🏷

Classifications

Harrison's Part

⚙

Pathophysiology

7

Tick-Borne Rickettsia japonica Inoculation

Infected ticks inject R. japonica into skin while feeding, seeding the local rickettsial infection that can create an eschar and disseminate systemically.

symbiont entry into host GO:0044409

Downstream

Intracytosolic Rickettsia japonica Niche Tick inoculation delivers R. japonica to intracellular host-cell niches.

Inoculation Eschar Local dermal infection at the bite site can necrose into an eschar.

Show evidence (1 reference)

PMID:42697132 SUPPORT Other

"Japanese spotted fever (JSF) is a tick-borne disease caused by Rickettsia japonica, a member of the spotted fever group rickettsiae."

The study states that JSF is transmitted by ticks and caused by R. japonica, supporting infected-tick inoculation as the initiating exposure.

Intracytosolic Rickettsia japonica Niche

R. japonica, like other spotted-fever-group rickettsiae, occupies the host-cell cytosol and depends on intracellular access to host metabolites, creating a need for cell-penetrant therapy.

vascular endothelial cell CL:0002139

biological process involved in interaction with host GO:0051701

Downstream

Rickettsial Ribosomal Translation (Tetracycline Target) Intracellular R. japonica remains dependent on bacterial ribosomal protein synthesis.

Small-Vessel Vasculitis Disseminated endothelial infection produces vasculitic tissue injury.

Show evidence (1 reference)

PMID:30148688 SUPPORT REVIEW SYNTHESIS Other

"Residing free in the cytosol of the host cell, they acquire many necessary components via transport mechanisms instead of maintaining genes for synthesizing sugars, lipids, nucleotides, and amino acids."

The rickettsial pathogenesis review supports the free cytosolic niche for Rickettsia species and the shared intracellular-pathogen persistence module.

Rickettsial Ribosomal Translation (Tetracycline Target)

R. japonica depends on bacterial ribosomal translation; tetracyclines such as minocycline inhibit the bacterial 30S ribosomal subunit and thereby arrest rickettsial protein synthesis.

Translation GO:0006412 response to antibiotic GO:0046677

Show evidence (1 reference)

PMID:24336183 SUPPORT REVIEW SYNTHESIS Other

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

Review evidence establishes the bacterial ribosome as the conserved target class for protein-synthesis inhibitors; the JSF treatment evidence below establishes minocycline use.

Small-Vessel Vasculitis

Systemic rickettsial spread injures the vascular endothelium and triggers small-vessel vasculitis, producing rash and purpura and marking severe pulmonary or multiorgan disease when it is widespread.

vascular endothelial cell CL:0002139

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Skin Rash Cutaneous microvascular inflammation contributes to the exanthem.

Purpura Vasculitic vascular injury permits purpuric hemorrhage into skin.

Hypercytokinemic Shock Response Disseminated endothelial inflammation amplifies systemic cytokine release.

Vasculitic Multiorgan Injury Widespread small-vessel injury can extend into renal, pulmonary, and hepatic organ injury.

Show evidence (1 reference)

PMID:38043152 SUPPORT Human Clinical

"The numerous inflammatory infiltrates were also observed in pulmonary interstitium, which were accompanied with histopathologic features of vasculitis."

Fatal autopsy evidence directly links disseminated JSF to vasculitic pulmonary injury.

Hypercytokinemic Shock Response

Severe Japanese spotted fever can couple the endothelial inflammatory response to excessive systemic cytokine signaling and shock.

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Severe Coagulation Activation Cytokine-amplified severe disease predisposes to DIC.

Vasculitic Multiorgan Injury Fulminant inflammatory injury can progress to renal and pulmonary failure.

Show evidence (1 reference)

PMID:11376087 SUPPORT Human Clinical

"We report a patient with Japanese spotted fever caused by Rickettsia japonica who developed shock associated with hypercytokinemia."

The fulminant case links JSF caused by R. japonica to hypercytokinemic shock.

Severe Coagulation Activation

In severe JSF, systemic vascular inflammation activates coagulation and progresses to disseminated intravascular coagulation with platelet consumption and, in a subset, purpura fulminans.

blood coagulation GO:0007596 ↑ INCREASED

Downstream

Disseminated Intravascular Coagulation Systemic consumptive coagulation manifests as DIC.

Thrombocytopenia Consumptive coagulation lowers the circulating platelet count.

Purpura Fulminans Severe DIC can produce purpura fulminans with ischemic skin injury.

Show evidence (1 reference)

PMID:36386421 SUPPORT Human Clinical

"Systemic manifestations such as vomiting (83%), neurological manifestations (100%), and disseminated intravascular coagulation (100%) were more frequently observed in the severe cases"

The severe Chinese JSF series identifies DIC as a frequent manifestation of severe disease.

Vasculitic Multiorgan Injury

Fulminant JSF can disseminate the vasculitic injury to kidneys and lungs, producing acute renal failure, acute respiratory failure, and liver injury.

Downstream

Elevated Hepatic Transaminases Severe systemic JSF commonly injures the liver.

Neurological Manifestations Fulminant systemic JSF can include neurological involvement.

Show evidence (1 reference)

PMID:38043152 SUPPORT Human Clinical

"Thus, we diagnosed her cause of death as JSF which had been occurred multiorgan failure such as acute renal failure and possibly acute respiratory failure."

Fatal autopsy evidence connects fulminant JSF to multiorgan failure.

⬡

Pathograph

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●

Phenotypes

10

Blood 4

Purpura HP:0000979

Show evidence (1 reference)

PMID:30124190 SUPPORT Human Clinical

"Clinical findings more frequently observed in JSF than in ST patients were purpura, palmar/plantar rash, hyponatremia, organ damage, and delayed defervescence after treatment."

The comparative Japanese cohort identifies purpura as a JSF-enriched skin feature relative to scrub typhus.

Disseminated Intravascular Coagulation OCCASIONAL HP:0005521

Show evidence (2 references)

PMID:35545515 SUPPORT Human Clinical

"The incidence of various clinical symptoms in the JSF patients was as follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%; and neurological symptoms, 11.0%."

DIC occurred in a minority of all JSF patients in the Ehime Prefecture series, supporting an occasional-frequency severe phenotype.

PMID:36386421 SUPPORT Human Clinical

"Systemic manifestations such as vomiting (83%), neurological manifestations (100%), and disseminated intravascular coagulation (100%) were more frequently observed in the severe cases"

The severe-case series shows that DIC is enriched in fulminant JSF.

Thrombocytopenia VERY_FREQUENT HP:0001873

Show evidence (1 reference)

PMID:36386421 SUPPORT Human Clinical

"Fever (91%), pulmonary effusion (91%), rash or erythema (100%), abnormal urine (100%), neutropenia (100%), lymphopenia (100%), and thrombocytopenia (100%) were the most common clinical signs."

Thrombocytopenia occurred in all 11 metagenomics-confirmed Yichang JSF cases.

Purpura Fulminans OCCASIONAL HP:0000979

Show evidence (1 reference)

PMID:36386421 SUPPORT Human Clinical

"33.3% of whom developed purpura fulminans requiring amputation or skin graft, and 16.6% died two days after admission."

Purpura fulminans occurred in one-third of the severe Yichang cases, making it an occasional phenotype across the full 11-patient series.

Immune 1

Skin Rash FREQUENT HP:0000988

Show evidence (1 reference)

PMID:39477520 SUPPORT Human Clinical

"Common symptoms included fever (87%), rash (48%), and fatigue (48%), with eschars detected in 50 (79.4%) patients."

The multicenter Nagasaki series quantifies rash among common JSF presenting symptoms.

Integument 1

Inoculation Eschar FREQUENT HP:6000793

Show evidence (1 reference)

PMID:39477520 SUPPORT Human Clinical

"Common symptoms included fever (87%), rash (48%), and fatigue (48%), with eschars detected in 50 (79.4%) patients."

Eschars were detected in most patients in the Nagasaki multicenter JSF series.

Metabolism 3

Fever VERY_FREQUENT HP:0001945

Show evidence (1 reference)

PMID:35545515 SUPPORT Human Clinical

"The incidence of various clinical symptoms in the JSF patients was as follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%; and neurological symptoms, 11.0%."

Fever was present in all JSF cases in the Ehime Prefecture series.

Hyponatremia HP:0002902

Show evidence (1 reference)

PMID:30124190 SUPPORT Human Clinical

"Clinical findings more frequently observed in JSF than in ST patients were purpura, palmar/plantar rash, hyponatremia, organ damage, and delayed defervescence after treatment."

The comparative cohort lists hyponatremia among clinical findings more frequently observed in JSF than in scrub typhus.

Elevated Hepatic Transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:35545515 SUPPORT Human Clinical

"The incidence of various clinical symptoms in the JSF patients was as follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%; and neurological symptoms, 11.0%."

The Ehime Prefecture clinical series reported liver dysfunction in 69.2% of JSF patients.

Nervous System 1

Neurological Manifestations OCCASIONAL Abnormality of the nervous system HP:0000707

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:35545515 SUPPORT Human Clinical

"The incidence of various clinical symptoms in the JSF patients was as follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%; and neurological symptoms, 11.0%."

The Ehime Prefecture clinical series quantified neurological symptoms in a minority of JSF patients but did not break down those symptoms into more specific neurologic phenotypes.

💊

Medical Actions

1

Early minocycline therapy

Action: Pharmacotherapy NCIT:C15986

Agent: minocycline CHEBI:50694

Platform: Small molecule

Minocycline is a tetracycline used to treat JSF and should be given early, before fulminant illness can progress to shock, DIC, and multiorgan injury; fulminant case reports and recommendations describe prompt tetracycline plus new-quinolone combination therapy.

Mechanism Target:

INHIBITS Rickettsial Ribosomal Translation (Tetracycline Target) — Minocycline arrests bacterial protein synthesis through the tetracycline class ribosomal target.

BYPASSES Intracytosolic Rickettsia japonica Niche — Minocycline can act against R. japonica in its intracellular cytosolic compartment.

Show evidence (2 references)

PMID:41341009 SUPPORT BACKGROUND Human Clinical

"Tetracyclines, such as minocycline (MINO), are widely used in the treatment of infectious diseases. Japanese spotted fever (JSF) is usually treated with MINO."

The JSF treatment-model paper states that minocycline is the usual tetracycline therapy for Japanese spotted fever.

PMID:26630793 SUPPORT BACKGROUND Human Clinical

"In the treatment of fulminant JSF (body temperature > 39 degrees C) the prompt administration of a combination of tetracycline and new quinolone has been recommended."

The case report supports prompt tetracycline-containing therapy, with fluoroquinolone combination considered for fulminant JSF.

🔬

Diagnosis

2

qPCR plus immunofluorescence serology for Asian SFG rickettsiosis

A pan-Asian spotted-fever-group rickettsiosis diagnostic review recommends tandem real-time qPCR and immunofluorescence assay, with qPCR more useful early before antibodies appear and serology more useful after antibodies are detectable.

laboratory testing NCIT:C25294

Results: Concordant molecular and serologic testing supports spotted-fever-group rickettsiosis confirmation; species-level JSF diagnosis still requires R. japonica-specific molecular or serologic interpretation.

Show evidence (1 reference)

PMID:31587667 SUPPORT REVIEW SYNTHESIS Other

"It is likely that the best strategy is to use a real-time quantitative polymerase chain reaction (qPCR) and immunofluorescence assay in tandem."

The pan-Asian SFG rickettsiosis review supports combined qPCR and IFA as the best currently available diagnostic strategy for Asian SFG infections such as JSF.

Clinical suspicion before confirmatory testing

JSF's fever-rash-eschar presentation is still often confused with other syndromes at first presentation, so clinicians in endemic areas must treat compatible cases empirically while awaiting confirmation.

clinical diagnosis NCIT:C18020

Results: A compatible acute illness after tick exposure in an endemic area should trigger suspicion even when JSF-specific laboratory confirmation is not yet available.

Show evidence (1 reference)

PMID:39477520 SUPPORT Human Clinical

"Thirty-eight (60.3%) patients were initially diagnosed with non-JSF conditions."

The multicenter Nagasaki series quantifies frequent initial misdiagnosis, supporting a diagnostic section that emphasizes clinical suspicion before confirmatory test results.

📈

Progression

1

Delayed-treatment severe JSF

Longer delays from symptom onset to minocycline initiation increase the risk of severe JSF, and delayed initial treatment, advanced age, and male sex significantly increase severity risk.

Show evidence (2 references)

PMID:42576956 SUPPORT Human Clinical

"In multivariable analysis, each 1-day delay in minocycline initiation was associated with higher odds of severe outcomes (adjusted odds ratio, 1.35; 95% confidence interval, 1.01-1.81; p = 0.043)."

The PCR-confirmed eastern Hiroshima cohort directly links each additional onset-to-minocycline day to increased odds of severe outcomes.

PMID:39477520 SUPPORT Human Clinical

"Delayed initial treatment, advanced age, and male sex significantly increase the risk of disease severity."

The multicenter Nagasaki series independently supports delayed treatment and demographic factors as severe-JSF risk factors.

🌍

Epidemiology

1

Rural agricultural tick exposure in endemic Japan

Japanese spotted fever occurs in Japanese endemic areas where daily activities and agricultural work near vegetation bring residents into contact with infected ticks.

residence near mountains and citrus cultivation agricultural tick exposure endemic Japanese tick exposure

Show evidence (1 reference)

PMID:35545515 SUPPORT Human Clinical

"Since 67.0% of the JSF patients resided near the mountains with citrus cultivations, there were high chances of contact with ticks during farm work or their daily routine even if they did not visit the mountain areas."

The Ehime Prefecture clinical series ties JSF risk to ordinary residential or farming exposure near tick habitats in endemic regions.

🦠

Infectious Agent

1

Rickettsia japonica

Obligate intracellular spotted-fever-group rickettsial bacterium that causes Japanese spotted fever after transmission by infected ticks.

Rickettsia japonica NCBITaxon:35790

Show evidence (1 reference)

PMID:42697132 SUPPORT Other

"Japanese spotted fever (JSF) is a tick-borne disease caused by Rickettsia japonica, a member of the spotted fever group rickettsiae."

The survey identifies R. japonica as the etiologic spotted-fever-group rickettsial species for JSF.

↔️

Transmission

1

Haemaphysalis tick bite transmission

Humans acquire Japanese spotted fever when infected ticks inoculate R. japonica during blood feeding; in Ibaraki Prefecture, Haemaphysalis hystricis carried R. japonica and wild boars were implicated as hosts that can transport infected ticks rather than as proven reservoirs.

Show evidence (1 reference)

PMID:42697132 SUPPORT Other

"These results suggest that H. hystricis is a potential vector of R. japonica in Ibaraki Prefecture and that wild boars may potentially transport H. hystricis carrying R. japonica."

The tick and wild-boar survey supports H. hystricis as a candidate local vector and restricts the wild-boar role to movement of infected ticks.

{ }

Source YAML

click to show

name: Japanese Spotted Fever
creation_date: "2026-09-27T08:33:00Z"
updated_date: "2026-09-27T08:33:00Z"
category: Infectious Disease
description: >-
  Japanese spotted fever is an acute tick-borne spotted-fever-group
  rickettsiosis caused by the obligately intracellular bacterium Rickettsia
  japonica. Infected Haemaphysalis ticks inoculate the organism into skin,
  where local infection can produce an eschar before systemic endothelial
  infection and small-vessel vasculitis drive fever, rash, purpura, hepatic
  enzyme elevation, and occasionally disseminated intravascular coagulation or
  multiorgan failure.
disease_term:
  preferred_term: Japanese spotted fever
  term:
    id: MONDO:0000233
    label: Japanese spotted fever
parents:
- Spotted fever rickettsiosis
synonyms:
- Rickettsia japonica infection
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:42697132
      reference_title: "Molecular survey of Rickettsia japonica in ticks and wild boars in Ibaraki Prefecture: a newly recognized endemic area of Japanese spotted fever in eastern Japan."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Japanese spotted fever (JSF) is a tick-borne disease caused by
        Rickettsia japonica, a member of the spotted fever group rickettsiae.
      explanation: >-
        The molecular survey frames Japanese spotted fever as a bacterial
        spotted-fever-group rickettsiosis, placing it in Harrison's Infectious
        Diseases Part.

infectious_agent:
- name: Rickettsia japonica
  infectious_agent_term:
    preferred_term: Rickettsia japonica
    term:
      id: NCBITaxon:35790
      label: Rickettsia japonica
  description: >-
    Obligate intracellular spotted-fever-group rickettsial bacterium that causes
    Japanese spotted fever after transmission by infected ticks.
  evidence:
  - reference: PMID:42697132
    reference_title: "Molecular survey of Rickettsia japonica in ticks and wild boars in Ibaraki Prefecture: a newly recognized endemic area of Japanese spotted fever in eastern Japan."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Japanese spotted fever (JSF) is a tick-borne disease caused by Rickettsia
      japonica, a member of the spotted fever group rickettsiae.
    explanation: >-
      The survey identifies R. japonica as the etiologic spotted-fever-group
      rickettsial species for JSF.

transmission:
- name: Haemaphysalis tick bite transmission
  description: >-
    Humans acquire Japanese spotted fever when infected ticks inoculate R.
    japonica during blood feeding; in Ibaraki Prefecture, Haemaphysalis
    hystricis carried R. japonica and wild boars were implicated as hosts that
    can transport infected ticks rather than as proven reservoirs.
  evidence:
  - reference: PMID:42697132
    reference_title: "Molecular survey of Rickettsia japonica in ticks and wild boars in Ibaraki Prefecture: a newly recognized endemic area of Japanese spotted fever in eastern Japan."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These results suggest that H. hystricis is a potential vector of R.
      japonica in Ibaraki Prefecture and that wild boars may potentially
      transport H. hystricis carrying R. japonica.
    explanation: >-
      The tick and wild-boar survey supports H. hystricis as a candidate local
      vector and restricts the wild-boar role to movement of infected ticks.

epidemiology:
- name: Rural agricultural tick exposure in endemic Japan
  description: >-
    Japanese spotted fever occurs in Japanese endemic areas where daily
    activities and agricultural work near vegetation bring residents into
    contact with infected ticks.
  factors:
  - residence near mountains and citrus cultivation
  - agricultural tick exposure
  - endemic Japanese tick exposure
  evidence:
  - reference: PMID:35545515
    reference_title: "[Infectious causes and management of Japanese spotted fever and severe fever thrombocytopenia syndrome in Ehime prefecture]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since 67.0% of the JSF patients resided near the mountains with citrus
      cultivations, there were high chances of contact with ticks during farm
      work or their daily routine even if they did not visit the mountain areas.
    explanation: >-
      The Ehime Prefecture clinical series ties JSF risk to ordinary residential
      or farming exposure near tick habitats in endemic regions.

pathophysiology:
- name: Tick-Borne Rickettsia japonica Inoculation
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Infected ticks inject R. japonica into skin while feeding, seeding the local
    rickettsial infection that can create an eschar and disseminate
    systemically.
  biological_processes:
  - preferred_term: symbiont entry into host
    term:
      id: GO:0044409
      label: symbiont entry into host
  downstream:
  - target: Intracytosolic Rickettsia japonica Niche
    causal_link_type: DIRECT
    description: Tick inoculation delivers R. japonica to intracellular host-cell niches.
  - target: Inoculation Eschar
    causal_link_type: DIRECT
    description: Local dermal infection at the bite site can necrose into an eschar.
  evidence:
  - reference: PMID:42697132
    reference_title: "Molecular survey of Rickettsia japonica in ticks and wild boars in Ibaraki Prefecture: a newly recognized endemic area of Japanese spotted fever in eastern Japan."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Japanese spotted fever (JSF) is a tick-borne disease caused by Rickettsia
      japonica, a member of the spotted fever group rickettsiae.
    explanation: >-
      The study states that JSF is transmitted by ticks and caused by R.
      japonica, supporting infected-tick inoculation as the initiating exposure.

- name: Intracytosolic Rickettsia japonica Niche
  role: intrinsic_resistance
  conforms_to: >-
    intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam
    Exclusion
  biological_scale: CELLULAR
  description: >-
    R. japonica, like other spotted-fever-group rickettsiae, occupies the
    host-cell cytosol and depends on intracellular access to host metabolites,
    creating a need for cell-penetrant therapy.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  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: Rickettsial Ribosomal Translation (Tetracycline Target)
    causal_link_type: DIRECT
    description: >-
      Intracellular R. japonica remains dependent on bacterial ribosomal protein
      synthesis.
  - target: Small-Vessel Vasculitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Disseminated endothelial infection produces vasculitic tissue injury.
  evidence:
  - reference: PMID:30148688
    reference_title: "Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Residing free in the cytosol of the host cell, they acquire many
      necessary components via transport mechanisms instead of maintaining genes
      for synthesizing sugars, lipids, nucleotides, and amino acids.
    explanation: >-
      The rickettsial pathogenesis review supports the free cytosolic niche for
      Rickettsia species and the shared intracellular-pathogen persistence
      module.

- name: Rickettsial Ribosomal Translation (Tetracycline Target)
  role: therapeutic_vulnerability
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  biological_scale: MOLECULAR
  description: >-
    R. japonica depends on bacterial ribosomal translation; tetracyclines such
    as minocycline inhibit the bacterial 30S ribosomal subunit and thereby
    arrest rickettsial protein synthesis.
  biological_processes:
  - preferred_term: Translation
    term:
      id: GO:0006412
      label: translation
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:24336183
    reference_title: Ribosome-targeting antibiotics and mechanisms of bacterial resistance.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The ribosome is one of the main antibiotic targets in the bacterial cell.
    explanation: >-
      Review evidence establishes the bacterial ribosome as the conserved target
      class for protein-synthesis inhibitors; the JSF treatment evidence below
      establishes minocycline use.

- name: Small-Vessel Vasculitis
  role: vascular_response
  biological_scale: TISSUE
  description: >-
    Systemic rickettsial spread injures the vascular endothelium and triggers
    small-vessel vasculitis, producing rash and purpura and marking severe
    pulmonary or multiorgan disease when it is widespread.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Skin Rash
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Cutaneous microvascular inflammation contributes to the exanthem.
  - target: Purpura
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Vasculitic vascular injury permits purpuric hemorrhage into skin.
  - target: Hypercytokinemic Shock Response
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Disseminated endothelial inflammation amplifies systemic cytokine release.
  - target: Vasculitic Multiorgan Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Widespread small-vessel injury can extend into renal, pulmonary, and hepatic organ injury.
  evidence:
  - reference: PMID:38043152
    reference_title: An autopsy case of fatal Japanese spotted fever in Wakayama.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The numerous inflammatory infiltrates were also observed in pulmonary
      interstitium, which were accompanied with histopathologic features of
      vasculitis.
    explanation: >-
      Fatal autopsy evidence directly links disseminated JSF to vasculitic
      pulmonary injury.

- name: Hypercytokinemic Shock Response
  role: inflammatory_amplification
  biological_scale: ORGANISM
  description: >-
    Severe Japanese spotted fever can couple the endothelial inflammatory
    response to excessive systemic cytokine signaling and shock.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Severe Coagulation Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Cytokine-amplified severe disease predisposes to DIC.
  - target: Vasculitic Multiorgan Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Fulminant inflammatory injury can progress to renal and pulmonary failure.
  evidence:
  - reference: PMID:11376087
    reference_title: Fulminant Japanese spotted fever associated with hypercytokinemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a patient with Japanese spotted fever caused by Rickettsia
      japonica who developed shock associated with hypercytokinemia.
    explanation: >-
      The fulminant case links JSF caused by R. japonica to hypercytokinemic
      shock.

- name: Severe Coagulation Activation
  role: severe_complication
  biological_scale: ORGANISM
  description: >-
    In severe JSF, systemic vascular inflammation activates coagulation and
    progresses to disseminated intravascular coagulation with platelet
    consumption and, in a subset, purpura fulminans.
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  downstream:
  - target: Disseminated Intravascular Coagulation
    causal_link_type: DIRECT
    description: Systemic consumptive coagulation manifests as DIC.
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Consumptive coagulation lowers the circulating platelet count.
  - target: Purpura Fulminans
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Severe DIC can produce purpura fulminans with ischemic skin injury.
  evidence:
  - reference: PMID:36386421
    reference_title: Fatal Rickettsia Japonica Infection Complicating Disseminated Intravascular Coagulation in Yichang, China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systemic manifestations such as vomiting (83%), neurological
      manifestations (100%), and disseminated intravascular coagulation (100%)
      were more frequently observed in the severe cases
    explanation: >-
      The severe Chinese JSF series identifies DIC as a frequent manifestation
      of severe disease.

- name: Vasculitic Multiorgan Injury
  role: severe_complication
  biological_scale: ORGANISM
  description: >-
    Fulminant JSF can disseminate the vasculitic injury to kidneys and lungs,
    producing acute renal failure, acute respiratory failure, and liver injury.
  downstream:
  - target: Elevated Hepatic Transaminases
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Severe systemic JSF commonly injures the liver.
  - target: Neurological Manifestations
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Fulminant systemic JSF can include neurological involvement.
  evidence:
  - reference: PMID:38043152
    reference_title: An autopsy case of fatal Japanese spotted fever in Wakayama.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, we diagnosed her cause of death as JSF which had been occurred
      multiorgan failure such as acute renal failure and possibly acute
      respiratory failure.
    explanation: Fatal autopsy evidence connects fulminant JSF to multiorgan failure.

phenotypes:
- name: Fever
  category: Constitutional
  frequency: VERY_FREQUENT
  description: Fever is a cardinal systemic manifestation of acute JSF.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:35545515
    reference_title: "[Infectious causes and management of Japanese spotted fever and severe fever thrombocytopenia syndrome in Ehime prefecture]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence of various clinical symptoms in the JSF patients was as
      follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver
      dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%;
      and neurological symptoms, 11.0%.
    explanation: >-
      Fever was present in all JSF cases in the Ehime Prefecture series.

- name: Skin Rash
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Japanese spotted fever commonly produces an erythematous cutaneous eruption.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:39477520
    reference_title: "Clinical Characteristics and Risk Factors for Severe Japanese Spotted Fever: A Retrospective Multicenter Study in the Nagasaki Prefecture, Western Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common symptoms included fever (87%), rash (48%), and fatigue (48%), with
      eschars detected in 50 (79.4%) patients.
    explanation: >-
      The multicenter Nagasaki series quantifies rash among common JSF
      presenting symptoms.

- name: Inoculation Eschar
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Necrosis at the infected tick-bite site commonly creates an inoculation
    eschar.
  phenotype_term:
    preferred_term: Eschar
    term:
      id: HP:6000793
      label: Eschar
  evidence:
  - reference: PMID:39477520
    reference_title: "Clinical Characteristics and Risk Factors for Severe Japanese Spotted Fever: A Retrospective Multicenter Study in the Nagasaki Prefecture, Western Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common symptoms included fever (87%), rash (48%), and fatigue (48%), with
      eschars detected in 50 (79.4%) patients.
    explanation: >-
      Eschars were detected in most patients in the Nagasaki multicenter JSF
      series.

- name: Purpura
  category: Dermatologic
  description: >-
    Palmar, plantar, or other purpuric lesions are more typical of JSF than of
    scrub typhus in central Japan.
  phenotype_term:
    preferred_term: Purpura
    term:
      id: HP:0000979
      label: Purpura
  evidence:
  - reference: PMID:30124190
    reference_title: Distinguishing Japanese Spotted Fever and Scrub Typhus, Central Japan, 2004- 2015.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings more frequently observed in JSF than in ST patients were
      purpura, palmar/plantar rash, hyponatremia, organ damage, and delayed
      defervescence after treatment.
    explanation: >-
      The comparative Japanese cohort identifies purpura as a JSF-enriched skin
      feature relative to scrub typhus.

- name: Hyponatremia
  category: Metabolic
  description: Hyponatremia helps distinguish JSF from scrub typhus in central Japan.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:30124190
    reference_title: Distinguishing Japanese Spotted Fever and Scrub Typhus, Central Japan, 2004- 2015.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings more frequently observed in JSF than in ST patients were
      purpura, palmar/plantar rash, hyponatremia, organ damage, and delayed
      defervescence after treatment.
    explanation: >-
      The comparative cohort lists hyponatremia among clinical findings more
      frequently observed in JSF than in scrub typhus.

- name: Elevated Hepatic Transaminases
  category: Digestive System
  frequency: FREQUENT
  description: Liver injury with transaminase elevation is common during acute JSF.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:35545515
    reference_title: "[Infectious causes and management of Japanese spotted fever and severe fever thrombocytopenia syndrome in Ehime prefecture]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence of various clinical symptoms in the JSF patients was as
      follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver
      dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%;
      and neurological symptoms, 11.0%.
    explanation: >-
      The Ehime Prefecture clinical series reported liver dysfunction in 69.2%
      of JSF patients.

- name: Disseminated Intravascular Coagulation
  category: Blood
  frequency: OCCASIONAL
  description: >-
    Disseminated intravascular coagulation is an uncommon but severe
    complication of JSF and becomes enriched in severe cases.
  phenotype_term:
    preferred_term: Disseminated intravascular coagulation
    term:
      id: HP:0005521
      label: Disseminated intravascular coagulation
  evidence:
  - reference: PMID:35545515
    reference_title: "[Infectious causes and management of Japanese spotted fever and severe fever thrombocytopenia syndrome in Ehime prefecture]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence of various clinical symptoms in the JSF patients was as
      follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver
      dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%;
      and neurological symptoms, 11.0%.
    explanation: >-
      DIC occurred in a minority of all JSF patients in the Ehime Prefecture
      series, supporting an occasional-frequency severe phenotype.
  - reference: PMID:36386421
    reference_title: Fatal Rickettsia Japonica Infection Complicating Disseminated Intravascular Coagulation in Yichang, China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systemic manifestations such as vomiting (83%), neurological
      manifestations (100%), and disseminated intravascular coagulation (100%)
      were more frequently observed in the severe cases
    explanation: >-
      The severe-case series shows that DIC is enriched in fulminant JSF.

- name: Thrombocytopenia
  category: Blood
  frequency: VERY_FREQUENT
  description: >-
    Severe Chinese JSF cases and non-severe metagenomics-confirmed cases had
    thrombocytopenia among the most common laboratory findings.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:36386421
    reference_title: Fatal Rickettsia Japonica Infection Complicating Disseminated Intravascular Coagulation in Yichang, China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever (91%), pulmonary effusion (91%), rash or erythema (100%), abnormal
      urine (100%), neutropenia (100%), lymphopenia (100%), and
      thrombocytopenia (100%) were the most common clinical signs.
    explanation: >-
      Thrombocytopenia occurred in all 11 metagenomics-confirmed Yichang JSF
      cases.

- name: Neurological Manifestations
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    JSF can include neurological symptoms in a minority of all patients and in a
    larger fraction of severe cases.
  phenotype_term:
    preferred_term: Neurological manifestations
    term:
      id: HP:0000707
      label: Abnormality of the nervous system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:35545515
    reference_title: "[Infectious causes and management of Japanese spotted fever and severe fever thrombocytopenia syndrome in Ehime prefecture]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence of various clinical symptoms in the JSF patients was as
      follows: fever and systemic erythema, 100%; tick bite, 73.6%; liver
      dysfunction, 69.2%; disseminated intravascular coagulation (DIC), 14.3%;
      and neurological symptoms, 11.0%.
    explanation: >-
      The Ehime Prefecture clinical series quantified neurological symptoms in
      a minority of JSF patients but did not break down those symptoms into
      more specific neurologic phenotypes.

- name: Purpura Fulminans
  category: Dermatologic
  frequency: OCCASIONAL
  description: >-
    Severe DIC complicating JSF can produce purpura fulminans severe enough to
    require amputation or skin grafting.
  phenotype_term:
    preferred_term: Purpura fulminans
    term:
      id: HP:0000979
      label: Purpura
  evidence:
  - reference: PMID:36386421
    reference_title: Fatal Rickettsia Japonica Infection Complicating Disseminated Intravascular Coagulation in Yichang, China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      33.3% of whom developed purpura fulminans requiring amputation or skin
      graft, and 16.6% died two days after admission.
    explanation: >-
      Purpura fulminans occurred in one-third of the severe Yichang cases,
      making it an occasional phenotype across the full 11-patient series.

diagnosis:
- name: qPCR plus immunofluorescence serology for Asian SFG rickettsiosis
  description: >-
    A pan-Asian spotted-fever-group rickettsiosis diagnostic review recommends
    tandem real-time qPCR and immunofluorescence assay, with qPCR more useful
    early before antibodies appear and serology more useful after antibodies are
    detectable.
  diagnosis_term:
    preferred_term: laboratory testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: >-
    Concordant molecular and serologic testing supports spotted-fever-group
    rickettsiosis confirmation; species-level JSF diagnosis still requires
    R. japonica-specific molecular or serologic interpretation.
  evidence:
  - reference: PMID:31587667
    reference_title: "Diagnosis of spotted fever group Rickettsia infections: the Asian perspective."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It is likely that the best strategy is to use a real-time quantitative
      polymerase chain reaction (qPCR) and immunofluorescence assay in tandem.
    explanation: >-
      The pan-Asian SFG rickettsiosis review supports combined qPCR and IFA as
      the best currently available diagnostic strategy for Asian SFG infections
      such as JSF.

- name: Clinical suspicion before confirmatory testing
  description: >-
    JSF's fever-rash-eschar presentation is still often confused with other
    syndromes at first presentation, so clinicians in endemic areas must treat
    compatible cases empirically while awaiting confirmation.
  diagnosis_term:
    preferred_term: clinical diagnosis
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    A compatible acute illness after tick exposure in an endemic area should
    trigger suspicion even when JSF-specific laboratory confirmation is not yet
    available.
  evidence:
  - reference: PMID:39477520
    reference_title: "Clinical Characteristics and Risk Factors for Severe Japanese Spotted Fever: A Retrospective Multicenter Study in the Nagasaki Prefecture, Western Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty-eight (60.3%) patients were initially diagnosed with non-JSF
      conditions.
    explanation: >-
      The multicenter Nagasaki series quantifies frequent initial misdiagnosis,
      supporting a diagnostic section that emphasizes clinical suspicion before
      confirmatory test results.

progression:
- phase: Delayed-treatment severe JSF
  notes: >-
    Longer delays from symptom onset to minocycline initiation increase the risk
    of severe JSF, and delayed initial treatment, advanced age, and male sex
    significantly increase severity risk.
  evidence:
  - reference: PMID:42576956
    reference_title: "Delayed Minocycline Initiation from Symptom Onset and Severe Outcomes in Japanese Spotted Fever: A Single-Center Retrospective Study in Eastern Hiroshima, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In multivariable analysis, each 1-day delay in minocycline initiation was
      associated with higher odds of severe outcomes (adjusted odds ratio, 1.35;
      95% confidence interval, 1.01-1.81; p = 0.043).
    explanation: >-
      The PCR-confirmed eastern Hiroshima cohort directly links each additional
      onset-to-minocycline day to increased odds of severe outcomes.
  - reference: PMID:39477520
    reference_title: "Clinical Characteristics and Risk Factors for Severe Japanese Spotted Fever: A Retrospective Multicenter Study in the Nagasaki Prefecture, Western Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Delayed initial treatment, advanced age, and male sex significantly
      increase the risk of disease severity.
    explanation: >-
      The multicenter Nagasaki series independently supports delayed treatment
      and demographic factors as severe-JSF risk factors.

treatments:
- name: Early minocycline therapy
  description: >-
    Minocycline is a tetracycline used to treat JSF and should be given early,
    before fulminant illness can progress to shock, DIC, and multiorgan injury;
    fulminant case reports and recommendations describe prompt tetracycline plus
    new-quinolone combination therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: minocycline
      term:
        id: CHEBI:50694
        label: minocycline
  target_mechanisms:
  - target: Rickettsial Ribosomal Translation (Tetracycline Target)
    treatment_effect: INHIBITS
    description: >-
      Minocycline arrests bacterial protein synthesis through the tetracycline
      class ribosomal target.
  - target: Intracytosolic Rickettsia japonica Niche
    treatment_effect: BYPASSES
    description: >-
      Minocycline can act against R. japonica in its intracellular cytosolic
      compartment.
  evidence:
  - reference: PMID:41341009
    reference_title: Combination of minocycline and ciprofloxacin enhances the inhibitory effect of tumor necrosis factor-alpha production in lipopolysaccharide-stimulated THP-1 monocytic cells.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Tetracyclines, such as minocycline (MINO), are widely used in the
      treatment of infectious diseases. Japanese spotted fever (JSF) is usually
      treated with MINO.
    explanation: >-
      The JSF treatment-model paper states that minocycline is the usual
      tetracycline therapy for Japanese spotted fever.
  - reference: PMID:26630793
    reference_title: "[Intravenous Minocycline and Levofloxacin for Treatment of Two Cases of Japanese Spotted Fever]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      In the treatment of fulminant JSF (body temperature > 39 degrees C) the
      prompt administration of a combination of tetracycline and new quinolone
      has been recommended.
    explanation: >-
      The case report supports prompt tetracycline-containing therapy, with
      fluoroquinolone combination considered for fulminant JSF.

📚

References & Deep Research

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Create: Japanese Spotted Fever · 2026-09-27T08:58:29Z · View source

Created a de novo Japanese spotted fever entry from OpenScientist deep research, including Rickettsia japonica etiology, tick transmission, endothelial rickettsial pathophysiology, exact-quote phenotypes, and minocycline treatment evidence.

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Japanese Spotted Fever (MONDO:0000233): A Comprehensive Disease Characteristics Report

openscientist-autonomous 34 citations 2026-09-27T01:48:44.622550

Japanese Spotted Fever (MONDO:0000233): A Comprehensive Disease Characteristics Report

Summary

Japanese Spotted Fever (JSF) is an acute, tick-borne rickettsiosis caused by Rickettsia japonica, an obligate intracellular Gram-negative alpha-proteobacterium of the spotted fever group (SFG). First clinically described by Mahara in 1984, JSF is endemic to Japan, where it is now the second most common acari-borne disease after scrub typhus (32.9% of 18,295 cases in national surveillance 1999–2025). Its incidence is rising and its geographic range is expanding both eastward and northward across the Japanese archipelago. The disease is a classic zoonosis: humans are incidental dead-end hosts infected when bitten by Haemaphysalis and related ixodid ticks that maintain the pathogen enzootically with wild boars, deer, and rodents as amplifying blood-meal hosts.

Clinically, JSF presents with a triad of fever, rash, and inoculation eschar (tache noire). The rash characteristically involves the palms and soles and may become petechial/purpuric — a feature that helps distinguish it from scrub typhus. The core pathophysiology is a disseminated small-vessel vasculitis: R. japonica infects and replicates within vascular endothelial cells, triggering a hypercytokinemic ("cytokine storm") inflammatory response that can escalate to disseminated intravascular coagulation (DIC), purpura fulminans, and multi-organ failure. Because JSF is an acquired infectious disease, host genetic causation and Mendelian inheritance are Not Applicable; there are no causal genes, pathogenic variants, or heritable risk loci.

The single most important prognostic lever is early tetracycline therapy (minocycline or doxycycline). Overall case-fatality is low (~1%) with prompt treatment but climbs to 14–16% in severe or delayed-treatment cohorts. Independent risk factors for severe disease are advanced age (≥75 years), male sex, and treatment delay (≥4 days from onset). Adjunctive fluoroquinolones are used for fulminant cases but show no nationwide mortality benefit over tetracyclines alone. No vaccine exists; prevention rests entirely on tick-bite avoidance (permethrin-treated clothing, DEET, tick checks).

Key Findings

1. Disease Information

Japanese Spotted Fever (synonyms: Oriental Spotted Fever) is an acute infectious tick-borne rickettsiosis. Key identifiers:

Identifier system	Value
Mondo	MONDO:0000233
ICD-10	A77.8 (other spotted fevers) / A77.9
NCBI Taxon (pathogen)	txid35790 (Rickettsia japonica)
OMIM	Not applicable (acquired infection, not Mendelian)
Orphanet	Not a distinct Mendelian rare-disease entry
MeSH	Indexed under spotted fever / Rickettsia infections

Information is derived overwhelmingly from aggregated disease-level resources — surveillance cohorts, multicenter case series, and autopsy reports — rather than individual EHR records. The disease was first clinically described in Japan in 1984 (Mahara). (Finding F010)

2. Etiology

Primary cause — infectious. JSF is caused by Rickettsia japonica, a spotted fever group rickettsia. In a molecular survey of 4,549 questing ticks (747 pools) in Ibaraki Prefecture, 38.7% of pools were Rickettsia-positive, and R. japonica was detected only in Haemaphysalis hystricis; nineteen nearby wild boars were heavily infested with this tick, implicating them as key blood-meal hosts/dispersers (PMID: 42697132). Other Japanese ticks carrying SFG rickettsiae include Amblyomma testudinarium, Haemaphysalis flava, and Ixodes spp. (PMID: 41720337, PMID: 40601071). (Finding F001)

"Among these positive samples, R. japonica was detected only in Haemaphysalis hystricis. Nineteen wild boars captured near the tick sampling sites exhibited heavy infestations with H. hystricis, suggesting that wild boars are important blood-meal hosts for this tick species" — PMID: 42697132

Risk factors. - Genetic: None identified. JSF has no known causal variants, susceptibility loci, or modifier genes — consistent with an acquired infection. - Environmental / host: Advanced age (≥75), male sex, rural/outdoor occupational exposure (farming, forestry, citrus cultivation), and seasonal activity April–October coinciding with tick questing. Treatment delay is the dominant modifiable determinant of severity. (Findings F003, F011)

Protective factors. No genetic protective alleles are known. Environmental protection is behavioral: avoiding tick bites and, critically, early empirical tetracycline on clinical suspicion. Gene–environment interactions are Not Applicable given the absence of a host-genetic component.

3. Phenotypes

The hallmark is the clinical triad: fever, rash, and eschar. Frequencies from Japanese surveillance cohorts:

Phenotype (suggested HPO)	Frequency	Source
Fever (HP:0001945)	87–100%	PMID: 35545515, PMID: 39477520
Systemic erythema / rash (HP:0000988)	48–100%	Same
Eschar / tache noire (HP:0200041 skin ulcer)	79.4%	PMID: 39477520
Tick-bite history	73.6%	PMID: 35545515
Liver dysfunction (HP:0001410)	~69%	PMID: 35545515
Purpura / palmar-plantar rash (HP:0000979)	Characteristic	PMID: 30124190
DIC (HP:0005521)	14.3% (overall); ~100% in severe ICU series	PMID: 35545515, PMID: 36386421
Neurological symptoms (HP:0000707)	11.0%	PMID: 35545515
Hyponatremia (HP:0002902)	Characteristic	PMID: 30124190

"Clinical findings more frequently observed in JSF than in ST patients were purpura, palmar/plantar rash, hyponatremia, organ damage, and delayed defervescence after treatment" — PMID: 30124190

Characteristics: onset is acute and adult/geriatric-skewed (median ages in the 70s in Japanese cohorts); severity ranges from mild self-limited to fulminant; progression is monophasic but can escalate rapidly over days without treatment. Quality-of-life impact in survivors is generally full recovery, though residual hyperpigmentation and prolonged neurocognitive deficits (see MERS below) can occur. (Findings F002, F011)

4. Genetic / Molecular Information

Not Applicable for host genetics. JSF is an acquired bacterial infection with no causal human genes, no pathogenic germline/somatic variants, no modifier genes, no disease-specific epigenetic signatures, and no chromosomal abnormalities.

The relevant molecular biology is that of the pathogen. The complete genome of R. japonica strain YH has been sequenced (~1.28 Mb circular chromosome, low G+C ~37%) and characterized comparatively against other SFG rickettsiae (PMID: 31866968). As an obligate intracellular organism, R. japonica invades and replicates free in the host endothelial cytosol; virulence involves actin-based motility and outer-membrane proteins (rOmpA/rOmpB, sca family) shared across SFG rickettsiae. (Finding F010)

5. Environmental Information

Environmental factors: rural/wooded/agricultural exposure where questing ticks are present; seasonality April–October.
Lifestyle factors: outdoor occupations (farming, forestry) and recreation increase tick contact.
Infectious agent: Rickettsia japonica (NCBI:txid35790), SFG, family Rickettsiaceae. Transmitted by Haemaphysalis hystricis, H. flava, H. longicornis, Amblyomma testudinarium, and Ixodes spp. (Findings F001, F010, F012)

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Infected tick bite inoculates R. japonica into the dermis → local endothelial infection produces the eschar (tache noire) at the bite site.
R. japonica invades vascular endothelial cells and replicates in the cytosol (actin-based motility) → causes cell-to-cell spread and endothelial injury.
Endothelial infection triggers a local and systemic inflammatory/immune response → results in small-vessel vasculitis (lymphohistiocytic capillaritis/venulitis progressing to leukocytoclastic vasculitis; inferred from analogous RMSF histology).
Vasculitis + endothelial damage drives hypercytokinemia (elevated M-CSF, IL-1β, IL-10, IFN-γ, TNF-α) → causes the "cytokine storm."
Cytokine storm + endothelial injury increases vascular permeability and activates coagulation → leads to the maculopapular/petechial rash, hyponatremia, and (in severe cases) DIC.
DIC + microvascular thrombosis/hemorrhage produce multi-organ injury — hepatitis, acute renal failure (glomerular microhemorrhage), interstitial pneumonitis, CNS involvement, purpura fulminans → culminating in multi-organ failure and, if untreated/delayed, death.

Branch: With early tetracycline (step 2 interrupted), rapid defervescence (24–48 h) and full recovery follow. Without it, the chain proceeds to steps 5–6.

Autopsy of fatal JSF confirmed vasculitis with neutrophilic dermal, pulmonary-interstitial, and glomerular infiltrates plus microhemorrhage and multi-organ failure (PMID: 38043152). The hypercytokinemia driver is demonstrated by a fulminant shock case in which elevated cytokines fell rapidly after minocycline + methylprednisolone (PMID: 11376087). (Finding F005)

"Elevated levels of cytokines (macrophage colony-stimulating factor, interleukin 1 beta, interleukin 10, and gamma interferon) decreased rapidly after a combination treatment using an antibiotic (minocycline hydrochloride [MINO]) and methylprednisolone" — PMID: 11376087

Suggested ontology terms: biological processes — inflammatory response (GO:0006954), cytokine production (GO:0001816), blood coagulation (GO:0007596); cell type — vascular endothelial cell (CL:0000115); chemical entities — TNF-α, IL-1β, IL-10, IFN-γ (CHEBI cytokine class).

7. Anatomical Structures Affected

JSF is a systemic small-vessel disease with multi-organ involvement:

Level	Structures (suggested UBERON/CL)
Skin (primary)	Rash, eschar, purpura, palmar/plantar involvement; skin (UBERON:0002097); purpura fulminans → gangrene/amputation in ~33% of critical cases
Liver	Dysfunction ~69% (UBERON:0002107)
Kidney	Acute renal failure, glomerular microhemorrhage (UBERON:0002113)
Lung	Interstitial pneumonitis, pleural effusion (91% in severe series) (UBERON:0002048)
CNS	Meningitis/encephalitis, altered consciousness; reversible splenial lesion (UBERON:0000955)
Blood/hematologic	Thrombocytopenia, leukopenia, DIC (UBERON:0000178)
Vasculature (core target)	Small-vessel endothelium; blood vessel (UBERON:0001981), endothelial cell (CL:0000115)

Involvement is generally bilateral/systemic rather than lateralized. In SFG rickettsioses broadly, CNS disease features microglial expansion and macrophage infiltration with perivascular T-cell infiltration (PMID: 33091013). (Findings F005, F009)

"33.3% of whom developed purpura fulminans requiring amputation or skin graft, and 16.6% died two days after admission" — PMID: 36386421

8. Temporal Development

Onset: acute, typically 2–8 days after tick bite (incubation ~2–8 days); patients often note symptoms 1–2 days after the bite in some series (PMID: 36386421).
Age: adult/geriatric-skewed (medians in the 70s).
Course: acute and monophasic. With early tetracycline, defervescence occurs within 24–48 h and recovery is usually complete. Without prompt treatment, the disease can progress to DIC and multi-organ failure within days; fatal cases may die ~2–3 days after admission (PMID: 18411764).
Seasonality: April–October, coinciding with tick activity (PMID: 30124190).
Sequelae: residual hyperpigmentation; prolonged neurocognitive deficits in MERS-type encephalopathy (PMID: 35945027).

Critical intervention window: the first ~3–4 days from onset — beyond this, severity risk rises sharply. (Finding F011)

9. Inheritance and Population

Inheritance: Not Applicable (acquired infection — no inheritance pattern, penetrance, expressivity, anticipation, founder effects, consanguinity, or carrier frequency).

Epidemiology. JSF is the second most common acari-borne disease in Japan. National surveillance 1999–2025 recorded 18,295 acari-borne cases; JSF accounted for 32.9% (scrub typhus 56.6%, SFTS 6.7%) (PMID: 42518741). Incidence is rising: in Shimane Prefecture (2000–2022, 301 cases), a gradual significant increase (prevalence rate ratio 1.03/yr, 95% CI 1.01–1.05) was followed by rapid acceleration since 2020 (1.57, 95% CI 1.39–1.78) (PMID: 38574815). The endemic zone, historically western Japan, is expanding eastward (Ibaraki now endemic) and into northern Japan. (Finding F004)

"scrub typhus (56.6%), Japanese spotted fever (32.9%) and severe fever with thrombocytopenia syndrome (6.7%) together accounted for more than 95% of all cases" — PMID: 42518741

Demographics. Predominantly older adults; male sex is over-represented among severe cases. Geographic distribution centers on Japan, with related R. japonica/near-relative detections reported in China and Southeast Asia. (Findings F003, F004)

10. Diagnostics

Diagnosis combines clinical triad recognition with laboratory confirmation:

Modality	Detail	Source
PCR (17-kDa antigen gene)	Eschar and blood samples; confirms R. japonica	PMID: 38043152, PMID: 41720337
Indirect immunofluorescence (IFA)	Paired sera ≥4-fold IgG rise = serological reference; negative early	PMID: 31587667
qPCR + IFA in tandem	Recommended combined strategy	PMID: 31587667
Metagenomic NGS (mNGS)	Diagnoses atypical/eschar-negative and non-endemic cases	PMID: 40922296, PMID: 40082238, PMID: 39383151
Weil-Felix	Insensitive/nonspecific; often negative — not recommended	PMID: 39383151

Common laboratory abnormalities: elevated transaminases/liver dysfunction (~69%), thrombocytopenia, leukopenia/neutropenia, hyponatremia, elevated CRP. (Finding F007)

"Metagenomic sequencing (MetaCAP) technology enabled a definitive diagnosis by identifying Rickettsia japonica-specific DNA sequences in the patient's blood" — PMID: 40922296

Differential diagnosis is critical because treatment differs. A five-hospital Nagasaki study (23 SFTS, 38 JSF) found leukopenia (WBC <4000/µL) and altered mental status best separated SFTS from JSF (AUC 1.000, 100% sensitivity/specificity); JSF characteristically has rash, preserved consciousness, and higher WBC/CRP (PMID: 36016429). JSF differs from scrub typhus by seasonality, palmar/plantar rash, purpura, and delayed defervescence (PMID: 30124190). Rare mimics include SLE (PMID: 41731438) and SFTSV co-infection (PMID: 34407756). (Finding F014)

"Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/μL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity" — PMID: 36016429

Genetic testing / omics screening / newborn screening: Not Applicable (no host-genetic component).

11. Outcome / Prognosis

Overall case-fatality is low with early treatment but rises steeply with severity:

Cohort	Severe outcome	Mortality	Source
Ehime surveillance (n=91)	—	1.1%	PMID: 35545515
Nagasaki multicenter (n=65)	33.3%	~1.5% (1/65)	PMID: 39477520
Eastern Hiroshima (n=42)	31.0%	14.3%	PMID: 42576956
Yichang, China ICU series	100% DIC	16.6%	PMID: 36386421

Prognostic factors: age ≥75, male sex, treatment delay ≥4 days, DIC, altered mental status, hypotension, hypoxia. A nationwide Diagnosis Procedure Combination inpatient study (n=1,060, 2010–2021) found that adding a fluoroquinolone to tetracycline on admission produced no significant difference in in-hospital mortality, complications, cost, or length of stay after inverse-probability weighting (PMID: 35987471). (Findings F003, F013)

"Inverse probability of treatment weighting showed no statistically significant differences between the groups in in-hospital mortality... This study did not show any significantly improved effectiveness using FQ antimicrobials in combination with TCs for treating JSF" — PMID: 35987471

Recovery potential is excellent with prompt treatment; complications (DIC, purpura fulminans → amputation, renal failure, MERS-type encephalopathy) drive morbidity in the severe minority.

12. Treatment

First-line: tetracyclines (minocycline or doxycycline) — NCIT clinical-intervention terms: Minocycline (NCIT:C61829), Doxycycline (NCIT:C513), Tetracycline (NCIT:C859). Fever typically resolves rapidly (e.g., within 36 h) after IV minocycline + levofloxacin (PMID: 26630793); doxycycline achieves rapid resolution in typical cases (PMID: 40922296).

Severe/fulminant disease: - Tetracycline + new quinolone (ciprofloxacin, tosufloxacin, levofloxacin) is recommended for fulminant JSF where minocycline alone is insufficient (PMID: 26630793, PMID: 11376087). Note the nationwide caveat that adjunctive fluoroquinolone shows no mortality benefit (PMID: 35987471). - Corticosteroids (methylprednisolone) suppress the cytokine storm in severe cases (PMID: 39328670, PMID: 11376087). - Supportive care for DIC/multi-organ failure (hemodialysis, mechanical ventilation, anticoagulation management).

"In the treatment of fulminant JSF (body temperature > 39 degrees C) the prompt administration of a combination of tetracycline and new quinolone has been recommended" — PMID: 26630793

Mechanistic rationale for combination: in vitro, minocycline + ciprofloxacin synergistically inhibit TNF-α and chemokine production in LPS-stimulated THP-1 monocytes — an anti-inflammatory effect beyond antimicrobial action (PMID: 41341009).

"Combination therapy with MINO and CPFX enhanced the inhibitory effects on inflammatory cytokine and chemokine production" — PMID: 41341009

Pharmacogenomics, gene/cell/RNA/targeted/immuno-therapies: Not Applicable. (Findings F006, F013)

13. Prevention

Primary prevention (behavioral): avoid tick bites — permethrin-treated clothing, DEET and other repellents, protective clothing, and prompt tick checks/removal. Against the vector Haemaphysalis longicornis, formulated repellents gave 93–97% repellency and permethrin-treated garments dislodged 96% of nymphs within 3 min (PMID: 32073128). General tick-borne disease prevention endorses DEET/permethrin and prompt tick removal (PMID: 38478946).
Secondary prevention: early empirical tetracycline on clinical suspicion is the key measure — the disease's decisive intervention. Doxycycline prophylaxis is not standard for JSF (PMID: 25527099), though prophylactic antibiotics after tick bite are commonly prescribed in Japanese practice (88.6% in one cohort); R. tamurae-positive bites remained asymptomatic without antibiotics (PMID: 41720337).
Immunization: No vaccine exists.
Genetic screening/counseling: Not Applicable. (Finding F008)

"all tested product formulations were highly effective with estimated repellencies ranging from 93 to 97%... 96% of introduced ticks dislodging" — PMID: 32073128

14. Other Species / Natural Disease

JSF is maintained in an enzootic tick–mammal cycle; humans are incidental dead-end hosts. Ticks (Haemaphysalis hystricis, H. flava, H. longicornis, Amblyomma testudinarium, Ixodes spp.) serve as both vectors and reservoirs (transovarial maintenance is typical of SFG rickettsiae); wild boars (Sus scrofa, NCBI:txid9823) and rodents act as amplifying/blood-meal hosts (PMID: 42697132, PMID: 40601071). No naturally occurring clinical JSF disease is well documented in companion animals, though dogs seroconvert to SFG rickettsiae and can serve as sentinels (PMID: 28569177). Zoonotic potential is central to the disease's ecology. (Findings F001, F012)

"wild boars are important blood-meal hosts for this tick species" — PMID: 42697132

15. Model Organisms

There is no dedicated genetic disease model (the disease is infectious, not Mendelian). Mechanistic understanding derives from: - In vitro: R. japonica is propagated in Vero cells and related cell lines, as for other SFG rickettsiae (PMID: 30529423); THP-1 monocytic cells are used for cytokine/anti-inflammatory drug studies (PMID: 41341009). - Murine models of related rickettsioses (scrub typhus/SFR) reveal cerebral T-cell infiltration, endothelial infection, and vascular damage underlying neuropathogenesis (PMID: 33091013).

Model limitations: most mechanistic inference is extrapolated from related rickettsioses (RMSF, scrub typhus) rather than R. japonica-specific in vivo models. (Finding F012)

"Animal models of scrub typhus have identified cerebral T-cell infiltration and vascular damage associated with endothelial infection and neuropathogenesis" — PMID: 33091013

Mechanistic Model / Interpretation

   Infected Haemaphysalis tick bite
      │ inoculates R. japonica
      ▼
   Local endothelial infection ──────────► ESCHAR (tache noire)
      │ invades & replicates (actin-based motility)
      ▼
   Systemic endothelial infection
      │ triggers immune/inflammatory response
      ▼
   SMALL-VESSEL VASCULITIS ◄──── perivascular T-cell / neutrophil infiltrate
      │ drives
      ▼
   HYPERCYTOKINEMIA (M-CSF, IL-1β, IL-10, IFN-γ, TNF-α)
      │ ↑ vascular permeability + coagulation activation
      ┌───────┴─────────────────────────────┐
      ▼                                       ▼
   RASH (palms/soles,          DISSEMINATED INTRAVASCULAR
   petechiae, purpura),        COAGULATION (DIC)
   hyponatremia                        │
                       ▼
       MULTI-ORGAN FAILURE
     (liver, kidney, lung, CNS, skin/purpura fulminans)
                       │
                       ▼
                    DEATH  (if untreated / delayed)

   ┌──────────────────────────────────────────────────────┐
   │ INTERVENTION: Early tetracycline halts step 2 →        │
   │ rapid defervescence (24–48h) → full recovery.          │
   │ Delay ≥4 d, age ≥75, male sex → severe branch.         │
   └──────────────────────────────────────────────────────┘

The unifying theme is endothelium-centric vasculitis amplified by cytokine storm. Upstream events (endothelial infection, vasculitis) are demonstrated by autopsy and cytokine kinetics; downstream events (DIC, multi-organ failure) are the clinical endpoints. The therapeutic model is elegantly simple: because the entire cascade depends on ongoing intracellular bacterial replication, an antibiotic that penetrates cells (tetracycline) and is given early can abort the whole chain — which is exactly why treatment timing dominates prognosis.

Evidence Base

PMID	Contribution
42697132	Identifies H. hystricis as vector and wild boar as blood-meal host; documents eastward endemic expansion
30124190	Distinguishing features vs scrub typhus (palmar/plantar rash, purpura, hyponatremia, seasonality)
35545515	Phenotype frequencies and 1.1% mortality (n=91)
39477520	Severe-disease risk factors: age ≥75, male sex, treatment delay ≥4 d
42576956	Dose-response of minocycline delay; 14.3% mortality in endemic cohort
42518741	National surveillance — JSF = 32.9% of acari-borne disease
38574815	Rising incidence, acceleration since 2020
38043152	Autopsy evidence of vasculitis and multi-organ microvascular injury
11376087	Hypercytokinemia as driver of fulminant shock; steroid response
26630793	Tetracycline + new quinolone for fulminant JSF
41341009	Anti-cytokine synergy of minocycline + ciprofloxacin (in vitro)
31587667	qPCR + IFA tandem diagnostic strategy
40922296	mNGS diagnosing atypical, eschar-negative JSF
32073128	Efficacy of repellents/permethrin against vector tick
36386421	Purpura fulminans, 100% DIC, 16.6% mortality in ICU series
33091013	Cellular basis of CNS involvement in SFG rickettsioses
35987471	Nationwide DB: adjunctive fluoroquinolone gives no mortality benefit
36016429	Objective criteria differentiating JSF from SFTS
31866968	Genomic characterization of R. japonica

Corroborating comparative literature (RMSF/Mediterranean spotted fever) supports the vasculitis mechanism (PMID: 9449487) and the caution that fluoroquinolones may worsen SFG rickettsiosis outcomes (PMID: 21642652), reinforcing the tetracycline-first strategy.

Limitations and Knowledge Gaps

Extrapolated mechanism. Much of the detailed cellular/immune pathogenesis (CNS T-cell infiltration, endothelial neuropathogenesis) is inferred from murine models of related rickettsioses (scrub typhus, RMSF), not R. japonica-specific in vivo experiments.
No host-genetic dimension. Sections on genetics, inheritance, genetic testing, gene/cell therapy, and genetic counseling are Not Applicable — a complete and expected gap for an acquired infection, not a research deficiency.
Geographic bias. Nearly all clinical cohorts are Japanese (plus a Chinese ICU series); prognostic estimates and risk-factor odds ratios may not generalize to the expanding/emerging range.
Small severe-cohort sizes. Severe-disease mortality (14–16%) derives from modest single-center/ICU cohorts with wide confidence intervals.
Corticosteroid evidence is weak. Steroid use rests on case reports and mechanistic plausibility, not randomized trials.
Serology timing. IFA is insensitive early, and Weil-Felix is unreliable — creating a diagnostic window where clinical suspicion alone must drive treatment.

Proposed Follow-up Experiments / Actions

Develop an R. japonica-specific animal model (immunocompetent and aged/comorbid mice) to test whether age-related endothelial/immune changes explain the geriatric severity skew.
Prospective multicenter RCT of adjunctive corticosteroids in severe JSF with DIC, given the strong mechanistic rationale but weak clinical evidence.
Biomarker study correlating admission cytokine profiles (M-CSF, IL-1β, IL-10, IFN-γ, TNF-α) and coagulation markers with progression to DIC, to build a validated severity-prediction score.
Deploy point-of-care mNGS/qPCR in expanding endemic areas (eastern/northern Japan) to close the early-diagnosis window and quantify true incidence.
One Health surveillance integrating tick, wild-boar, deer, and rodent sampling across the expanding range to map emerging endemic foci and inform targeted vector control.
Formal cost-effectiveness analysis of empirical early tetracycline vs confirmatory-test-then-treat strategies, given that treatment delay is the dominant modifiable driver of mortality.

Report prepared from a 5-iteration autonomous investigation: 14 confirmed findings, 61 papers reviewed. Evidence source types span human clinical cohorts, autopsy pathology, in vitro pharmacology, and comparative model-organism studies of related rickettsioses.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	34
Resolved	34
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	34
On topic	17
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	23
Resolved	23
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	8
Terms named correctly	3
Terms named as a different term	4
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0000233 (2 mentions) - the report calls it "Mondo"; MONDO calls it Japanese spotted fever
HP:0000988 (1 mention) - the report calls it "Systemic erythema / rash"; HP calls it Skin rash
HP:0000979 (1 mention) - the report calls it "Purpura / palmar-plantar rash"; HP calls it Purpura
HP:0005521 (1 mention) - the report calls it "DIC"; HP calls it Disseminated intravascular coagulation

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0000707 (1 mention) - the report calls it "Neurological symptoms"; HP calls it Abnormality of the nervous system, and lists "Neurological abnormality" among its other names

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Japanese Spotted Fever (MONDO:0000233): A Comprehensive Disease Characteristics Report

Summary

Key Findings

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

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