (IFA) is the reference standard, though it is rarely available in developing nations
      where prevalence is high.
    explanation: >-
      Establishes IFA as the reference standard and states the availability inversion that
      limits its practical use.

- name: Immunochromatographic rapid antibody tests
  description: >-
    Rapid ICTs using pooled Orientia cell lysates or recombinant p56 outer-membrane protein as
    antigen detect IgG, IgM and IgA with better sensitivity and specificity than IFA in field
    conditions and may eventually replace it. Sensitivity is only moderate at around 70% and
    rises with fever duration, so a negative test early in illness carries a substantial
    false-negative rate - which is precisely when the treatment decision has to be made.
  diagnosis_term:
    preferred_term: serology testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: >-
    Detection of IgM, IgG or IgA against O. tsutsugamushi supports the diagnosis; a negative
    result early in the febrile course does not exclude it.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ICTs detect IgG, IgM and IgA antibodies against O. tsutsugamushi with moderate
      sensitivity (~70%). Sensitivity increases with fever duration but has a substantial
      number of false negative results.
    explanation: >-
      Quantifies ICT sensitivity and states the time-dependence and false-negative rate that
      bound its clinical use.

- name: PCR detection of Orientia tsutsugamushi DNA
  description: >-
    PCR assays usually target outer-membrane-protein genes and may be more sensitive than
    serology, detecting Orientia DNA in blood even during persistent phases of infection
    without obvious clinical symptoms. PCR is best early, during the rickettsaemic phase that
    precedes seroconversion, which makes it complementary to serology rather than an
    alternative to it. It accounted for only 4.6% of diagnoses in the reviewed Indian
    literature.
  diagnosis_term:
    preferred_term: molecular diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    Detection of O. tsutsugamushi DNA, commonly by amplification of the 56-kDa type-specific
    antigen gene, confirms infection.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PCRs usually target the genes of outer membrane proteins. They may be more sensitive
      than serological tests detecting Orientia DNA in blood even during persistent phases of
      infection with no obvious clinical symptoms.
    explanation: >-
      Establishes the molecular target and the sensitivity advantage of PCR over serology.
  - reference: PMID:27645781
    reference_title: Comparison of Preferred Bite Sites Between Mites and Ticks on Humans in Korea.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      confirmed by indirect immunofluorescence assay or nested polymerase chain reaction on
      the 56-kDa type-specific antigen gene of Orientia tsutsugamushi
    explanation: >-
      Documents the 56-kDa type-specific antigen gene as the routine nested-PCR target, the
      same TSA56 gene that this entry models as the adhesin.

- name: Weil-Felix agglutination test
  description: >-
    An old, cheap OXK-antigen agglutination test with poor sensitivity of about 15% and
    specificity of about 96%, which is therefore not the preferred method. It is recorded here
    because of an implementation gap that is itself a finding: despite being the least reliable
    option, Weil-Felix was the primary diagnostic method in about 61% of cases across two
    decades of Indian literature, while PCR accounted for 4.6%. Any epidemiological figure
    drawn from that literature inherits the misclassification of a 15%-sensitivity test, which
    is a reason to treat reported case counts as underestimates.
  diagnosis_term:
    preferred_term: serology testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: >-
    Agglutination against Proteus OXK antigen; a positive result is suggestive but a negative
    result excludes very little given approximately 15% sensitivity.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While providing a cheap option for identifying rickettsial infections in resource-poor
      settings, the Weil-Felix agglutination test has poor sensitivity (~15%) and specificity
      (~96%) and is thus not preferred.
    explanation: >-
      Quantifies the poor performance of the Weil-Felix test and states that it is not the
      preferred method.
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary choice of diagnosis in the reviewed studies was the Weil-Felix test, based on
      ~61% of the cases
    explanation: >-
      Documents the implementation gap - the least reliable test was the most used - which is
      why reported case counts from this literature should be read as underestimates.

- name: Clinical recognition of the eschar
  description: >-
    Careful whole-body examination for an eschar remains a decisive bedside step because the
    lesion is pathognomonic when found. It is present in only a minority of patients and
    concentrates on the trunk, groin and axilla, so it is missed unless covered areas are
    deliberately examined; eliciting it by directed history and examination is associated with
    correct diagnosis at the first visit.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    A necrotic, black-crusted ulcer with an erythematous halo at a chigger attachment site is
    pathognomonic; its absence does not exclude the diagnosis.
  evidence:
  - reference: PMID:42160320
    reference_title: How rash and eschar came to clinical attention in scrub typhus and Japanese spotted fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In endemic settings, patients correctly diagnosed at the first visit to a participating
      site more often had rash and eschar brought to clinical attention in specific ways.
      Directed inquiry about skin symptoms and careful examination for eschar may help
      recognition in routine care.
    explanation: >-
      States the study's finding that deliberately eliciting rash and eschar is associated with
      correct diagnosis at the first visit, and the practice recommendation that follows.
  - reference: PMID:39282546
    reference_title: >-
      Frequency and distribution of eschar in patients with scrub typhus in India: systematic
      review of literature and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a need to create awareness amongst physicians of the need for thorough physical
      examination.
    explanation: >-
      States the practical conclusion that follows from eschars concentrating on covered body
      areas.

treatments:
- name: Doxycycline
  description: >-
    A tetracycline and the standard first-line agent for scrub typhus in adults and
    children. It satisfies both mechanistic constraints simultaneously: it binds the
    30S ribosomal subunit, which is the drug target in this organism, and it
    accumulates intracellularly, so it reaches an organism replicating free in the host
    cytosol. Because laboratory confirmation is usually retrospective, treatment is
    started empirically on clinical suspicion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Orientia Ribosomal Translation (Tetracycline and Macrolide Target)
    treatment_effect: INHIBITS
    description: >-
      Doxycycline binds the 30S ribosomal subunit and arrests bacterial protein
      synthesis, the molecular target that makes a tetracycline first-line.
  - target: Requirement for Cell-Penetrant Antimicrobials
    description: >-
      Doxycycline accumulates intracellularly and therefore reaches the cytosolic
      organism that beta-lactams cannot.
  evidence:
  - reference: PMID:36856615
    reference_title: Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we compared the efficacy of intravenous doxycycline, azithromycin, or a
      combination of both in treating severe scrub typhus
    explanation: >-
      Establishes doxycycline as one of the two standard agents evaluated in the
      definitive randomised trial of severe scrub typhus.
  - reference: PMID:42126901
    reference_title: >-
      Eschars and estate fever: A case series from the Johorean oil palm heartland
      highlighting the changing face of scrub typhus in Malaysia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients achieved clinical defervescence and symptomatic improvement within
      24-48 hours of doxycycline initiation, consistent with the characteristic brisk
      antimicrobial response.
    explanation: >-
      Documents the rapid defervescence on doxycycline that is characteristic of
      treated scrub typhus.

- name: Azithromycin
  description: >-
    A macrolide with efficacy equivalent to doxycycline in adults and in children, and
    the preferred agent in pregnancy where tetracyclines are avoided. It acts on the
    50S ribosomal subunit - a different site on the same target - and, like
    doxycycline, concentrates intracellularly.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Orientia Ribosomal Translation (Tetracycline and Macrolide Target)
    treatment_effect: INHIBITS
    description: >-
      Azithromycin binds the 50S ribosomal subunit and blocks nascent-chain elongation,
      acting on the same ribosomal target as doxycycline by a different mechanism.
  - target: Requirement for Cell-Penetrant Antimicrobials
    description: >-
      Azithromycin achieves high intracellular concentrations, satisfying the
      cell-penetration requirement imposed by the cytosolic niche.
  evidence:
  - reference: PMID:37773623
    reference_title: >-
      Open-labeled Randomized Controlled Trial on Efficacy of Azithromycin Versus
      Doxycycline in Pediatric Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AZ and DX had comparable rates of defervescence among children with scrub typhus.
    explanation: >-
      Randomised comparison establishing azithromycin as equivalent to doxycycline in
      paediatric scrub typhus.
  - reference: PMID:37773623
    reference_title: >-
      Open-labeled Randomized Controlled Trial on Efficacy of Azithromycin Versus
      Doxycycline in Pediatric Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Macrolides, especially azithromycin (AZ), have been found to be equally
      efficacious as DX for treating scrub typhus in adults.
    explanation: >-
      States the prior adult equivalence that motivates azithromycin as an alternative
      first-line agent.

- name: Combination intravenous doxycycline plus azithromycin for severe disease
  description: >-
    In severe scrub typhus with organ involvement, combining the two ribosome-active
    agents outperformed either alone. In a 794-patient double-blind randomised trial
    the composite outcome of death, persistent complications or persistent fever
    occurred in 33% with combination therapy versus 47% with doxycycline and 48% with
    azithromycin, with no difference between the two monotherapies and no excess of
    adverse events. This is the current evidence-based regimen for severe disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Orientia Ribosomal Translation (Tetracycline and Macrolide Target)
    treatment_effect: INHIBITS
    description: >-
      Both agents inhibit the same bacterial ribosome at different subunits, which is
      the mechanistic rationale for combining them.
  - target: Multi-Organ Vascular Leak and End-Organ Dysfunction
    description: >-
      Faster and more complete bacterial clearance limits progression of the
      vasculitic organ injury that defines severe disease.
  evidence:
  - reference: PMID:36856615
    reference_title: Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combination therapy with intravenous doxycycline and azithromycin was a better
      therapeutic option for the treatment of severe scrub typhus than monotherapy with
      either drug alone.
    explanation: >-
      The trial's primary conclusion, establishing combination therapy as superior in
      severe scrub typhus.
  - reference: PMID:36856615
    reference_title: Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The use of combination therapy resulted in a lower incidence of the composite
      primary outcome than the use of doxycycline (33% and 47%, respectively)
    explanation: >-
      Quantifies the benefit of combination therapy over doxycycline monotherapy on the
      composite primary outcome.

- name: Chloramphenicol
  description: >-
    The historical treatment for scrub typhus and still an option where the first-line agents
    cannot be used. Its role is now limited by toxicity in exactly the groups that most need an
    alternative: it is avoided in pregnancy and not prescribed to neonates. That constraint,
    together with the teratogenicity of tetracyclines in pregnancy and their effect on
    children's teeth, is what makes azithromycin the agent of choice in pregnancy rather than
    a mere alternative.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: chloramphenicol
      term:
        id: CHEBI:17698
        label: chloramphenicol
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Orientia Ribosomal Translation (Tetracycline and Macrolide Target)
    treatment_effect: INHIBITS
    description: >-
      Chloramphenicol binds the 50S ribosomal subunit and blocks peptidyl transferase, acting
      on the same bacterial ribosome as the first-line agents.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Historically, scrub typhus has been treated with chloramphenicol. However, its use in
      pregnant women and infants is fraught with complications, due to which it is avoided in
      pregnancy and not prescribed to neonates.
    explanation: >-
      Establishes chloramphenicol as an effective historical agent while stating the toxicity
      constraints that limit it. Recorded as PARTIAL because the same sentence both supports
      and restricts the treatment.
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the same time, tetracycline is contraindicated during pregnancy due to teratogenicity,
      and it can discolour children's teeth.
    explanation: >-
      Supplies the counterpart constraint on tetracyclines that jointly determines agent choice
      in pregnancy and childhood.

clinical_trials:
- name: NCT03083197
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >-
    The Scrub Typhus Antibiotic Resistance Trial (START): an open-label randomised
    comparison of 7 days of oral doxycycline, 3 days of oral doxycycline and 3 days of
    oral azithromycin in patients with acute scrub typhus, conducted in an area of
    reported antimicrobial resistance. It is the trial that directly addresses the
    reduced-susceptibility question recorded in the
    `orientia-doxycycline-susceptibility` discussion.
  target_phenotypes:
  - preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: clinicaltrials:NCT03083197
    reference_title: "The Scrub Typhus Antibiotic Resistance Trial (START) Comparing Doxycycline and Azithromycin Treatment Modalities in Areas of Reported Antimicrobial Resistance for Scrub Typhus"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary Objective: To evaluate the clinical and microbiological responses in
      scrub typhus patients to three oral treatment regimens: 7 days of doxycycline, 3
      days of doxycycline, and 3 days of azithromycin
    explanation: >-
      States the trial's objective, which is to compare the two ribosome-active
      first-line agents and duration in an area of reported resistance.

- name: NCT00351182
  phase: PHASE_III
  status: UNKNOWN
  description: >-
    A controlled trial of a 5-day course of telithromycin versus doxycycline for mild
    to moderate scrub typhus, motivated by the need for agents usable in pregnancy and
    childhood and active against strains with reduced doxycycline susceptibility.
    Telithromycin is a ketolide and therefore also acts on the bacterial ribosome.
  target_phenotypes:
  - preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: clinicaltrials:NCT00351182
    reference_title: "Phase 3 Study of Controlled Trial: 5-day Course of Telithromycin Versus Doxycycline for the Treatment of Mild to Moderate Scrub Typhus"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study was designed to prove the clinical usefulness of telithromycin by
      comparing it with doxycycline for treating mild or moderate scrub typhus.
    explanation: >-
      States the trial's design and comparator, supporting telithromycin as an
      investigational ribosome-active alternative.

- name: CTRI/2018/08/015159
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    INTREST (Intravenous Treatment for Scrub Typhus), the multicentre double-blind
    randomised controlled trial of intravenous doxycycline versus azithromycin versus
    both in severe scrub typhus, reported in PMID:36856615. It has no ClinicalTrials.gov
    record and is registered instead on the Clinical Trials Registry - India, so it is
    keyed on its WHO ICTRP identifier.
  evidence:
  - reference: ICTRP:CTRI/2018/08/015159
    reference_title: "Optimal treatment for a potentially life threatening infection called scrub typhus"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Public title: Optimal treatment for a potentially life threatening infection
      called scrub typhus
    explanation: >-
      WHO ICTRP registration record establishing the trial's identity and registry of
      record. Evidence source is OTHER because a registration document is not itself
      study evidence.

- name: NCT06675110
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >-
    QuEST - Quick and Easy Scrub Typhus diagnostic tools. Evaluates insulated isothermal PCR
    (iiPCR) for direct detection of Orientia tsutsugamushi in Chiang Rai Province, Thailand.
    It targets precisely the gap this entry's `diagnosis:` section documents: a
    field-deployable molecular test able to detect the organism during the early rickettsaemic
    window, in the resource-limited settings where the IFA reference standard is unavailable
    and the low-sensitivity Weil-Felix test is still the commonest method used.
  target_phenotypes:
  - preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: clinicaltrials:NCT06675110
    reference_title: "Diagnostic Tools for the Direct Detection of Orientia Tsutsugamushi"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Evaluate the performance of insulated isothermal polymerase chain reaction (iiPCR) in the
      diagnosis of scrub typhus in Chiang Rai Province
    explanation: >-
      States the trial's objective, which is direct molecular detection of the organism in a
      field setting.

discussions:
- discussion_id: orientia-peptidoglycan-status
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Peptidoglycan-Poor Atypical Cell Envelope
  - pathophysiology#Requirement for Cell-Penetrant Antimicrobials
  prompt: >-
    Does Orientia tsutsugamushi possess a peptidoglycan layer capable of serving as a
    beta-lactam target? The 1987 chemical analysis that underpinned the reclassification
    out of Rickettsia found no detectable muramic acid or glucosamine and concluded the
    organism has little or no peptidoglycan; a 2017 structural study reported evidence
    for a peptidoglycan-like structure alongside a cross-linked outer-membrane protein
    network. The two results have not been reconciled.
  rationale: >-
    The answer determines how beta-lactam inactivity in scrub typhus should be modelled.
    If peptidoglycan is genuinely absent, the correct model is target absence and this
    entry should conform to
    `bacterial_cell_wall_synthesis_inhibition#Intrinsic Resistance in Cell-Wall-Deficient
    Organisms` alongside the Mollicutes. If a functional peptidoglycan-like layer exists,
    the exclusion of beta-lactams is purely pharmacokinetic - they cannot reach a
    cytosolic organism - and belongs entirely to
    `intracellular_pathogen_persistence`. This entry currently declares only the latter,
    because asserting target absence on contested evidence would be the stronger and
    less defensible claim. The distinction is not merely taxonomic: it bears on whether
    any cell-wall-active agent could ever be made to work if delivery were solved.
  proposed_experiments:
  - experiment_id: orientia-pg-muropeptide-analysis
    name: Direct muropeptide analysis of purified Orientia
    description: >-
      Apply quantitative muropeptide profiling (LC-MS of mutanolysin digests) and
      D-amino-acid metabolic labelling to highly purified Orientia tsutsugamushi from
      several strains, with Chlamydia and a Mollicute as positive and negative controls,
      to determine whether cross-linked peptidoglycan is present and at what abundance.
    readouts:
    - name: Cross-linked muropeptide abundance
      target: pathophysiology#Peptidoglycan-Poor Atypical Cell Envelope
    would_support:
    - pathophysiology#Peptidoglycan-Poor Atypical Cell Envelope

- discussion_id: orientia-doxycycline-susceptibility
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Orientia Ribosomal Translation (Tetracycline and Macrolide Target)
  prompt: >-
    Do clinically significant doxycycline-resistant strains of Orientia tsutsugamushi
    exist, and if so what is the molecular basis? Poor clinical response to doxycycline
    has been reported from parts of northern Thailand and has motivated dedicated
    trials, but the organism is genetically intractable and cannot be susceptibility
    tested by routine methods, so the phenotype has not been tied to a ribosomal target
    mutation, an efflux mechanism, or to host and pharmacokinetic factors instead.
  rationale: >-
    The module `bacterial_protein_synthesis_inhibition` models ribosomal target
    resistance as a distinct node, and whether scrub typhus conforms to it is currently
    unanswerable. Because every agent with established activity in scrub typhus acts on
    the same ribosome, a true target-level resistance mechanism would threaten the entire
    therapeutic repertoire at once, which is why the question matters more here than in
    infections with several independent drug targets. Until it is resolved this entry
    does not curate a resistance node.
  proposed_experiments:
  - experiment_id: orientia-resistance-genotype-phenotype
    name: Genotype-phenotype study of poor doxycycline responders
    description: >-
      Couple a prospective treatment-response cohort in a reported low-response area with
      whole-genome sequencing of infecting strains and measurement of plasma and
      intracellular doxycycline exposure, to separate ribosomal or efflux-mediated
      bacterial resistance from inadequate drug exposure.
    readouts:
    - name: Association of ribosomal or efflux variants with delayed defervescence
      target: pathophysiology#Orientia Ribosomal Translation (Tetracycline and Macrolide Target)
    would_support:
    - pathophysiology#Orientia Ribosomal Translation (Tetracycline and Macrolide Target)

- discussion_id: scrub-typhus-neuroinflammation-model-fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response
  - pathophysiology#Multi-Organ Vascular Leak and End-Organ Dysfunction
  prompt: >-
    The mechanistic account of scrub typhus neuroinflammation - excessive interferon
    responses, microglial activation and blood-brain-barrier disruption - rests on brain
    RNA-seq and immunostaining in a murine model of severe infection. Do these pathways
    operate the same way in human scrub typhus encephalitis, where the CNS is rarely
    sampled?
  rationale: >-
    Evidence for the CNS arm exists and is internally coherent, but it is predominantly
    murine, so its translational validity rather than its existence is the open question
    - which is what distinguishes this from a plain knowledge gap. The monocyte arm of
    this entry is anchored partly in patient mononuclear cells and so is on firmer human
    ground; the brain-specific mechanism is not. Human CNS validation matters because
    interferon-directed or barrier-directed adjunctive therapy would be prescribed on the
    strength of exactly these pathways.
  evidence:
  - reference: PMID:37426673
    reference_title: >-
      Brain transcriptomics reveal the activation of neuroinflammation pathways during
      acute Orientia tsutsugamushi infection in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This study provides new insights into neuroinflammation in scrub typhus,
      highlighting the impact of excessive IFN responses, microglial activation, and BBB
      dysregulation on disease pathogenesis.
    explanation: >-
      The murine brain RNA-seq study that is the source of the interferon, microglial
      and blood-brain-barrier mechanism whose human validity this discussion questions.
      Evidence source is MODEL_ORGANISM, which is precisely the mismatch at issue.
  - reference: PMID:37426673
    reference_title: >-
      Brain transcriptomics reveal the activation of neuroinflammation pathways during
      acute Orientia tsutsugamushi infection in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By using a well-established murine model of severe scrub typhus and brain RNA-seq,
      we studied the brain transcriptome dynamics and identified the activated
      neuroinflammation pathways.
    explanation: >-
      States explicitly that the evidence base for this mechanism is a murine model and
      mouse brain transcriptomics, establishing the model-to-human gap.
  proposed_experiments:
  - experiment_id: scrub-typhus-human-csf-validation
    name: Human CSF and neuroimaging validation of the murine neuroinflammation programme
    description: >-
      In patients with scrub typhus-associated acute encephalitis syndrome, measure CSF
      interferon-stimulated protein signatures, microglial activation markers and
      barrier-integrity indices, and compare the pattern against the murine brain
      transcriptome programme.
    readouts:
    - name: Concordance of human CSF interferon and barrier markers with the murine programme
      target: pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response
    would_support:
    - pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response

- discussion_id: orientia-strain-variation
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#TSA56-Fibronectin Binding and Integrin-Mediated Host Cell Entry
  - pathophysiology#Eschar Formation at the Inoculation Site
  - pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response
  prompt: >-
    Orientia tsutsugamushi is antigenically extremely diverse - Karp-like, Kato-like,
    Gilliam-like and JG-like strains circulate in different proportions across India alone, and
    the diversity is defined by the very TSA56 protein this entry models as the adhesin. Two
    strain-dependent observations are unexplained: it is postulated that some strains produce
    eschars less commonly than other antigenic types, and dual RNA-seq of two clinical isolates
    found them driving divergent host programmes, with the Karp strain associated with
    IL33-linked responses and UT176 with IL6-mediated inflammation, differences that tracked
    relative virulence in mice. Does strain genotype determine eschar formation, host
    inflammatory programme, and severity in humans?
  rationale: >-
    This bears directly on three curated nodes. If TSA56 variation alters adhesion or entry,
    that is a property of this entry's molecular node, not a bystander observation. If it
    determines whether an eschar forms, then eschar frequency is not a single number at all -
    which would explain the wide geographic variation this entry already records (under 12% to
    over 46% between Indian states) as strain composition rather than examination technique,
    and would change how the diagnostic sign should be weighted regionally. And if strains
    drive different cytokine programmes, the interferon/M1 node is strain-conditioned rather
    than uniform. The practical obstacle is that most surveillance genotyping is done on the
    same TSA56 gene used for diagnosis, so genotype and detection are not independent.
  evidence:
  - reference: PMID:40754340
    reference_title: >-
      Spatiotemporal epidemiology and clinical manifestations of two decades of scrub typhus
      in India: a systematic review and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is postulated that some strains produce eschars less commonly than other antigenic
      types.
    explanation: >-
      The eschar-strain link is stated as a postulate rather than a finding, which is the gap.
      Recorded as PARTIAL for that reason.
  - reference: PMID:32620750
    reference_title: >-
      Dual RNA-seq of Orientia tsutsugamushi informs on host-pathogen interactions for this
      neglected intracellular human pathogen.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Comparing the host response to two clinical isolates, we identify distinct immune
      response networks for each strain, leading to predictions of relative virulence that are
      validated in a mouse infection model.
    explanation: >-
      Establishes that different clinical isolates drive distinct host immune programmes with
      differing virulence. Evidence source is MODEL_ORGANISM because the virulence prediction
      was validated in mice.
  proposed_experiments:
  - experiment_id: orientia-genotype-phenotype-cohort
    name: Strain genotype versus eschar, cytokine programme and severity
    description: >-
      A prospective multi-site cohort in regions with differing circulating genotypes, in which
      infecting strain is typed by whole-genome sequencing rather than TSA56 alone, and
      correlated with eschar presence, host cytokine profile and severity - separating strain
      effects from examination technique and from host factors.
    readouts:
    - name: Eschar presence and host cytokine programme by infecting strain genotype
      target: pathophysiology#Eschar Formation at the Inoculation Site
    would_support:
    - pathophysiology#Eschar Formation at the Inoculation Site
    - pathophysiology#Type I Interferon-Driven M1 Monocyte Polarisation and Cytokine Response

notes: >-
  Pathograph edge semantics. Two edges were removed in review because they encoded clinical
  motivation rather than causation, which would export to KGX/cx2 as false causal assertions:
  eschar formation to multi-organ dysfunction (the eschar marks where disease began, it does
  not cause organ failure - its own description had conceded as much), and multi-organ
  dysfunction to the cell-penetrant-drug requirement (organ failure makes therapy urgent, it
  does not create the pharmacokinetic constraint). Both rationales are retained in the
  relevant node descriptions. All 13 nodes remain connected.

  The graph deliberately has four directed roots rather than one. Besides the trigger, the
  Ank13 effector, the bacterial ribosome and the bacterial envelope have no incoming edge
  because they are properties of the organism rather than consequences of the disease
  process - nothing in a human pathograph causes a bacterium to have a ribosome. That is a
  different situation from an orphaned host node and is intentional.

  Frequency discipline. Bands in this entry come only from pooled meta-analytic proportions,
  never from severity-selected cohorts. Eschar is banded from a 34,002-case eschar-specific
  meta-analysis; thirteen further phenotypes are banded from the pooled prevalences of a
  systematic review of two decades of Indian literature. The INTREST organ-involvement
  percentages (respiratory 62%, hepatic 54%, cardiovascular 42%, renal 30%, neurologic 20%)
  are quoted in phenotype descriptions for their clinical value but are deliberately NOT
  mapped to FrequencyEnum, because that cohort was selected for severe disease with at least
  one organ involved.

  The cardiac phenotypes make the reason for that rule concrete. The severity-selected trial
  reports cardiovascular complications in 42% of patients; the population-representative
  systematic review reports myocarditis in 4%. Both numbers are curated, each labelled with
  its cohort, and the frequency band is taken from the population figure - so the entry
  records myocarditis as VERY_RARE while still carrying the severe-disease number in prose.
  Banding from the trial arm would have overstated cardiac involvement roughly tenfold.

  All banded percentages remain India-weighted, and several (eschar most clearly) vary
  substantially by region and possibly by circulating strain - see the
  `orientia-strain-variation` discussion.

  Module conformance: this entry conforms to both nodes of
  `intracellular_pathogen_persistence` and to the translation node of
  `bacterial_protein_synthesis_inhibition`, following the pattern established by
  `Murine_Typhus` and `Oroya_Fever`. It deliberately does NOT conform to
  `bacterial_cell_wall_synthesis_inhibition#Intrinsic Resistance in Cell-Wall-Deficient
  Organisms` despite the classic report that Orientia lacks peptidoglycan, because that
  finding is contested by later structural work - see the `orientia-peptidoglycan-status`
  discussion.

  Orphanet: ORPHA:83317 is the Orphanet concept for scrub typhus and would be a natural
  additional evidence source for epidemiology and clinical description. It is not cited
  here because `just refresh-orphadata` currently fails with a drifted bulk-file sha256
  against the pinned manifest, so no fresh ORPHA cache entry could be produced.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Scrub Typhus: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 25 citations 2026-08-19T22:23:26.817577

Scrub Typhus: Comprehensive Disease-Characteristics Report

Executive summary

Scrub typhus is an acute, potentially fatal, mite-borne infection caused principally by the obligate intracellular bacterium Orientia tsutsugamushi. Humans are accidental dead-end hosts; larval trombiculid mites (“chiggers”), especially Leptotrombidium species, transmit infection, while small mammals—particularly rodents—support the enzootic cycle. Approximately 2 billion people live in at-risk regions and the commonly cited burden is about 1 million cases annually, although weak surveillance and non-standardized diagnostics make this estimate uncertain. The central lesion is disseminated infection of endothelial and mononuclear-phagocyte compartments, producing vasculitis-like endothelial dysfunction, capillary leak, inflammation, and potentially respiratory, hepatic, cardiovascular, renal, or neurologic failure. (lynnette2024scrubtyphusdiagnostics pages 1-2, adhikari2024editorialscrubtyphus pages 2-3, ravishankar2024rickettsialinfectionsprevalence pages 4-5)

The most consequential recent therapeutic development is the 2023 INTREST randomized trial: intravenous doxycycline plus azithromycin reduced a composite of death at day 28, persistent organ complications at day 7, or fever at day 5 to 33%, versus 47% with doxycycline and 48% with azithromycin alone. Mortality itself remained similar at 11–13%, so the benefit principally concerned earlier resolution of fever/organ complications rather than demonstrated survival benefit. (varghese2023intravenousdoxycyclineazithromycin pages 4-6, varghese2023intravenousdoxycyclineazithromycin pages 21-23, varghese2023intravenousdoxycyclineazithromycin pages 8-10)

The following table provides a knowledge-base-ready synopsis; details and evidentiary qualifications follow.

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	(lynnette2024scrubtyphusdiagnostics pages 1-2, adhikari2024editorialscrubtyphus pages 2-3, ravishankar2024rickettsialinfectionsprevalence pages 4-5)
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	(lynnette2024scrubtyphusdiagnostics pages 1-2, adhikari2024editorialscrubtyphus pages 2-3, ravishankar2024rickettsialinfectionsprevalence pages 4-5)
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	(ravishankar2024rickettsialinfectionsprevalence pages 4-5, chaturvedi2025spatiotemporalepidemiologyand pages 7-8, lynnette2024scrubtyphusdiagnostics pages 1-2, liang2023braintranscriptomicsreveal pages 1-2)
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	(vashishtha2025scrubtyphusupdate pages 6-7, chaturvedi2025spatiotemporalepidemiologyand pages 7-8, varghese2023intravenousdoxycyclineazithromycin pages 4-6, varghese2023intravenousdoxycyclineazithromycin pages 21-23)
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	(mikagospodorz2020dualrnaseqof pages 9-9, tantibhedhyangkul2011orientiatsutsugamushistimulates pages 1-2, liang2023braintranscriptomicsreveal pages 1-2, lynnette2024scrubtyphusdiagnostics pages 1-2)
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	(lynnette2024scrubtyphusdiagnostics pages 1-2, adhikari2024editorialscrubtyphus pages 2-3, chaturvedi2025spatiotemporalepidemiologyand pages 2-3, NCT06675110 chunk 1)
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	(varghese2023intravenousdoxycyclineazithromycin pages 4-6, varghese2023intravenousdoxycyclineazithromycin pages 21-23, varghese2023intravenousdoxycyclineazithromycin pages 6-8, varghese2023intravenousdoxycyclineazithromycin pages 8-10)
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	(lynnette2024scrubtyphusdiagnostics pages 1-2, chaturvedi2025spatiotemporalepidemiologyand pages 2-3, adhikari2024editorialscrubtyphus pages 2-3)
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	(vashishtha2025scrubtyphusupdate pages 11-12, varghese2023intravenousdoxycyclineazithromycin pages 4-6, varghese2023intravenousdoxycyclineazithromycin pages 21-23, ravishankar2024rickettsialinfectionsprevalence pages 7-8)
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	(vashishtha2025scrubtyphusupdate pages 11-12, adhikari2024editorialscrubtyphus pages 2-3, lynnette2024scrubtyphusdiagnostics pages 1-2)
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	(NCT02876367 chunk 1, lynnette2024scrubtyphusdiagnostics pages 1-2, ravishankar2024rickettsialinfectionsprevalence pages 4-5, liang2023braintranscriptomicsreveal pages 1-2)
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	(tantibhedhyangkul2011orientiatsutsugamushistimulates pages 1-2, NCT03083197 chunk 1)

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.

1. Disease information

Definition and names

Scrub typhus is an acute undifferentiated febrile illness caused mainly by O. tsutsugamushi. Synonyms include tsutsugamushi disease, tsutsugamushi fever, mite-borne typhus, and historically Japanese river fever. Despite its historical grouping with rickettsioses, the organism belongs to Orientia, not Rickettsia. A recent review describes it as a “vector-borne, zoonotic disease” that becomes diagnostically difficult when the characteristic eschar is absent. (lynnette2024scrubtyphusdiagnostics pages 1-2, chaturvedi2025spatiotemporalepidemiologyand pages 2-3)

Identifiers

ICD-10/ICD-10-CM: A75.3, Typhus fever due to Rickettsia tsutsugamushi; the legacy organism name persists in the label.
ICD-11: classified under rickettsioses/other specified rickettsioses; the exact browser code should be validated against the current ICD-11 release before ingestion.
MeSH: Scrub Typhus; entry terms include tsutsugamushi disease.
MONDO: a scrub-typhus concept exists, but the exact numerical MONDO identifier was not recoverable from the retrieved primary literature and should be resolved directly through the current MONDO release rather than inferred.
OMIM/Orphanet: no causal-disease entry is expected in the Mendelian-disease sense; this is an acquired infectious disease, not a monogenic disorder.

The evidence summarized here is aggregated disease-level evidence from reviews, cohorts, trials, and experimental studies—not patient-level EHR data.

2. Etiology, risk, and protective factors

Cause and transmission

The immediate cause is inoculation of Orientia by an infected chigger. The principal agent is O. tsutsugamushi, a gram-negative, non-motile, non-capsulated, pleomorphic obligate intracellular bacterium. More than 20 genotypes have been described in India alone, and antigenic/genomic diversity is a major obstacle to universal serodiagnostics and vaccines. (chaturvedi2025spatiotemporalepidemiologyand pages 2-3, ravishankar2024rickettsialinfectionsprevalence pages 4-5)

Chiggers acquire and maintain Orientia within mite populations; rodents and other small mammals serve as feeding hosts and ecological reservoirs. Humans do not ordinarily transmit infection onward. Risk is therefore ecological rather than hereditary: agricultural work, paddy cultivation, plantations, brush or scrub vegetation, contact with mite-infested soil, and residence or travel in endemic rural landscapes increase exposure. Temperature, humidity, rainfall, rodent suitability, and season influence transmission. (adhikari2024editorialscrubtyphus pages 2-3, ravishankar2024rickettsialinfectionsprevalence pages 4-5, NCT02876367 chunk 1)

Demographic and host risk

All ages can be affected. Exposure patterns often make farmers, field workers, military personnel, and rural residents overrepresented. Older age and comorbidity may worsen outcomes, but the retrieved evidence does not support a universal sex ratio. Pregnancy is clinically important because maternal infection can be severe and influences antibiotic selection.

Genetic risk and gene–environment interaction

There are no causal human genes, pathogenic germline variants, inheritance pattern, penetrance, carrier frequency, founder mutations, or chromosomal abnormalities. Limited candidate-gene literature has examined immune-response loci such as TLR2, TLR4, and HSP70, but the relevant primary article was not available in full text during this retrieval; these associations should not be treated as validated clinical susceptibility markers. Exposure to infected mites overwhelmingly dominates risk, and no host genotype is used for diagnosis, prognosis, or treatment selection.

Protective factors

Protection is primarily environmental and behavioral: avoiding mite habitats, using protective clothing and repellents, clearing vegetation around camps or dwellings, and prompt recognition and treatment. No reproducible protective human allele is established. Natural immunity is strain-limited and may be short-lived; antigenic heterogeneity limits cross-protection.

3. Phenotypes

The incubation period is usually 6–21 days. Disease begins acutely with fever, headache, myalgia, chills, malaise, and sometimes cough or gastrointestinal symptoms. In an India meta-analysis, fever/AUFI had a pooled prevalence of 97%, while headache, chills, myalgia, and arthralgia individually or collectively occurred in approximately 33–56%. (ravishankar2024rickettsialinfectionsprevalence pages 4-5, chaturvedi2025spatiotemporalepidemiologyand pages 7-8)

Principal phenotype annotations

Fever—acute, nearly universal, variable severity; suggested HPO: Fever.
Eschar—painless necrotic crust at the bite site, often hidden in axillae, groin, inframammary or genital regions. Pooled prevalence was about 26% in the India analysis, whereas reports range from 7–80% across populations. Absence does not exclude infection. Suggested HPO: Eschar or closest available necrotic-skin-lesion term. (vashishtha2025scrubtyphusupdate pages 6-7, chaturvedi2025spatiotemporalepidemiologyand pages 7-8)
Maculopapular rash—often appears near the end of week 1 and spreads from trunk to limbs; variably present. Suggested HPO: Maculopapular rash.
Regional lymphadenopathy—typically near the inoculation site; suggested HPO: Lymphadenopathy.
Hepatic disease—hepatomegaly 46% and hepatic dysfunction 44% in the cited meta-analysis; transaminase elevation and hyperbilirubinemia are common laboratory abnormalities. Suggested HPO: Hepatomegaly, Elevated hepatic transaminases, Hyperbilirubinemia. (chaturvedi2025spatiotemporalepidemiologyand pages 7-8)
Respiratory disease—interstitial pneumonitis, hypoxemia, pulmonary edema/capillary leak, and ARDS. Respiratory involvement occurred in 62% of the severe-disease trial population. Suggested HPO: Interstitial pulmonary disease, Hypoxemia, Acute respiratory distress syndrome. (varghese2023intravenousdoxycyclineazithromycin pages 4-6)
Cardiovascular disease—hypotension/shock, myocarditis, arrhythmia, heart failure, and occasionally myocardial infarction. Cardiovascular involvement occurred in 42% of severe trial participants. Suggested HPO: Hypotension, Myocarditis, Cardiac arrhythmia, Heart failure. (adhikari2024editorialscrubtyphus pages 2-3, varghese2023intravenousdoxycyclineazithromycin pages 4-6)
Renal disease—acute kidney injury from hypoperfusion, endothelial injury, inflammation, and multiorgan dysfunction; 30% in the severe trial. Suggested HPO: Acute kidney injury, Elevated serum creatinine. (varghese2023intravenousdoxycyclineazithromycin pages 4-6)
Neurologic disease—meningitis, meningoencephalitis, delirium, seizures, tremor, cerebellitis, hearing loss, or altered consciousness; 20% had neurologic involvement in the severe trial. Suggested HPO: Meningitis, Encephalitis, Seizure, Delirium, Tremor, Sensorineural hearing impairment. (vashishtha2025scrubtyphusupdate pages 6-7, varghese2023intravenousdoxycyclineazithromycin pages 4-6)
Hematologic abnormalities—thrombocytopenia and, in severe cases, coagulopathy; suggested HPO: Thrombocytopenia.

Phenotypes are acute and progressive when untreated rather than stable or lifelong. Quality-of-life studies using EQ-5D or SF-36 were not identified. During acute severe disease, ICU admission, ventilation, encephalopathy, and organ failure profoundly impair function; survivors treated promptly generally recover, although neurologic, auditory, renal, or cardiac sequelae may persist in a minority.

4. Genetic and molecular information

Human genetics

Classical disease-genetics fields are not applicable: no causal HGNC gene, OMIM gene, ACMG-classified pathogenic variant, germline/somatic distinction, allele frequency, modifier gene, chromosomal abnormality, or clinically actionable pharmacogenomic marker defines scrub typhus. WES, WGS, panels, CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing have no role in routine diagnosis.

Pathogen genomics

O. tsutsugamushi has an unusually repetitive, rearranged genome with poor strain-to-strain gene-order collinearity. Dual RNA-seq indicated that virulence differences between Karp and UT176 strains related substantially to differential expression, not simply gene presence or absence. The Karp strain induced an IL33–NOS3–FAS-associated anoikis program in endothelial cells, whereas UT176 produced a more IL6-dominant response. The experiment used a high multiplicity of infection (~30:1), limiting direct physiological extrapolation. (mikagospodorz2020dualrnaseqof pages 9-9)

The ongoing START trial incorporates whole-genome sequencing of isolates to relate genotype to clearance, relapse, and antimicrobial susceptibility—an example of pathogen precision medicine rather than inherited human genetics. (NCT03083197 chunk 1)

5. Environmental and infectious-agent information

The infectious agent is Orientia, transmitted through chigger-infested environments. Farming, scrub vegetation, forest edges, soil contact, rainfall, humidity, temperature, and rodent abundance shape risk. A One Health framework is therefore appropriate. Tobacco, alcohol, diet, and exercise are not established causal factors, although nutritional status and comorbidity could influence severity nonspecifically. (adhikari2024editorialscrubtyphus pages 2-3, ravishankar2024rickettsialinfectionsprevalence pages 4-5)

The traditional “tsutsugamushi triangle” extends broadly from northern Asia/Japan through South and Southeast Asia to northern Australia, but recent literature emphasizes transmission or Orientia-like organisms beyond this historical boundary. This changing geography may reflect improved detection, travel, land-use change, vector-range shifts, climate, and genuine emergence. (vashishtha2025scrubtyphusupdate pages 11-12, lynnette2024scrubtyphusdiagnostics pages 1-2, adhikari2024editorialscrubtyphus pages 2-3)

6. Mechanism and pathophysiology

Causal chain

Chigger bite → dermal inoculation and eschar → intracellular invasion/replication → lymphatic and hematogenous dissemination → endothelial and mononuclear-phagocyte infection → interferon- and cytokine-rich inflammation plus endothelial dysfunction → capillary leak, microvascular injury, tissue hypoxia, and organ-specific inflammation → pneumonitis/ARDS, hepatitis, myocarditis/shock, AKI, meningoencephalitis, or multiorgan failure.

Cells and pathways

Orientia preferentially infects endothelial cells, but dendritic cells, monocytes, and macrophages are also involved. Suggested Cell Ontology mappings are endothelial cell, monocyte, macrophage, dendritic cell, and microglial cell; suggested GO biological processes include response to bacterium, inflammatory response, type I interferon signaling, cytokine-mediated signaling, apoptotic process, leukocyte activation, and regulation of vascular permeability. (lynnette2024scrubtyphusdiagnostics pages 1-2, tantibhedhyangkul2011orientiatsutsugamushistimulates pages 1-2)

Human/in-vitro transcriptomics: Infection altered more than 4,500 genes in healthy-donor monocytes, upregulating type-I-interferon and interferon-stimulated genes, M1-polarization features, and apoptosis-related genes. Patient mononuclear cells showed 613 upregulated genes, including interferon-related signatures. The authors’ abstract concluded that “interferon-mediated activation of monocytes and their subsequent polarization into an M1 phenotype appear critical.” (tantibhedhyangkul2011orientiatsutsugamushistimulates pages 1-2)

Endothelial dual RNA-seq: Karp-infected HUVECs showed IL33 approximately 5.1 log-fold higher than UT176-infected cells and activation of IL33–NOS3–FAS-associated anoikis, while UT176 favored IL6-mediated inflammation. Mouse validation linked these strain-specific programs to relative virulence. (mikagospodorz2020dualrnaseqof pages 9-9)

Neuropathogenesis—mouse and in-vitro evidence: The 2023 brain RNA-seq study found enrichment of IFN responses, defense against bacteria, immunoglobulin-mediated immunity, IL-6/JAK–STAT, and TNF/NF-κB signaling, accompanied by blood–brain-barrier-disruption genes and activated, cytokine-producing microglia. Its abstract states that the work highlights “excessive IFN responses, microglial activation, and BBB dysregulation.” These results are mechanistically persuasive but remain predominantly murine and require human CNS validation. (liang2023braintranscriptomicsreveal pages 1-2)

No consistent disease-specific epigenomic, lipidomic, or clinically validated metabolomic signature was identified. Single-cell and spatial-transcriptomic evidence remains limited. No CRISPR-based host-dependency screen has yet produced an actionable therapeutic target in the retrieved evidence.

7. Anatomical structures affected

The skin is the inoculation site and eschar location. Dissemination affects vascular endothelium throughout the body. Major secondary organs are the lungs, liver, heart, kidneys, brain/meninges, spleen, lymph nodes, and bone marrow/blood. Suggested UBERON mappings include skin, blood vessel endothelium, lung, liver, heart, kidney, brain, meninges, spleen, and lymph node. No characteristic lateralization exists. (vashishtha2025scrubtyphusupdate pages 6-7, varghese2023intravenousdoxycyclineazithromycin pages 4-6)

At the subcellular level, Orientia is cytosolic after host-cell entry and escape from its vacuole; bacterial ribosomes are pharmacologic targets. No primary human mitochondrial, lysosomal, nuclear, or ER genetic defect underlies disease.

8. Temporal development

Onset may occur in children or adults and is acute, not congenital. After 6–21 days of incubation, fever and systemic symptoms begin; rash may emerge near the end of week 1. Untreated disease can broaden during week 2 into pulmonary, neurologic, cardiac, renal, or hepatic complications. (vashishtha2025scrubtyphusupdate pages 6-7, ravishankar2024rickettsialinfectionsprevalence pages 4-5)

The clinically important intervention window is early febrile illness, before organ dysfunction. PCR is most useful during early bacteremia; serologic sensitivity rises later. Effective antibiotics typically produce defervescence over the following days. Relapse or persistent infection can occur, but chronic symptomatic lifelong disease is not the usual course. In an intradermally infected mouse model, viable organisms or the 47-kDa target remained detectable in organs through 84 days, showing biological persistence even after acute illness; human significance remains incompletely defined.

9. Inheritance and population epidemiology

There is no Mendelian inheritance, penetrance, expressivity, anticipation, germline mosaicism, founder effect, or carrier state. Population differences principally reflect ecology, occupation, surveillance, healthcare access, and circulating strain/vector distributions.

Approximately 2 billion people are considered at risk and roughly 1 million annual cases are commonly cited. These are modeled/legacy estimates rather than complete surveillance counts. (lynnette2024scrubtyphusdiagnostics pages 1-2)

A 2025 systematic review covering India from 2003–2023 identified 47,650 cases and a 5% case-fatality rate among 35,243 evaluable cases, with notable increases after 2010 and peaks in 2019 and 2022. Although published in 2025, its observation window supplies recent 2023 epidemiology. (chaturvedi2025spatiotemporalepidemiologyand pages 2-3)

A completed South India cohort enrolled 32,566 people across approximately 40 villages and monitored symptomatic, serologic, and complicated infections through two seasons, while also trapping rodents to characterize spatial-temporal risk. (NCT04506944 chunk 1, NCT04506944 chunk 2)

10. Diagnostics

Clinical suspicion and criteria

Suspect scrub typhus in an endemic-area resident or traveler with acute fever, headache/myalgia, thrombocytopenia or transaminitis, an eschar, or unexplained pulmonary, neurologic, renal, cardiac, or hepatic dysfunction. The eschar is highly informative but not invariably present and may be concealed. There is no universally standardized clinical case definition.

Laboratory methods

PCR/qPCR: detects Orientia DNA and is most useful early, before antibiotics reduce bacteremia. Eschar material can remain highly productive; one recent editorial summarized 100% positivity in eschar samples and 94% in buffy coat in highlighted work. Targets include 47-kDa, 56-kDa/TSA, and other conserved loci; claims of “100% detection” for individual target sets should not be generalized across settings. (ravishankar2024rickettsialinfectionsprevalence pages 7-8, adhikari2024editorialscrubtyphus pages 2-3)
IgM ELISA: practical and widely implemented; becomes more useful after antibodies develop. Endemic-background antibodies and locally inappropriate cutoffs can cause false positives.
Indirect immunofluorescence assay: commonly treated as a reference serologic method, but dependence on subjective interpretation, paired sera, antigen panels, and locally validated cutoffs limits standardization. Prototype Karp/Gilliam/Kato antigens may miss local diversity. (lynnette2024scrubtyphusdiagnostics pages 1-2, chaturvedi2025spatiotemporalepidemiologyand pages 2-3)
Rapid immunochromatographic tests: useful near the point of care but variable; one review cited approximately 70% sensitivity. (chaturvedi2025spatiotemporalepidemiologyand pages 2-3)
Weil–Felix: inexpensive but insufficiently sensitive/specific and should not be preferred where validated ELISA/PCR is available; nevertheless, it accounted for about 61% of tests in the India literature synthesis, illustrating a real-world implementation gap. (chaturvedi2025spatiotemporalepidemiologyand pages 7-8)
Metagenomic sequencing: potentially useful in atypical or diagnostically unresolved cases, but cost and infrastructure preclude routine use.

QuEST (NCT06675110) enrolled 345 participants in Thailand beginning July 17, 2024 to compare insulated isothermal PCR with qPCR/IFA, directly addressing decentralized rapid molecular diagnosis. (NCT06675110 chunk 1)

Imaging, ECG/echocardiography, EEG, CSF examination, renal/liver tests, and chest imaging assess complications rather than establish etiology. Biopsy is rarely necessary; pathology may show endothelial infection, perivascular inflammation, interstitial pneumonitis, and focal necrosis.

Differential diagnosis and screening

Differentials include dengue, malaria, leptospirosis, enteric fever, murine/spotted-fever rickettsioses, hantavirus, viral hepatitis, influenza/COVID-19, bacterial sepsis, and meningoencephalitis. No population, newborn, carrier, prenatal, or genetic screening is indicated. Targeted fever surveillance in endemic seasons is the appropriate public-health analogue.

11. Outcome and prognosis

Early appropriate antibiotics usually produce full recovery. Delay permits multiorgan dysfunction and increases ICU use and death. In severe trial participants, organ involvement was respiratory 62%, hepatic 54%, cardiovascular 42%, renal 30%, and neurologic 20%. Trial-defined severe disease included hypoxemia/infiltrates, bilirubin >2 mg/dL, creatinine >2 mg/dL, hypotension/myocarditis/arrhythmia, seizures or meningoencephalitis, or profound thrombocytopenia. (varghese2023intravenousdoxycyclineazithromycin pages 4-6, varghese2023intravenousdoxycyclineazithromycin pages 21-23)

Despite treatment, 28-day mortality in INTREST was 11% with doxycycline, 12% with azithromycin, and 13% with combination therapy. Thus, combination therapy improved the composite recovery endpoint but did not establish lower mortality. Adverse prognostic features include delayed therapy, shock, ARDS, myocarditis, AKI, encephalopathy, high organism burden, and multiple-organ involvement. (varghese2023intravenousdoxycyclineazithromycin pages 10-11, varghese2023intravenousdoxycyclineazithromycin pages 21-23)

Five- or ten-year survival metrics are not meaningful for this acute infection. Standardized long-term disability and quality-of-life data are sparse.

12. Treatment

Uncomplicated disease

Doxycycline is the conventional first-line agent; azithromycin is an effective alternative and is generally favored in pregnancy. Chloramphenicol is effective but limited by marrow toxicity and pregnancy/infant concerns. Rifampicin can be active but should be used cautiously where tuberculosis is prevalent because monotherapy can select rifampicin resistance. Fluoroquinolones are not dependable first-line agents. Supportive management includes oxygen/ventilation, hemodynamic support, renal replacement where needed, seizure management, and correction of fluid/electrolyte disturbances. (ravishankar2024rickettsialinfectionsprevalence pages 7-8, chaturvedi2025spatiotemporalepidemiologyand pages 2-3)

Severe disease: high-quality randomized evidence

INTREST was a multicenter, double-blind RCT in 794 modified-intention-to-treat patients aged ≥15 years with at least one involved organ system. Regimens were:

IV doxycycline 200 mg twice on day 1, then 100 mg twice daily for 6 days;
IV azithromycin 500 mg twice on day 1, then 500 mg daily for 6 days;
both regimens together for 7 days. (varghese2023intravenousdoxycyclineazithromycin pages 6-8)

The primary composite occurred in 33% with combination therapy versus 47% with doxycycline (risk difference −13.3 percentage points; 95% CI −21.6 to −5.1; P=0.002) and 48% with azithromycin (−14.8 points; 95% CI −23.1 to −6.5; P<0.001). Monotherapies did not differ (P=0.73). The abstract’s conclusion was: “Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option.” (varghese2023intravenousdoxycyclineazithromycin pages 4-6)

Bacterial-DNA clearance was faster with combination therapy than doxycycline alone (HR 1.33, 95% CI 1.09–1.62). Grade ≥3 adverse events occurred in approximately 8–11% and were broadly similar across groups. The trial excluded children and pregnant patients, limiting direct generalization. DOI: 10.1056/NEJMoa2208449, published March 2023; Clinical Trials Registry–India CTRI/2018/08/015159. (varghese2023intravenousdoxycyclineazithromycin pages 10-11)

Suggested NCIT annotations: doxycycline treatment, azithromycin treatment, combination antimicrobial therapy, intravenous administration, supportive care, mechanical ventilation, renal replacement therapy.

Experimental/current studies

START, NCT03083197: 177 participants; 7-day doxycycline versus 3-day doxycycline versus 3-day azithromycin; outcomes include fever clearance, relapse, PK/PD, MIC, WGS, and immune responses; active, not recruiting. (NCT03083197 chunk 1)
NCT07513103: 27 adults; IV tigecycline (100-mg loading dose, then 50 mg every 12 hours for 5 days) versus oral doxycycline 100 mg every 12 hours for 7 days; completed January 2025, but definitive efficacy results were unavailable. (NCT07513103 chunk 1)
NCT00351182: 92 adults with mild/moderate disease; five days of telithromycin 800 mg/day versus doxycycline 200 mg/day; completed. Telithromycin is not a routine preferred option. (NCT00351182 chunk 1)

There is no role for gene, cell, RNA, or immune-checkpoint therapy.

13. Prevention

No licensed broadly effective vaccine is available. Primary prevention comprises long trousers and sleeves, boots, repellents, avoidance of sitting directly on infested ground, vegetation management, and targeted vector-control measures. Because chiggers and small mammals occupy complex ecosystems, broad rodent eradication or indiscriminate insecticide use is unlikely to be sustainable.

Secondary prevention is rapid case recognition, regionally validated testing, and prompt empiric treatment when clinical suspicion is high. Tertiary prevention is early monitoring and treatment of hypoxemia, shock, renal failure, myocarditis, thrombocytopenia, and CNS disease. Routine antibiotic prophylaxis is not recommended for general populations, and there is no genetic counseling indication. (vashishtha2025scrubtyphusupdate pages 11-12, adhikari2024editorialscrubtyphus pages 2-3)

Vaccine development is hampered by marked strain diversity and incompletely durable heterologous immunity. Conserved antigens, multivalent constructs, and T-cell-focused strategies remain research priorities rather than current implementations.

14. Other species and natural disease

The natural cycle involves trombiculid mites and small mammals, especially rodents and shrews. Mites are both vectors and long-term maintenance hosts; mammals provide blood meals and ecological amplification. Humans are accidental hosts and scrub typhus is therefore zoonotic/vector-borne, but not normally transmitted directly from rodents or person to person. (lynnette2024scrubtyphusdiagnostics pages 1-2, NCT02876367 chunk 1)

Field study NCT02876367 enrolled approximately 1,200 participants and linked human, rodent, and mite Orientia genotypes to habitats using sequencing. This provides a real-world One Health implementation for identifying key hosts, vectors, and intervention sites. (NCT02876367 chunk 1)

Clinically recognized natural disease is chiefly human; overt scrub-typhus-like illness in domestic animal breeds is not well established. VBO breed annotation and orthologous human causal genes are therefore not applicable. NCBI Taxonomy identifiers should be assigned directly from current taxonomy records for O. tsutsugamushi, individual Leptotrombidium species, and locally sampled rodent species.

15. Model organisms

Mouse models

Intradermal inoculation of C57BL/6 mice more closely approximates natural cutaneous entry than intraperitoneal or intravenous challenge. After ear inoculation with 6×10⁴ organisms, mice developed fever at days 11–12, hypothermia/weight loss at days 14–19, and peak bacteremia, tissue burden, and pathology near day 14. Cytokines included CCL2, CCL3, IL-10, IL-6, IL-12, IFN-γ, CCL5, IL-1, TNF-α, and GM-CSF; organisms remained detectable through day 84. The model supports studies of acute disease, persistence, immunity, and vaccines, but it does not consistently reproduce the human eschar and differs in immune kinetics.

The 2023 severe-mouse model with brain RNA-seq recapitulates neuroinflammation, microglial activation, and BBB dysregulation, making it useful for neurologic pathogenesis but not a substitute for human CNS tissue evidence. (liang2023braintranscriptomicsreveal pages 1-2)

Nonhuman primates and cellular systems

Nonhuman primates can model eschar, fever, lymphadenopathy, and immune responses more faithfully, but cost, ethics, and limited availability constrain use. HUVEC/endothelial cultures, primary monocytes/macrophages, dendritic cells, and microglia permit mechanistic and drug studies. Their limitations include high experimental inocula, absent tissue architecture, and inability to reproduce systemic vascular disease. (mikagospodorz2020dualrnaseqof pages 9-9, tantibhedhyangkul2011orientiatsutsugamushistimulates pages 1-2)

Recent developments and expert interpretation

Therapy: The 2023 INTREST RCT is practice-changing for severe disease: dual IV doxycycline–azithromycin accelerates recovery compared with either alone, although equal mortality cautions against claiming a survival advantage. (varghese2023intravenousdoxycyclineazithromycin pages 10-11, varghese2023intravenousdoxycyclineazithromycin pages 4-6)
Mechanisms: The 2023 mouse brain-transcriptomics study links severe neurologic disease to excessive IFN activity, microglia, IL-6/JAK–STAT, TNF/NF-κB, and BBB disruption. This supplies testable mechanisms but not yet validated therapeutic targets. (liang2023braintranscriptomicsreveal pages 1-2)
Diagnostics: The 2024 diagnostic literature emphasizes a stage-adapted strategy—PCR early, serology later—and locally validated antigen panels/cutoffs. QuEST represents current implementation research on field-compatible iiPCR. (lynnette2024scrubtyphusdiagnostics pages 1-2, NCT06675110 chunk 1)
Epidemiology: Current authoritative opinion favors a One Health, spatially targeted response incorporating rainfall, temperature, land use, rodents, mites, and healthcare access rather than treating scrub typhus solely as a clinical rickettsiosis. (adhikari2024editorialscrubtyphus pages 2-3, NCT04506944 chunk 1)

Evidence and identifier caveats

PMIDs were requested, but the retrieved full-text records supplied DOIs and registry identifiers more consistently than PMIDs. To prevent database contamination, PMIDs not explicitly available in the evidence were not guessed. Exact MONDO, HPO, GO, CL, UBERON, CHEBI, and NCIT numerical identifiers likewise require validation against the current ontology releases; the report therefore supplies defensible term labels and only the independently supported ICD-10 code. Frequencies vary sharply by geography, case definition, disease severity, test timing, and referral setting; severe-hospital cohorts must not be used as population prevalence estimates.

References

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(NCT06675110 chunk 1): QuEST - Quick and Easy Scrub Typhus Diagnostic Tools. University of Oxford. 2024. ClinicalTrials.gov Identifier: NCT06675110
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(NCT02876367 chunk 1): The Clinical Epidemiology of Scrub Typhus in Humans, Chiggers and Rodents. University of Oxford. 2016. ClinicalTrials.gov Identifier: NCT02876367
(NCT03083197 chunk 1): Scrub Typhus Antibiotic Resistance Trial. University of Oxford. 2017. ClinicalTrials.gov Identifier: NCT03083197
(NCT04506944 chunk 1): The Epidemiology of Rickettsial Infections in South India: Cohort Study. London School of Hygiene and Tropical Medicine. 2020. ClinicalTrials.gov Identifier: NCT04506944
(NCT04506944 chunk 2): The Epidemiology of Rickettsial Infections in South India: Cohort Study. London School of Hygiene and Tropical Medicine. 2020. ClinicalTrials.gov Identifier: NCT04506944
(varghese2023intravenousdoxycyclineazithromycin pages 10-11): George M. Varghese, Divya Dayanand, Karthik Gunasekaran, Debasree Kundu, Mukta Wyawahare, Navneet Sharma, Dhruva Chaudhry, Sanjay K. Mahajan, Kavitha Saravu, Blessed W. Aruldhas, Binu S. Mathew, Roshini G. Nair, Nalini Newbigging, Aswathy Mathew, Kundavaram P.P. Abhilash, Manisha Biswal, Ann H. Prasad, Anand Zachariah, Ramya Iyadurai, Samuel G. Hansdak, Sowmya Sathyendra, Thambu D. Sudarsanam, John A.J. Prakash, Abi Manesh, Alladi Mohan, Joel Tarning, Stuart D. Blacksell, Pimnara Peerawaranun, Naomi Waithira, Mavuto Mukaka, Phaik Yeong Cheah, John V. Peter, Ooriapadickal C. Abraham, and Nicholas P.J. Day. Intravenous doxycycline, azithromycin, or both for severe scrub typhus. The New England journal of medicine, 388 9:792-803, Mar 2023. URL: https://doi.org/10.1056/nejmoa2208449, doi:10.1056/nejmoa2208449. This article has 125 citations and is from a highest quality peer-reviewed journal.
(NCT07513103 chunk 1): Jin Soo Lee. Clinical Effectiveness of Tigecycline for Scrub Typhus.. Jin Soo Lee. 2022. ClinicalTrials.gov Identifier: NCT07513103
(NCT00351182 chunk 1): Dong-Min Kim. Controlled Trial: 5-day Course of Telithromycin Versus Doxycycline for the Treatment of Mild to Moderate Scrub Typhus. Dong-Min Kim. 2005. ClinicalTrials.gov Identifier: NCT00351182

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Outcome	Count
References checked	9
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Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	9
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Classifications

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Diagnosis

Prevalence

Infectious Agent

Transmission

Clinical Trials

Source YAML

References & Deep Research

Deep Research

Scrub Typhus: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

Definition and names

Identifiers

2. Etiology, risk, and protective factors

Cause and transmission

Demographic and host risk

Genetic risk and gene–environment interaction

Protective factors

3. Phenotypes

Principal phenotype annotations

4. Genetic and molecular information

Human genetics

Pathogen genomics

5. Environmental and infectious-agent information

6. Mechanism and pathophysiology

Causal chain

Cells and pathways

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population epidemiology

10. Diagnostics

Clinical suspicion and criteria

Laboratory methods

Differential diagnosis and screening

11. Outcome and prognosis

12. Treatment

Uncomplicated disease

Severe disease: high-quality randomized evidence

Experimental/current studies

13. Prevention

14. Other species and natural disease

15. Model organisms

Mouse models

Nonhuman primates and cellular systems

Recent developments and expert interpretation

Evidence and identifier caveats

Artifacts

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