African Tick-Bite Fever

Infectious Disease MONDO:0000227 Pathograph 17 Show in embeddings browser Spotted fever rickettsiosis

African tick-bite fever is an acute, usually self-limited spotted fever group rickettsiosis caused by the obligately intracellular bacterium Rickettsia africae. Infection follows bites from Amblyomma ticks, whose hunting habits explain the frequent multiple-eschar and case-cluster presentations. Dermal inoculation produces one or more eschars and regional lymphadenopathy, while the systemic illness is a febrile headache-myalgia syndrome with only modest endothelial inflammatory activation compared with more severe spotted fevers.

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6
Pathophys.
10
Phenotypes
17
Pathograph
2
Medical Actions
1
Deep Research
🏷

Classifications

Harrison's Part
INFECTIOUS DISEASES
⚙

Pathophysiology

6
Amblyomma-Borne Rickettsia africae Inoculation
Infected Amblyomma ticks inoculate R. africae into the dermis. Because Amblyomma ticks actively hunt hosts, one exposure can create multiple inoculation lesions and clustered illness among co-travelers.
symbiont entry into host cell GO:0046718 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves symbiont entry into host cell (GO:0046718). GO:0046718 is a biological process from the Gene Ontology.
Downstream
Dermal Mononuclear Phagocyte Infection Dermal inoculation exposes macrophage or dendritic target cells to R. africae.
Show evidence (1 reference)
PMID:20233665 SUPPORT Human Clinical
"It is caused by the bite of an infected Amblyomma tick, whose hunting habits explain the typical presence of multiple inoculation skin lesions and the occurrence of clustered cases."
The review ties the initiating infected-tick bite to the multiple inoculation lesions that distinguish ATBF from many other spotted fevers.
Dermal Mononuclear Phagocyte Infection
After dermal inoculation, R. africae first infects mononuclear phagocytes (CD68+ macrophages and dendritic cells) at the bite site, establishing the local dermal infection.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
Downstream
Multiple Inoculation Eschars Local dermal infection creates one or more tache-noire eschars.
Lymphatic Dissemination to Regional Nodes Dermal infection spreads through lymphatic vessels to draining lymph nodes.
Rickettsial Ribosomal Translation (Doxycycline Target) R. africae depends on bacterial ribosomal protein synthesis.
Intracytosolic Rickettsia africae Niche R. africae resides in host-cell cytosol during infection.
Show evidence (2 references)
PMID:30148688 SUPPORT REVIEW SYNTHESIS Other
"The pathogenic sequence of events that occur in rickettsial infection begins with the entry of organisms inoculated by the feeding tick or mite or scratched into the skin from infected louse or flea feces deposited on the skin."
The rickettsial pathogenesis review supports skin inoculation as the first step of arthropod-borne rickettsial infection.
PMID:30148688 SUPPORT REVIEW SYNTHESIS Other
"The initial target cells of infection are CD68+ cells (macrophages and/or dendritic cells)"
The review identifies dermal mononuclear phagocytes as the first infected host cells.
Lymphatic Dissemination to Regional Nodes
R. africae spreads through dermal lymphatic vessels to the regional draining lymph nodes.
Downstream
Regional Lymphadenopathy Lymphatic spread to draining nodes contributes to regional lymphadenopathy.
Mild Systemic Endothelial Activation Lymphatic and hematogenous spread seeds endothelial infection.
Show evidence (1 reference)
PMID:30148688 SUPPORT REVIEW SYNTHESIS Other
"The rickettsiae then spread via lymphatic vessels to the regional lymph nodes"
The rickettsial pathogenesis review states that infection spreads via lymphatic vessels to the regional lymph nodes.
Mild Systemic Endothelial Activation
Compared with R. conorii in Mediterranean spotted fever, R. africae provokes only modest IL-8 and adhesion-molecule induction in endothelial cells and in patient serum, fitting the usually self-limited ATBF course.
vascular endothelial cell CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Fever Systemic inflammatory signaling drives the acute febrile syndrome.
Headache Systemic infection produces headache as part of the flu-like syndrome.
Myalgia Systemic infection produces myalgia as part of the flu-like syndrome.
Papulovesicular Rash Cutaneous microvascular infection and inflammation produce the variable rash.
Chills The systemic febrile illness is accompanied by chills.
Aphthous stomatitis Mucosal involvement can produce an enanthema with aphthous stomatitis.
Myocarditis Severe disease, described in elderly patients, can include myocarditis.
Show evidence (2 references)
PMID:19091423 SUPPORT In Vitro
"R. conorii induced a marked increase in MCP-1, IL-8, and adhesion molecules in endothelial cells, involving toll-like receptor 4 activation. In contrast, R. africae induced MCP-1 expression, but only modest or no responses were seen on IL-8 and adhesion molecules."
Human endothelial-cell stimulation directly supports the attenuated cytokine and adhesion-molecule response to R. africae.
PMID:19091423 SUPPORT Human Clinical
"Comparable to the in vitro response, levels of IL-8 and adhesion molecules showed no or only a modest increase in ATBF patients while these inflammatory markers were markedly elevated during MSF."
Patient serum findings mirror the endothelial-cell experiment and support modest systemic endothelial activation in ATBF.
Rickettsial Ribosomal Translation (Doxycycline Target)
R. africae, like other bacteria, depends on 70S ribosomal translation of its mRNA; doxycycline binds the 30S ribosomal subunit and blocks bacterial protein synthesis.
Translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. response to antibiotic GO:0046677 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to antibiotic (GO:0046677). GO:0046677 is a biological process from the Gene Ontology.
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 for the bacterial ribosome as the conserved target class for tetracyclines such as doxycycline; the ATBF treatment item below establishes that doxycycline is used for tick-borne rickettsioses.
Intracytosolic Rickettsia africae Niche
Spotted-fever-group rickettsiae live free in the host-cell cytosol and exploit intracellular host metabolites, so effective drugs for ATBF must reach an intracytosolic bacterial compartment.
biological process involved in interaction with host GO:0051701 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves biological process involved in interaction with host (GO:0051701). GO:0051701 is a biological process from the Gene Ontology.
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 review supports the free cytosolic niche for Rickettsia species and the metabolic dependence represented by the shared intracellular-pathogen persistence module.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for African Tick-Bite Fever Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Cardiovascular 2
Regional Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Regional lymphadenopathy, annotated with Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Bound to the general term HP:0002716 Lymphadenopathy; no localized/regional lymphadenopathy HPO term was found on searching cache/hp/terms.csv, so the regional qualifier is carried in preferred_term.
Show evidence (1 reference)
PMID:27172113 SUPPORT Human Clinical
"Patients with African tick bite fever typically have fever, headache, myalgia, one or more inoculation eschars, regional lymphadenopathy, and sometimes maculopapular or vesicular rash"
The CDC report lists regional lymphadenopathy as a typical ATBF feature.
Myocarditis HP:0012819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocarditis (HP:0012819). HP:0012819 is a phenotype from the Human Phenotype Ontology.
A rare severe manifestation; the cited support is a single elderly-patient case series, so this is not a common feature of ATBF.
Show evidence (1 reference)
PMID:18558881 SUPPORT Human Clinical
"lymphangitis and myocarditis in 1 patient and suspected brain involvement in 2 patients"
The elderly case series reports myocarditis among the severe manifestations.
Head and Neck 1
Aphthous stomatitis Aphthous ulcer HP:0032154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aphthous stomatitis, annotated with Aphthous ulcer (HP:0032154). HP:0032154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12766836 SUPPORT Human Clinical
"aphthous stomatitis were seen in < or = 50% of patients"
The prospective traveler cohort lists aphthous stomatitis among the specific ATBF features seen in up to half of patients.
Immune 1
Papulovesicular Rash OCCASIONAL Papulovesicular eruption HP:0033700 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Papulovesicular rash, annotated with Papulovesicular eruption (HP:0033700). HP:0033700 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27172113 SUPPORT Human Clinical
"Patients with African tick bite fever typically have fever, headache, myalgia, one or more inoculation eschars, regional lymphadenopathy, and sometimes maculopapular or vesicular rash"
The CDC report lists maculopapular or vesicular rash as an intermittent ATBF feature.
PMID:20233665 SUPPORT Human Clinical
"a cutaneous rash is described in 15-46% of cases"
The review quantifies the ATBF rash frequency at 15-46% of cases.
Integument 1
Multiple Inoculation Eschars FREQUENT HP:6000793 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eschar (HP:6000793). HP:6000793 is a phenotype from the Human Phenotype Ontology.
The eschar's local mechanism (dermal vasculitic necrosis at the inoculation site) is extrapolated from spotted-fever-group rickettsioses in general; no ATBF-specific histopathology snippet is cited for the local lesion.
Sequelae: Cellulitis
Show evidence (1 reference)
PMID:20233665 SUPPORT Human Clinical
"Indeed, the presence of at least one inoculation eschar is observed in 53-100% of cases and multiple eschars in 21-54%."
The review quantifies eschars as present in a majority of reported ATBF cases and multiple eschars as a distinctive subset.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12766836 SUPPORT Human Clinical
"More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients."
The prospective traveler cohort places fever in the dominant acute symptom complex; the greater-than-80% figure is a disjunction across fever, headache, and myalgia and is not used as a frequency for fever alone.
Musculoskeletal 1
Cellulitis HP:0100658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cellulitis (HP:0100658). HP:0100658 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18503259 SUPPORT Human Clinical
"may be a risk factor for cellulitis"
The case report identifies the inoculation eschar as a risk factor for secondary cellulitis.
Nervous System 1
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12766836 SUPPORT Human Clinical
"More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients."
The cohort places headache in the dominant nonspecific ATBF symptom complex but does not give a headache-only rate.
Constitutional 2
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12766836 SUPPORT Human Clinical
"More than 80% of the patients had fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis, cutaneous rash, and aphthous stomatitis were seen in < or = 50% of patients."
The cohort places myalgia in the dominant nonspecific ATBF symptom complex but reports the fever/headache/myalgia figure as a disjunction.
Chills HP:0025143 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chills (HP:0025143). HP:0025143 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18558881 SUPPORT Human Clinical
"long-lasting general symptoms, including fever (in 75% of patients), chills (87.5%), asthenia (50%)"
Chills occurred in 87.5% of the elderly ATBF case series.
💊

Medical Actions

2
Empiric doxycycline
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: doxycycline CHEBI:50845 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxycycline (CHEBI:50845). CHEBI:50845 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Doxycycline is first-line therapy for tick-borne rickettsial diseases, including ATBF, because the drug arrests the bacterial 30S-ribosomal target and penetrates the host-cell cytosol where R. africae resides.
Mechanism Target:
INHIBITS Rickettsial Ribosomal Translation (Doxycycline Target) — Doxycycline binds the bacterial 30S ribosomal subunit and arrests rickettsial protein synthesis.
BYPASSES Intracytosolic Rickettsia africae Niche — Doxycycline can reach the cytosolic rickettsial compartment.
Show evidence (1 reference)
PMID:27172113 SUPPORT Human Clinical
"Doxycycline is the drug of choice for treatment of all tickborne rickettsial diseases in patients of all ages, including children aged <8 years, and should be initiated immediately in persons with signs and symptoms suggestive of rickettsial disease"
The CDC recommendation covers ATBF as a tick-borne rickettsial disease and supports immediate empiric doxycycline for clinically compatible illness.
Personal protection against tick bites
Platform: Behavioral / lifestyle
No vaccine exists, so personal protection against ticks -- skin repellents, permethrin-impregnated clothing, and behavioral measures -- is the principal means of preventing ATBF.
Show evidence (1 reference)
PMID:21302476 SUPPORT REVIEW SYNTHESIS Other
"Personal protection measures (PPM) are essential and often the only means"
The review establishes personal protection measures as the essential means of preventing tick-borne infection.
🔬

Diagnosis

3
Clinical diagnosis with retrospective laboratory confirmation
Initial diagnosis is usually clinical, based on a compatible fever-eschar syndrome after travel or tick exposure, because early laboratory tests are insensitive or unavailable at symptom onset.
clinical diagnosis NCIT:C18020 NCI Thesaurus (NCIT)
Results: Compatible travel or Amblyomma tick exposure plus fever and one or more eschars supports empiric treatment before confirmatory testing returns.
Show evidence (1 reference)
PMID:27488618 SUPPORT Human Clinical
"The diagnosis of African tick bite fever is often based on clinical grounds due to a lack of reliable diagnostic tests at commencement of symptoms."
The case report's introduction states the acute diagnostic constraint that makes clinical diagnosis necessary at presentation.
Eschar-swab PCR for Rickettsia africae
PCR on material swabbed non-invasively from an eschar can detect R. africae DNA during early disease, including after doxycycline has already been started in at least one reported imported case.
polymerase chain reaction NCIT:C17003 NCI Thesaurus (NCIT)
Results: A positive eschar-swab PCR identifies the R. africae DNA in an inoculation lesion.
Show evidence (1 reference)
PMID:27488618 SUPPORT Human Clinical
"In this patient direct molecular detection of R. africae was performed by PCR from a sample obtained non-invasively with a swab from the rickettsial eschar."
The imported Tanzanian case demonstrates noninvasive molecular detection from an eschar swab.
Indirect immunofluorescence serology
Retrospective confirmation uses indirect immunofluorescence antibody serology, but antibodies cross-react across spotted-fever-group species (notably R. conorii), so serology alone does not distinguish ATBF from Mediterranean spotted fever.
serology testing NCIT:C25294 NCI Thesaurus (NCIT)
Results: Rising anti-spotted-fever-group antibody titers confirm rickettsiosis retrospectively; species-level distinction requires molecular methods.
Show evidence (2 references)
PMID:9916419 SUPPORT Human Clinical
"apparent cross reaction between the two organisms hampers the use of conventional antibody"
The report documents serologic cross-reaction between R. africae and R. conorii, limiting species-level serology.
PMID:9916419 SUPPORT Human Clinical
"beta-lactam antibiotics commonly used as an empiric therapy are not effective"
The report notes that empiric beta-lactam antibiotics are ineffective against spotted-fever-group rickettsioses, underscoring the need for doxycycline.
📈

Progression

1
Self-limited acute illness
ATBF is usually a mild, self-limited illness; in one traveler outbreak most patients recovered spontaneously before antibiotics were started, though recovery can be slow, especially in elderly patients.
Show evidence (1 reference)
PMID:11939395 SUPPORT Human Clinical
"all but one of the patients recovered spontaneously before antibiotic treatment was initiated."
The Italian outbreak shows spontaneous recovery in most patients, supporting the self-limited course.
🌍

Epidemiology

1
Returned-traveler ATBF risk after rural sub-Saharan Africa exposure
African tick-bite fever is enriched among travelers with rural or game exposure in sub-Saharan Africa and can present as case clusters after shared exposure to Amblyomma ticks.
sub-Saharan Africa travel rural tick exposure Amblyomma tick exposure
Show evidence (2 references)
PMID:20233665 SUPPORT Human Clinical
"African tick-bite fever (ATBF) is a newly described spotted fever rickettsiosis that frequently presents with multiple eschars in travelers returning from sub-Saharan Africa and, to a lesser extent, from the West Indies."
The case series and review identify sub-Saharan African travel, plus a smaller West Indies signal, as the usual imported-case epidemiologic context.
PMID:28544092 SUPPORT Human Clinical
"ATBF has been reported as the second most commonly documented etiology of fever, after malaria"
ATBF is the second most common documented cause of fever after malaria in ill travelers returning from sub-Saharan Africa.
🦠

Infectious Agent

1
Rickettsia africae
Obligate intracellular spotted-fever-group rickettsial bacterium that is transmitted by Amblyomma ticks and causes African tick-bite fever.
Rickettsia africae NCBITaxon:35788 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:20233665 SUPPORT Human Clinical
"The etiological agent of ATBF is Rickettsia africae, an emerging tick-borne pathogenic bacterium."
The case series and review names R. africae as the etiologic bacterium of ATBF.
↔️

Transmission

1
Amblyomma tick bite transmission
Rickettsia africae is transmitted to humans by infected Amblyomma ticks, whose host-hunting behavior helps explain the multiple inoculation skin lesions and clustered cases characteristic of ATBF.
Show evidence (1 reference)
PMID:20233665 SUPPORT Human Clinical
"It is caused by the bite of an infected Amblyomma tick, whose hunting habits explain the typical presence of multiple inoculation skin lesions and the occurrence of clustered cases."
Imported traveler cases support infected Amblyomma tick bites as the clinically relevant route of acquisition.
{ }

Source YAML

click to show 
name: African Tick-Bite Fever
creation_date: "2026-09-25T11:07:39Z"
updated_date: "2026-09-25T11:07:39Z"
category: Infectious Disease
description: >-
  African tick-bite fever is an acute, usually self-limited spotted fever group
  rickettsiosis caused by the obligately intracellular bacterium Rickettsia
  africae. Infection follows bites from Amblyomma ticks, whose hunting habits
  explain the frequent multiple-eschar and case-cluster presentations. Dermal
  inoculation produces one or more eschars and regional lymphadenopathy, while
  the systemic illness is a febrile headache-myalgia syndrome with only modest
  endothelial inflammatory activation compared with more severe spotted fevers.
disease_term:
  preferred_term: African tick-bite fever
  term:
    id: MONDO:0000227
    label: African tick-bite fever
parents:
- Spotted fever rickettsiosis
synonyms:
- African tick bite fever
- African tick typhus
- Rickettsia africae infection
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:20233665
      reference_title: "African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The etiological agent of ATBF is Rickettsia africae, an emerging
        tick-borne pathogenic bacterium.
      explanation: >-
        The traveler case series and review identifies African tick-bite fever
        as a bacterial spotted-fever rickettsiosis, placing it in Harrison's
        Infectious Diseases Part.

infectious_agent:
- name: Rickettsia africae
  infectious_agent_term:
    preferred_term: Rickettsia africae
    term:
      id: NCBITaxon:35788
      label: Rickettsia africae
  description: >-
    Obligate intracellular spotted-fever-group rickettsial bacterium that is
    transmitted by Amblyomma ticks and causes African tick-bite fever.
  evidence:
  - reference: PMID:20233665
    reference_title: "African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The etiological agent of ATBF is Rickettsia africae, an emerging
      tick-borne pathogenic bacterium.
    explanation: The case series and review names R. africae as the etiologic bacterium of ATBF.

transmission:
- name: Amblyomma tick bite transmission
  description: >-
    Rickettsia africae is transmitted to humans by infected Amblyomma ticks,
    whose host-hunting behavior helps explain the multiple inoculation skin
    lesions and clustered cases characteristic of ATBF.
  evidence:
  - reference: PMID:20233665
    reference_title: "African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by the bite of an infected Amblyomma tick, whose hunting
      habits explain the typical presence of multiple inoculation skin lesions
      and the occurrence of clustered cases.
    explanation: >-
      Imported traveler cases support infected Amblyomma tick bites as the
      clinically relevant route of acquisition.

epidemiology:
- name: Returned-traveler ATBF risk after rural sub-Saharan Africa exposure
  description: >-
    African tick-bite fever is enriched among travelers with rural or game
    exposure in sub-Saharan Africa and can present as case clusters after shared
    exposure to Amblyomma ticks.
  factors:
  - sub-Saharan Africa travel
  - rural tick exposure
  - Amblyomma tick exposure
  evidence:
  - reference: PMID:20233665
    reference_title: "African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      African tick-bite fever (ATBF) is a newly described spotted fever
      rickettsiosis that frequently presents with multiple eschars in travelers
      returning from sub-Saharan Africa and, to a lesser extent, from the West
      Indies.
    explanation: >-
      The case series and review identify sub-Saharan African travel, plus a
      smaller West Indies signal, as the usual imported-case epidemiologic
      context.
  - reference: PMID:28544092
    reference_title: "Fever and Multiple Eschars After an African Safari: Report of Three Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATBF has been reported as the second most commonly documented etiology of fever, after malaria"
    explanation: ATBF is the second most common documented cause of fever after malaria in ill travelers returning from sub-Saharan Africa.

pathophysiology:
- name: Amblyomma-Borne Rickettsia africae Inoculation
  role: trigger
  description: >-
    Infected Amblyomma ticks inoculate R. africae into the dermis. Because
    Amblyomma ticks actively hunt hosts, one exposure can create multiple
    inoculation lesions and clustered illness among co-travelers.
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  evidence:
  - reference: PMID:20233665
    reference_title: "African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by the bite of an infected Amblyomma tick, whose hunting
      habits explain the typical presence of multiple inoculation skin lesions
      and the occurrence of clustered cases.
    explanation: >-
      The review ties the initiating infected-tick bite to the multiple
      inoculation lesions that distinguish ATBF from many other spotted fevers.
  downstream:
  - target: Dermal Mononuclear Phagocyte Infection
    causal_link_type: DIRECT
    description: Dermal inoculation exposes macrophage or dendritic target cells to R. africae.

- name: Dermal Mononuclear Phagocyte Infection
  role: primary_infection
  description: >-
    After dermal inoculation, R. africae first infects mononuclear phagocytes
    (CD68+ macrophages and dendritic cells) at the bite site, establishing the
    local dermal infection.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  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: >-
      The pathogenic sequence of events that occur in rickettsial infection
      begins with the entry of organisms inoculated by the feeding tick or mite
      or scratched into the skin from infected louse or flea feces deposited on
      the skin.
    explanation: >-
      The rickettsial pathogenesis review supports skin inoculation as the first
      step of arthropod-borne rickettsial infection.
  - 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: >-
      The initial target cells of infection are CD68+ cells (macrophages and/or
      dendritic cells)
    explanation: >-
      The review identifies dermal mononuclear phagocytes as the first infected
      host cells.
  downstream:
  - target: Multiple Inoculation Eschars
    causal_link_type: DIRECT
    description: Local dermal infection creates one or more tache-noire eschars.
  - target: Lymphatic Dissemination to Regional Nodes
    causal_link_type: DIRECT
    description: Dermal infection spreads through lymphatic vessels to draining lymph nodes.
  - target: Rickettsial Ribosomal Translation (Doxycycline Target)
    causal_link_type: DIRECT
    description: R. africae depends on bacterial ribosomal protein synthesis.
  - target: Intracytosolic Rickettsia africae Niche
    causal_link_type: DIRECT
    description: R. africae resides in host-cell cytosol during infection.

- name: Lymphatic Dissemination to Regional Nodes
  role: primary_infection
  description: >-
    R. africae spreads through dermal lymphatic vessels to the regional draining
    lymph nodes.
  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: >-
      The rickettsiae then spread via lymphatic vessels to the regional lymph
      nodes
    explanation: >-
      The rickettsial pathogenesis review states that infection spreads via
      lymphatic vessels to the regional lymph nodes.
  downstream:
  - target: Regional Lymphadenopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Lymphatic spread to draining nodes contributes to regional lymphadenopathy.
  - target: Mild Systemic Endothelial Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Lymphatic and hematogenous spread seeds endothelial infection.

- name: Mild Systemic Endothelial Activation
  role: vascular_response
  description: >-
    Compared with R. conorii in Mediterranean spotted fever, R. africae provokes
    only modest IL-8 and adhesion-molecule induction in endothelial cells and in
    patient serum, fitting the usually self-limited ATBF course.
  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
  evidence:
  - reference: PMID:19091423
    reference_title: Relative chemokine and adhesion molecule expression in Mediterranean spotted fever and African tick bite fever.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      R. conorii induced a marked increase in MCP-1, IL-8, and adhesion
      molecules in endothelial cells, involving toll-like receptor 4 activation.
      In contrast, R. africae induced MCP-1 expression, but only modest or no
      responses were seen on IL-8 and adhesion molecules.
    explanation: >-
      Human endothelial-cell stimulation directly supports the attenuated
      cytokine and adhesion-molecule response to R. africae.
  - reference: PMID:19091423
    reference_title: Relative chemokine and adhesion molecule expression in Mediterranean spotted fever and African tick bite fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comparable to the in vitro response, levels of IL-8 and adhesion molecules
      showed no or only a modest increase in ATBF patients while these
      inflammatory markers were markedly elevated during MSF.
    explanation: >-
      Patient serum findings mirror the endothelial-cell experiment and support
      modest systemic endothelial activation in ATBF.
  downstream:
  - target: Fever
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Systemic inflammatory signaling drives the acute febrile syndrome.
  - target: Headache
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Systemic infection produces headache as part of the flu-like syndrome.
  - target: Myalgia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Systemic infection produces myalgia as part of the flu-like syndrome.
  - target: Papulovesicular Rash
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Cutaneous microvascular infection and inflammation produce the variable rash.
  - target: Chills
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The systemic febrile illness is accompanied by chills.
  - target: Aphthous stomatitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Mucosal involvement can produce an enanthema with aphthous stomatitis.
  - target: Myocarditis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Severe disease, described in elderly patients, can include myocarditis.

- name: Rickettsial Ribosomal Translation (Doxycycline Target)
  role: therapeutic_vulnerability
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  description: >-
    R. africae, like other bacteria, depends on 70S ribosomal translation of its
    mRNA; doxycycline binds the 30S ribosomal subunit and blocks bacterial
    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 for the bacterial ribosome as the conserved target class
      for tetracyclines such as doxycycline; the ATBF treatment item below
      establishes that doxycycline is used for tick-borne rickettsioses.

- name: Intracytosolic Rickettsia africae Niche
  role: intrinsic_resistance
  conforms_to: "intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion"
  description: >-
    Spotted-fever-group rickettsiae live free in the host-cell cytosol and
    exploit intracellular host metabolites, so effective drugs for ATBF must
    reach an intracytosolic bacterial compartment.
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  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 review supports the free cytosolic niche for Rickettsia species and
      the metabolic dependence represented by the shared intracellular-pathogen
      persistence module.

phenotypes:
- name: Multiple Inoculation Eschars
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    ATBF commonly produces at least one inoculation eschar, and the Amblyomma
    tick exposure pattern often yields multiple eschars.
  notes: >-
    The eschar's local mechanism (dermal vasculitic necrosis at the inoculation
    site) is extrapolated from spotted-fever-group rickettsioses in general; no
    ATBF-specific histopathology snippet is cited for the local lesion.
  phenotype_term:
    preferred_term: Eschar
    term:
      id: HP:6000793
      label: Eschar
  sequelae:
  - target: Cellulitis
    description: An inoculation eschar can be a risk factor for secondary cellulitis.
  evidence:
  - reference: PMID:20233665
    reference_title: "African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Indeed, the presence of at least one inoculation eschar is observed in
      53-100% of cases and multiple eschars in 21-54%.
    explanation: >-
      The review quantifies eschars as present in a majority of reported ATBF
      cases and multiple eschars as a distinctive subset.

- name: Regional Lymphadenopathy
  category: Immune
  description: Regional lymph-node enlargement accompanies local eschar infection.
  notes: >-
    Bound to the general term HP:0002716 Lymphadenopathy; no localized/regional
    lymphadenopathy HPO term was found on searching cache/hp/terms.csv, so the
    regional qualifier is carried in preferred_term.
  phenotype_term:
    preferred_term: Regional lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:27172113
    reference_title: "Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with African tick bite fever typically have fever, headache,
      myalgia, one or more inoculation eschars, regional lymphadenopathy, and
      sometimes maculopapular or vesicular rash
    explanation: The CDC report lists regional lymphadenopathy as a typical ATBF feature.

- name: Fever
  category: Constitutional
  description: Fever is part of the acute systemic ATBF syndrome.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of the patients had fever, headache, and/or myalgia, whereas
      specific clinical features such as inoculation eschars, lymphadenitis,
      cutaneous rash, and aphthous stomatitis were seen in < or = 50% of
      patients.
    explanation: >-
      The prospective traveler cohort places fever in the dominant acute
      symptom complex; the greater-than-80% figure is a disjunction across
      fever, headache, and myalgia and is not used as a frequency for fever
      alone.

- name: Headache
  category: Neurological
  description: Headache is part of the flu-like systemic ATBF presentation.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of the patients had fever, headache, and/or myalgia, whereas
      specific clinical features such as inoculation eschars, lymphadenitis,
      cutaneous rash, and aphthous stomatitis were seen in < or = 50% of
      patients.
    explanation: >-
      The cohort places headache in the dominant nonspecific ATBF symptom
      complex but does not give a headache-only rate.

- name: Myalgia
  category: Musculoskeletal
  description: Myalgia completes the nonspecific fever-headache-myalgia triad.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of the patients had fever, headache, and/or myalgia, whereas
      specific clinical features such as inoculation eschars, lymphadenitis,
      cutaneous rash, and aphthous stomatitis were seen in < or = 50% of
      patients.
    explanation: >-
      The cohort places myalgia in the dominant nonspecific ATBF symptom complex
      but reports the fever/headache/myalgia figure as a disjunction.

- name: Papulovesicular Rash
  category: Dermatologic
  frequency: OCCASIONAL
  description: A maculopapular or vesicular rash is a variable ATBF skin manifestation, described in 15-46% of cases.
  phenotype_term:
    preferred_term: Papulovesicular rash
    term:
      id: HP:0033700
      label: Papulovesicular eruption
  evidence:
  - reference: PMID:27172113
    reference_title: "Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with African tick bite fever typically have fever, headache,
      myalgia, one or more inoculation eschars, regional lymphadenopathy, and
      sometimes maculopapular or vesicular rash
    explanation: >-
      The CDC report lists maculopapular or vesicular rash as an intermittent
      ATBF feature.
  - reference: PMID:20233665
    reference_title: "African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a cutaneous rash is described in 15-46% of cases"
    explanation: The review quantifies the ATBF rash frequency at 15-46% of cases.

- name: Chills
  category: Constitutional
  description: Chills are a common general symptom of ATBF, prominent in elderly patients.
  phenotype_term:
    preferred_term: Chills
    term:
      id: HP:0025143
      label: Chills
  evidence:
  - reference: PMID:18558881
    reference_title: "African tick bite fever in elderly patients: 8 cases in French tourists returning from South Africa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long-lasting general symptoms, including fever (in 75% of patients), chills (87.5%), asthenia (50%)"
    explanation: Chills occurred in 87.5% of the elderly ATBF case series.

- name: Aphthous stomatitis
  category: Mucosal
  description: An oral enanthema with aphthous stomatitis is a specific ATBF feature seen in a minority of patients.
  phenotype_term:
    preferred_term: Aphthous stomatitis
    term:
      id: HP:0032154
      label: Aphthous ulcer
  evidence:
  - reference: PMID:12766836
    reference_title: African tick bite fever in travelers to rural sub-Equatorial Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aphthous stomatitis were seen in < or = 50% of patients"
    explanation: The prospective traveler cohort lists aphthous stomatitis among the specific ATBF features seen in up to half of patients.

- name: Myocarditis
  category: Cardiovascular
  description: Myocarditis is a severe ATBF complication reported in elderly patients.
  notes: >-
    A rare severe manifestation; the cited support is a single elderly-patient
    case series, so this is not a common feature of ATBF.
  phenotype_term:
    preferred_term: Myocarditis
    term:
      id: HP:0012819
      label: Myocarditis
  evidence:
  - reference: PMID:18558881
    reference_title: "African tick bite fever in elderly patients: 8 cases in French tourists returning from South Africa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphangitis and myocarditis in 1 patient and suspected brain involvement in 2 patients"
    explanation: The elderly case series reports myocarditis among the severe manifestations.

- name: Cellulitis
  category: Dermatologic
  description: Secondary cellulitis can complicate an ATBF inoculation eschar.
  phenotype_term:
    preferred_term: Cellulitis
    term:
      id: HP:0100658
      label: Cellulitis
  evidence:
  - reference: PMID:18503259
    reference_title: "Two cases of cellulitis in the course of African tick bite fever: a fortuitous association?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "may be a risk factor for cellulitis"
    explanation: The case report identifies the inoculation eschar as a risk factor for secondary cellulitis.

diagnosis:
- name: Clinical diagnosis with retrospective laboratory confirmation
  description: >-
    Initial diagnosis is usually clinical, based on a compatible fever-eschar
    syndrome after travel or tick exposure, because early laboratory tests are
    insensitive or unavailable at symptom onset.
  diagnosis_term:
    preferred_term: clinical diagnosis
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    Compatible travel or Amblyomma tick exposure plus fever and one or more
    eschars supports empiric treatment before confirmatory testing returns.
  evidence:
  - reference: PMID:27488618
    reference_title: Molecular diagnosis of African tick bite fever using eschar swabs in a traveller returning from Tanzania.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of African tick bite fever is often based on clinical
      grounds due to a lack of reliable diagnostic tests at commencement of
      symptoms.
    explanation: >-
      The case report's introduction states the acute diagnostic constraint that
      makes clinical diagnosis necessary at presentation.

- name: Eschar-swab PCR for Rickettsia africae
  description: >-
    PCR on material swabbed non-invasively from an eschar can detect R. africae
    DNA during early disease, including after doxycycline has already been
    started in at least one reported imported case.
  diagnosis_term:
    preferred_term: polymerase chain reaction
    term:
      id: NCIT:C17003
      label: Polymerase Chain Reaction
  results: A positive eschar-swab PCR identifies the R. africae DNA in an inoculation lesion.
  evidence:
  - reference: PMID:27488618
    reference_title: Molecular diagnosis of African tick bite fever using eschar swabs in a traveller returning from Tanzania.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this patient direct molecular detection of R. africae was performed by
      PCR from a sample obtained non-invasively with a swab from the rickettsial
      eschar.
    explanation: >-
      The imported Tanzanian case demonstrates noninvasive molecular detection
      from an eschar swab.

- name: Indirect immunofluorescence serology
  description: >-
    Retrospective confirmation uses indirect immunofluorescence antibody
    serology, but antibodies cross-react across spotted-fever-group species
    (notably R. conorii), so serology alone does not distinguish ATBF from
    Mediterranean spotted fever.
  diagnosis_term:
    preferred_term: serology testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: >-
    Rising anti-spotted-fever-group antibody titers confirm rickettsiosis
    retrospectively; species-level distinction requires molecular methods.
  evidence:
  - reference: PMID:9916419
    reference_title: "[Two cases of spotted fever group rickettsiosis contracted in southern parts of Africa]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "apparent cross reaction between the two organisms hampers the use of conventional antibody"
    explanation: The report documents serologic cross-reaction between R. africae and R. conorii, limiting species-level serology.
  - reference: PMID:9916419
    reference_title: "[Two cases of spotted fever group rickettsiosis contracted in southern parts of Africa]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "beta-lactam antibiotics commonly used as an empiric therapy are not effective"
    explanation: >-
      The report notes that empiric beta-lactam antibiotics are ineffective
      against spotted-fever-group rickettsioses, underscoring the need for
      doxycycline.

progression:
- phase: Self-limited acute illness
  notes: >-
    ATBF is usually a mild, self-limited illness; in one traveler outbreak most
    patients recovered spontaneously before antibiotics were started, though
    recovery can be slow, especially in elderly patients.
  evidence:
  - reference: PMID:11939395
    reference_title: Outbreak of African tick-bite fever in six Italian tourists returning from South Africa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all but one of the patients recovered spontaneously before antibiotic treatment was initiated."
    explanation: The Italian outbreak shows spontaneous recovery in most patients, supporting the self-limited course.

treatments:
- name: Empiric doxycycline
  description: >-
    Doxycycline is first-line therapy for tick-borne rickettsial diseases,
    including ATBF, because the drug arrests the bacterial 30S-ribosomal target
    and penetrates the host-cell cytosol where R. africae resides.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  target_mechanisms:
  - target: Rickettsial Ribosomal Translation (Doxycycline Target)
    treatment_effect: INHIBITS
    description: >-
      Doxycycline binds the bacterial 30S ribosomal subunit and arrests
      rickettsial protein synthesis.
  - target: Intracytosolic Rickettsia africae Niche
    treatment_effect: BYPASSES
    description: Doxycycline can reach the cytosolic rickettsial compartment.
  evidence:
  - reference: PMID:27172113
    reference_title: "Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Doxycycline is the drug of choice for treatment of all tickborne
      rickettsial diseases in patients of all ages, including children aged <8
      years, and should be initiated immediately in persons with signs and
      symptoms suggestive of rickettsial disease
    explanation: >-
      The CDC recommendation covers ATBF as a tick-borne rickettsial disease and
      supports immediate empiric doxycycline for clinically compatible illness.

- name: Personal protection against tick bites
  description: >-
    No vaccine exists, so personal protection against ticks -- skin repellents,
    permethrin-impregnated clothing, and behavioral measures -- is the principal
    means of preventing ATBF.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: personal tick-bite protection
  evidence:
  - reference: PMID:21302476
    reference_title: "[Personal protection measures against blood-sucking insects and ticks]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Personal protection measures (PPM) are essential and often the only means"
    explanation: The review establishes personal protection measures as the essential means of preventing tick-borne infection.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: African Tick-Bite Fever · 2026-09-25T11:34:04Z · View source

Added a standalone African tick-bite fever entry from OpenScientist deep research and verified rickettsial evidence. The entry grounds Rickettsia africae and Amblyomma tick transmission, wires dermal inoculation through lymphatic spread and modest endothelial activation to fever, headache, myalgia, eschars, lymphadenopathy, and rash, and records clinical diagnosis, eschar-swab PCR, and doxycycline therapy. Also updated the spotted-fever parent to point at the new standalone ATBF record.

OpenScientist ▸
African Tick-Bite Fever (ATBF) — Comprehensive Disease Characterization
openscientist-autonomous 32 citations 2026-09-25T04:24:26.253942

African Tick-Bite Fever (ATBF) — Comprehensive Disease Characterization

Disease: African Tick-Bite Fever · MONDO ID: MONDO:0000227 · Category: Infectious Disease (zoonotic, vector-borne rickettsiosis) Causative agent: Rickettsia africae (spotted-fever group) · Vectors: Amblyomma hebraeum, Amblyomma variegatum

Summary

African Tick-Bite Fever (ATBF) is an acute, usually mild and self-limited zoonotic spotted-fever-group (SFG) rickettsiosis caused by the obligate intracellular Gram-negative bacterium Rickettsia africae. It is transmitted by aggressive, host-hunting ticks of the genus Amblyomma — principally A. hebraeum (southern Africa) and A. variegatum (West, Central and East Africa, and the eastern Caribbean). Because Amblyomma ticks actively hunt and attack hosts in clusters, ATBF characteristically produces multiple inoculation eschars and simultaneous illness among groups of co-travelers, two features considered pathognomonic. The disease is overwhelmingly reported in returning travelers to rural sub-Saharan Africa (especially South Africa) and is the second most common cause of febrile illness after malaria in ill returned travelers from that region.

Mechanistically, ATBF is a rickettsial vasculitis. R. africae infects vascular endothelial cells, triggering an IL-1α–dependent proinflammatory cytokine cascade (IL-6, IL-8) that produces vascular inflammation, loss of vascular integrity, and increased permeability. At the site of the tick bite, endothelial infection and a lymphohistiocytic/granulomatous vasculitis produce dermal necrosis — the clinical eschar (tache noire). Systemically, the same endothelial process, amplified by cytokine release, produces fever, headache, myalgia, regional lymphadenopathy, and a variable maculopapular or vesicular rash 5–10 days after the bite. Notably, R. africae is a comparatively low-virulence pathogen; comparative genomics shows it possesses one of the least gene-decayed rickettsial genomes and does not impair the fitness of its tick vector — consistent with the hypothesis that rickettsial virulence increases with genome reduction.

ATBF has no human genetic component — it is a purely infectious/environmental disease driven by occupational and recreational tick exposure in endemic rural areas. Diagnosis is largely clinical at presentation (serology is insensitive in the first 1–2 weeks and cross-reacts across the SFG), with confirmation by eschar-swab PCR (which remains positive even after doxycycline is started) or convalescent immunofluorescence antibody assay. Treatment with doxycycline yields an excellent prognosis; complications (lymphangitis, myocarditis, suspected CNS involvement, secondary cellulitis, prolonged convalescence) are uncommon and concentrated in older patients, and deaths are essentially unreported. Prevention relies entirely on personal anti-tick protection (repellents, permethrin-treated clothing, prompt tick removal); no vaccine exists.

Section-by-Section Report

1. Disease Information

Overview. ATBF is an acute febrile zoonotic illness caused by Rickettsia africae, an obligate intracellular SFG rickettsia, transmitted by Amblyomma ticks. The clinical syndrome comprises fever, one or (characteristically) several inoculation eschars, regional lymphadenopathy, and a variable rash. "Caused by Rickettsia africae, African tick bite fever presents with characteristic cutaneous findings such as eschar (tache noir) and a rash" (PMID: 30537329).

Key identifiers. - MONDO: MONDO:0000227 - MeSH: Indexed under spotted fever group / tick-borne rickettsial diseases. - ICD-10: A77.8 (Other spotted fevers) is the applicable rubric; ICD-11 maps to "Spotted fever due to Rickettsia africae." - OMIM / Orphanet: Not a Mendelian disorder; no OMIM gene/phenotype entry. As an infectious disease it is not a classic Orphanet rare-disease entry. - Causative organism (NCBI Taxonomy): Rickettsia africae (species within genus Rickettsia, SFG).

Synonyms / alternative names. African tick-bite fever; African tick bite fever; Rickettsia africae infection; SFG rickettsiosis due to R. africae. Historically conflated with "tick bite fever" / boutonneuse-like fever in southern Africa before R. africae was recognized as a distinct species (PMID: 9916419, PMID: 31700846).

Source of information. The disease-level knowledge base is derived almost exclusively from aggregated case reports and case series of returning travelers plus tick-surveillance/meta-analytic studies — not from EHR/population cohorts. "Human disease case reports were exclusively among returning travellers from non-endemic areas, which limits our disease knowledge among at-risk populations: people living in endemic regions" (PMID: 38813598).

2. Etiology

Primary cause (infectious). ATBF is caused by infection with Rickettsia africae, transmitted through the bite of an infected Amblyomma tick. "This pathogen is transmitted by ticks of the genus Amblyomma, with Amblyomma hebraeum and Amblyomma variegatum being the major vectors" (PMID: 34516408).

Risk factors (environmental / behavioral). - Occupational and recreational exposure to Amblyomma-infested rural habitats: game hunting, safaris, ecotourism, farming, military deployment in sub-Saharan Africa. Multiple-eschar case clusters are repeatedly reported after safaris and game hunting (PMID: 28544092, PMID: 20233665). - Geography and season: rural southern/eastern Africa (highest), West/Central Africa, and the eastern Caribbean/French West Indies. - Vector behavior: Amblyomma ticks actively hunt hosts and attack in clusters, so travelers in groups are frequently co-infected. - Age/sex: no strong sex predilection; most reported cases are middle-aged adult travelers, but children are affected (a cluster of 3 children aged 7–16 after a hunting safari) (PMID: 28544092). Older age is associated with more severe manifestations and slower recovery (PMID: 18558881).

Genetic risk factors. None identified. ATBF is not a heritable disease; there are no known human causal variants, susceptibility loci, or modifier genes. Host-genetic susceptibility to ATBF has not been demonstrated.

Protective factors. No genetic protective factors are known. Environmental protection is behavioral: use of tick repellents, permethrin-treated clothing, protective clothing, and prompt tick removal (Section 13). No dietary or metabolic protective factors are established.

Gene–environment interactions. Not applicable — the disease has no established genetic axis.

3. Phenotypes

ATBF is a monophasic acute febrile illness. Phenotype frequencies (pooled from case series and reviews):

Phenotype Type Frequency Suggested HPO term
Fever Symptom/sign ~75–100% Fever (HP:0001945)
Inoculation eschar (tache noire) Physical manifestation 53–100% (≥1); multiple in 21–54% Skin ulcer (HP:0200042); Skin necrosis
Regional lymphadenopathy Sign Common Localized lymphadenopathy (HP:0100762); Lymphadenopathy (HP:0002716)
Maculopapular / vesicular rash Manifestation 15–46% (up to 87.5% in one elderly series) Maculopapular exanthema (HP:0040186); Vesicular rash
Headache Symptom Frequent Headache (HP:0002315)
Myalgia Symptom Frequent Myalgia (HP:0003326)
Chills Symptom ~87.5% (elderly series) —
Enanthema (mucosal) Sign ~50% of those with rash Oral mucosal blistering / enanthem
Lymphangitis Sign Uncommon Lymphangitis
Fatigue / prolonged asthenia Symptom Variable; may persist in convalescence Fatigue (HP:0012378)
Neck stiffness Sign Occasional Nuchal rigidity (HP:0031179)
Myocarditis / suspected CNS involvement Complication Rare (mostly elderly) Myocarditis (HP:0012133)

Characteristics. Onset: adult-onset in the reported population; acute, ~5–10 days after tick bite. Severity: usually mild; moderate/severe manifestations rare and skewed to older patients. Progression: self-limited single episode; resolves with treatment (and often spontaneously). Frequency: eschar is the most consistent feature.

Quantitative anchors: "the presence of at least one inoculation eschar is observed in 53-100% of cases and multiple eschars in 21-54%" and "a cutaneous rash is described in 15-46% of cases" (PMID: 20233665). In an elderly-traveler series, "Rash was frequent (present in 87.5% of patients), vesicular (in 100% of patients with rash), and often associated with an enanthema (in 50% of patients with rash)" (PMID: 18558881).

Pathognomonic features. "the presence of multiple inoculation eschars, two features pathognomonic of this rickettsial disease" — multiple eschars plus clustered co-traveler infections (PMID: 20233665).

Quality-of-life impact. Generally limited and transient: an acute febrile week, occasionally with prolonged asthenia during a slow convalescence ("complete recovery was slow"; PMID: 18558881). Long-term disability is not a feature. Disease-specific QoL instruments (EQ-5D/SF-36) have not been applied to ATBF.

4. Genetic / Molecular Information

Human genetics: not applicable. ATBF has no causal genes, pathogenic variants, modifier genes, epigenetic signatures, or chromosomal abnormalities in the human host. There are no ClinVar/OMIM/HGMD entries; allele-frequency, germline/somatic, penetrance and expressivity concepts do not apply.

Pathogen genomics (the relevant "molecular information"). Whole-genome sequencing of R. africae reveals a circular chromosome of 1,278,540 bp plus an unstable 12,377-bp plasmid (GenBank NZ_AAUY01000001). Comparative genomics against R. prowazekii, R. rickettsii, and R. conorii shows R. africae has one of the least-decayed rickettsial genomes, with 18 species-unique genes, one carrying a putative protease domain upregulated at 37 °C. Clonality was assessed across 70 patients and 155 ticks. The central inference: "we speculate that in Rickettsia species virulence is mostly associated with gene loss" (PMID: 19379498) — i.e., R. africae's relatively intact genome underlies its mild phenotype.

Molecular typing / targets. Species confirmation and phylogenetics use the citrate synthase gene (gltA), outer-membrane protein genes (ompA, ompB), and the 17-kDa antigen gene. R. africae clusters within the SFG subgroup containing the major human pathogens by gltA phylogeny (PMID: 9103608).

5. Environmental Information

Environmental factors. The dominant environmental determinant is presence in Amblyomma-infested rural landscapes of sub-Saharan Africa (grassland, bush, game reserves, farmland) and the eastern Caribbean. No chemical toxin, pollutant, or radiation exposure contributes.

Lifestyle factors. Activities that increase tick contact: safari/ecotourism, big-game hunting, farming/animal husbandry, and rural fieldwork. Failure to use repellents or protective clothing increases risk.

Infectious agent. Rickettsia africae — obligate intracellular SFG rickettsia. It is "a bacterium of zoonotic importance, which causes African tick bite fever (ATBF) in humans" (PMID: 34516408). Reservoir/vector = Amblyomma ticks; livestock and wildlife amplify the transmission cycle (Sections 9/14). Relevant chemical entities (CHEBI) appear in Sections 12–13 (doxycycline; DEET, icaridin, PMD, IR3535, permethrin).

6. Mechanism / Pathophysiology

Ordered causal chain

  1. An infected Amblyomma tick actively hunts and attacks the host, often multiple ticks in a cluster → inoculates R. africae into the dermis at one or several bite sites (→ predisposes to multiple eschars).
  2. R. africae, an obligate intracellular bacterium, adheres to and invades vascular endothelial cells at the bite site (the O-antigen/polysaccharide-synthesis operon modulates adhesion/invasion) → leads to intracellular replication within endothelium.
  3. Endothelial infection activates an IL-1α–dependent proinflammatory program → results in secretion of IL-6 and IL-8 (and other chemokines) by infected endothelial cells.
  4. Cytokine/chemokine release recruits perivascular T cells (CD3+) and histiocytes (CD68+) and triggers lymphohistiocytic/granulomatous vasculitis → leads to loss of vascular integrity and increased permeability ("rickettsial vasculitis").
  5. Local vasculitis with fibrin thrombi and vacuolar change causes necrosis of the epidermis and superficial dermis → results in the clinical eschar (tache noire) with draining regional lymphadenopathy.
  6. In parallel (branch), the same endothelial-tropic process and systemic cytokines produce fever, headache, myalgia, and — where dissemination occurs — a maculopapular/vesicular rash.
  7. Because R. africae has a relatively intact genome and limits damage, the process is usually contained and self-limiting; severe systemic vasculitis (myocarditis, CNS) is rare (branch, mostly in elderly). [Systemic-dissemination steps are inferred from SFG-rickettsiosis biology; the endothelial/eschar steps are directly demonstrated in SFG lesions.]

Detail by category

  • Molecular pathways / cellular processes. Endothelial innate-immune activation via an IL-1α–dependent pathway drives NF-κB–type cytokine responses. "human umbilical vein endothelial cells (HUVEC) infected with R. conorii actively secrete high levels of IL-8 and IL-6" (IL-8 P<0.002; IL-6 P<0.03 vs uninfected; 80–85% suppressed by IL-1 receptor antagonist/anti-IL-1α) (PMID: 8675654). Suggested GO terms: inflammatory response (GO:0006954), cytokine-mediated signaling pathway (GO:0019221), response to bacterium (GO:0009617).
  • Endothelial tropism / tissue damage. "a majority of sequelae associated with human rickettsioses are the outcome of the pathogen's affinity for endothelium lining the blood vessels, the consequences of which are vascular inflammation, insult to vascular integrity and compromised vascular permeability, collectively termed 'Rickettsial vasculitis'" (PMID: 19327117).
  • Immune evasion / protein-level mechanism. The polysaccharide synthesis operon (pso) governs O-antigen biosynthesis and surface-protein assembly and shields LPS/peptidoglycan from immune recognition, modulating adhesion/invasion and innate stimulation — its loss (variant HK2) reduces invasion but provokes stronger cytokine responses and premature host-cell death (PMID: 40570043).
  • Low-virulence genomic basis. R. africae's benign phenotype tracks with minimal genome decay; "the mild pathogen R. africae, the agent of African tick-bite fever, which does not affect the fitness of its tick vector" (PMID: 19379498).
  • Histopathology (eschar correlate). In immunostain-confirmed SFG rickettsial skin lesions, "Vacuolar alterations and vasculitis were present in all specimens (6/6; 100%)," granulomatous inflammation in 83.3%, fibrin thrombi/extravasated RBCs in 50%, epidermal/superficial-dermal necrosis in 33.3%; perivascular CD3+ T cells with fewer CD20+ B cells and abundant CD68+ histiocytes (83.3%). "The histopathology of rickettsialpox infection is septic lymphocytic and granulomatous vasculitis" (PMID: 31955452).

Cell types (CL) and biological processes (GO): vascular endothelial cell (CL:0000115) — primary target; T cell (CL:0000084); macrophage/histiocyte (CL:0000235). Processes: bacterial entry into host cell, actin-based intracellular motility, inflammatory response, vasculitis.

7. Anatomical Structures Affected

  • Primary organ/tissue: Skin at the bite site (UBERON:0002097, skin of body) — eschar; and the vascular endothelium / blood vessel wall (UBERON:0001981 blood vessel; UBERON:0001986 endothelium) as the fundamental target tissue.
  • Lymphatic system: draining regional lymph nodes (UBERON:0000029) — lymphadenopathy; lymphatic vessels — occasional lymphangitis.
  • Secondary/complication organs (rare): heart/myocardium (UBERON:0002349) — myocarditis; central nervous system — suspected involvement in rare severe cases.
  • Body systems: integumentary, cardiovascular (vascular), and lymphatic/immune systems primarily.
  • Cell/tissue level: vascular endothelial cells (CL:0000115); perivascular lymphohistiocytic infiltrate (T cells, histiocytes/macrophages); epidermal and superficial dermal necrosis.
  • Subcellular level: Rickettsia replicates free in the host-cell cytoplasm (GO:0005737, cytoplasm) after phagosomal escape.
  • Localization / lateralization: eschars localize to bite sites and can be single or multiple and asymmetric (wherever ticks attached); lymphadenopathy is regional to the draining basin.

8. Temporal Development

  • Onset: Acute, typically ~5–10 days (SFG-rickettsiosis incubation broadly 5–28 days; average ~7–14) after tick attachment. In the reported (traveler) population, onset is in adulthood; pediatric onset occurs.
  • Course/stages: Monophasic acute illness → eschar formation, fever, lymphadenopathy → resolution. Not staged like chronic/neoplastic disease.
  • Progression rate: Usually mild and self-limited; "The clinical course of disease was mild in all cases, and all but one of the patients recovered spontaneously before antibiotic treatment was initiated" (PMID: 11939395).
  • Duration: Self-limited over days to ~2 weeks; convalescence (asthenia) can be prolonged, especially in older patients.
  • Remission: Both spontaneous and treatment-induced (doxycycline shortens illness). Relapse is not a characteristic feature of ATBF.
  • Critical period for intervention: Early empiric doxycycline; for SFG rickettsioses generally, treatment delay is the key driver of severe outcomes (PMID: 25697742).

9. Inheritance and Population

Inheritance: Not applicable — infectious, non-heritable. No inheritance pattern, penetrance, expressivity, anticipation, mosaicism, founder effect, consanguinity, or carrier frequency.

Epidemiology. - Endemic range: rural sub-Saharan Africa (highest in southern and eastern Africa), West/Central Africa, and the eastern Caribbean/French West Indies (where Amblyomma variegatum was introduced with cattle). - Travelers: ATBF is "the second most commonly documented etiology of fever, after malaria, in travelers who return ill from sub-Saharan Africa" (PMID: 28544092). Among travelers to South Africa, "spotted fever group rickettsiosis was the most common individual diagnosis" (GeoSentinel, 13 years) (PMID: 20519590). - Endemic-population burden: poorly quantified because case reports are "exclusively among returning travellers from non-endemic areas" (PMID: 38813598). Formal incidence/prevalence per 100,000 are not reliably established. - Demographics: all ages; middle-aged adults dominate reported series; both sexes; clustered co-traveler cases characteristic.

Vector/pathogen prevalence (transmission pressure). Meta-analysis (32 studies, 12,301 ticks): R. africae prevalence "was higher in Amblyomma spp. (48%, 95% CI: 26-70%) compared to Rhipicephalus spp. (1%, 95% CI: 0-5%), Hyalomma spp. (1%, 95% CI: 0-3%)" (PMID: 35537238). Field surveys: up to 69–81% of A. variegatum positive in Ghana (PMID: 38295420); 46.9% of A. hebraeum on Eastern Cape cattle (PMID: 36468449); 81% of A. variegatum on dogs in Chad (PMID: 39427603).

10. Diagnostics

Approach. Diagnosis is often clinical at presentation because reliable early tests are lacking, with retrospective/laboratory confirmation. "The diagnosis of African tick bite fever is often based on clinical grounds due to a lack of reliable diagnostic tests at commencement of symptoms" (PMID: 27488618).

Test Utility / notes
Eschar-swab PCR (gltA, ompA, ompB, 17-kDa) Early, non-invasive confirmation; remains positive after doxycycline started. "direct molecular detection of R. africae was performed by PCR from a sample obtained non-invasively with a swab from the rickettsial eschar. A positive PCR result was achieved although the patient had already started antibiotic treatment with doxycycline" (PMID: 27488618)
Serology (IFA, IgM/IgG) Reference standard but insensitive acutely — antibodies appear ~7–15 days into illness and cross-react across SFG (e.g., against R. conorii); best for retrospective/convalescent confirmation (PMID: 9916419, PMID: 7622271)
Culture Possible from eschar biopsy; restricted to specialized/biosafety labs
Eschar/skin biopsy histopathology + IHC Lymphohistiocytic/granulomatous vasculitis, dermal necrosis; immunostaining localizes rickettsiae (PMID: 31955452)
Routine labs Nonspecific; may show elevated ESR, mild transaminase elevation, occasional thrombocytopenia/leukopenia (by analogy to SFG rickettsioses; PMID: 7622271)
Imaging Not routinely diagnostic

Genetic/omics testing: not applicable to the human host. Molecular diagnostics target the pathogen genome (PCR/sequencing of gltA, ompA, ompB, 17-kDa).

Clinical criteria / differential. Diagnosis rests on the epidemiologic setting (rural sub-Saharan Africa/Caribbean travel + tick exposure) plus eschar(s), fever, and lymphadenopathy. Differential diagnosis: malaria (must exclude), Mediterranean spotted fever (R. conorii), other SFG rickettsioses, scrub typhus, typhoid, arboviral fevers, Lyme borreliosis, and localized bacterial skin infection. Multiple eschars and clustered cases strongly favor ATBF over single-eschar R. conorii infection.

Screening: No population screening is applicable (no clinically relevant asymptomatic carrier state).

11. Outcome / Prognosis

  • Prognosis: Excellent. With doxycycline, "the outcome was favorable in all cases, but complete recovery was slow" (PMID: 18558881). Many patients recover spontaneously (PMID: 11939395).
  • Mortality: Deaths from ATBF are essentially not reported — a key contrast with the severe SFG rickettsiosis Rocky Mountain spotted fever (RMSF), where treatment delay drives fatality (PMID: 25697742).
  • Morbidity/complications (uncommon, older patients): lymphangitis, myocarditis, suspected CNS involvement, prolonged asthenia, and reactive/subacute events. The eschar disrupts the cutaneous barrier and can predispose to secondary bacterial cellulitis: "In African tick bite fever (ATBF), inoculation eschar - resulting from disruption of the cutaneous barrier - may be a risk factor for cellulitis" (2 PCR-confirmed cases, good recovery on doxycycline + beta-lactam) (PMID: 18503259).
  • Recovery: Full recovery is the norm; long-term disability is not characteristic. QoL instruments have not been formally applied.
  • Prognostic factors: older age → more severe manifestations/slower convalescence; timeliness of doxycycline. No molecular prognostic biomarkers are established.

12. Treatment

First-line pharmacotherapy — Doxycycline (tetracycline-class; CHEBI:50845; NCIT: Doxycycline). Typical regimen 100 mg twice daily for ~7 days; consistently curative with favorable outcomes (PMID: 18558881). Mechanism: inhibition of bacterial 30S ribosomal protein synthesis in the obligate intracellular pathogen. Doxycycline is the treatment of choice for tick-borne rickettsial diseases in adults and children (PMID: 16572105).

Important caveat — beta-lactams are ineffective: empiric beta-lactam therapy does not treat rickettsiosis, so a high index of suspicion is essential (PMID: 9916419).

Alternatives: Other tetracyclines (e.g., minocycline used in a reported case; PMID: 9916419); macrolides may be considered in pregnancy/children where tetracyclines are contraindicated (extrapolated from SFG-rickettsiosis practice — evidence limited).

Complication-directed therapy: Secondary cellulitis of an eschar treated with doxycycline plus an anti-staphylococcal/streptococcal beta-lactam (PMID: 18503259).

Advanced/experimental therapeutics: None specific to ATBF (no gene, cell, RNA, targeted, or immunotherapies; no ATBF-specific registered clinical trials). Pharmacogenomics not applicable.

Supportive care: antipyretics/analgesics; wound care of the eschar.

13. Prevention

No vaccine or chemoprophylaxis exists. Prevention depends on personal protection measures (PPM) against ticks. "The registered and recommended active ingredients for skin application are Deet, picaridin (icaridin), p-menthane-3,8-diol (PMD) and IR3535. Volatile pyrethrins are used as space repellents while pyrethroids, especially permethrin, are employed for impregnation" (PMID: 21302476). PPM "are essential and often the only means available" when no vaccine/prophylaxis exists.

  • Primary prevention: repellents (DEET, picaridin/icaridin, PMD, IR3535); permethrin-impregnated clothing; protective clothing; prompt tick removal and body checks after exposure; pre-travel advice for those visiting endemic rural areas.
  • Secondary prevention: early clinical recognition and prompt doxycycline in returned travelers with fever + eschar.
  • Tertiary prevention: timely treatment of complications (e.g., cellulitis) and appropriate management of severe manifestations in the elderly.
  • Public-health/vector control: livestock tick control reduces Amblyomma burden; surveillance of tick-borne pathogens in endemic regions (PMID: 38095712, PMID: 39285746).
  • Immunization/genetic counseling: not applicable.

14. Other Species / Natural Disease

  • Causative organism taxonomy: Rickettsia africae (NCBI Taxonomy; SFG Rickettsia).
  • Vectors/reservoirs (NCBI Taxonomy genus Amblyomma): A. hebraeum, A. variegatum are both vector and reservoir; the tick maintains the organism (transstadial/transovarial), and humans are incidental/dead-end hosts. "Rickettsia africae is a bacterium of zoonotic importance" (PMID: 34516408).
  • Amplifying hosts: cattle, camels, dogs, and wild game across sub-Saharan Africa carry infected Amblyomma; e.g., "Rickettsia africae was detected in 46.92% (95% CI = 41%-53%, n = 260) of ticks" on Eastern Cape cattle (PMID: 36468449); R. africae in A. variegatum on dogs in Chad (81%) (PMID: 39427603) and on camel ticks in Kenya (PMID: 38698904) and Egypt (PMID: 22217182).
  • Geographic spread: Amblyomma variegatum introduced to the eastern Caribbean with cattle, extending the endemic range (PMID: 16887719).
  • Zoonotic potential: High as an exposure risk, but human infection is a spillover; no human-to-human transmission.
  • Comparative pathology: The closely related agent R. rickettsii causes severe, sometimes fatal RMSF in dogs and humans, providing a comparative model of SFG-rickettsial vasculitis and doxycycline responsiveness (PMID: 25542001); R. africae is comparatively benign.

15. Model Organisms

There is no established dedicated animal model of ATBF (R. africae) that recapitulates human disease, and no genetically engineered (knockout/knock-in/humanized) host models exist — consistent with a mild, self-limited human illness of limited severe-disease modeling need.

Available/analogous systems: - In vitro (best-characterized mechanistic system): human endothelial cell cultures (HUVEC, microvascular endothelial cells) infected with SFG Rickettsia recapitulate endothelial infection and the IL-1α/IL-6/IL-8 cytokine cascade (PMID: 8675654, PMID: 40570043); bone-marrow-derived macrophages used to assess intracellular survival. - Mouse model of spotted fever: used to test rickettsial mutants (e.g., pso variant HK2) and a live-attenuated-vaccine concept (PMID: 40570043) — an SFG-Rickettsia model, not R. africae-specific. - Natural/experimental canine RMSF (R. rickettsii): models tick-borne SFG-rickettsial clinical course, convalescence, and doxycycline response (PMID: 25542001). - Tick model: R. africae is maintained in Amblyomma without fitness cost — an intact natural "vector model" of low-virulence rickettsial persistence (PMID: 19379498).

Limitation: these systems model SFG-rickettsial endothelial biology broadly; the specific mild phenotype and multiple-eschar clustering of ATBF (driven by Amblyomma hunting behavior) are not fully captured by rodent models.

Mechanistic Model / Interpretation

 Amblyomma tick (cluster attack) ── inoculates R. africae into dermis
                          │  (→ often MULTIPLE bite sites)
                          ▼
       Adhesion + invasion of VASCULAR ENDOTHELIUM
       (pso/O-antigen modulates invasion + immune shielding)
                          ▼
       Intracellular replication in endothelial cytoplasm
                          ▼
       IL-1α–dependent activation → IL-6, IL-8, chemokines
                          ▼
       Perivascular CD3+ T cells + CD68+ histiocytes
       → LYMPHOHISTIOCYTIC / GRANULOMATOUS VASCULITIS
       → loss of vascular integrity, ↑ permeability
          │                                   │
       (LOCAL branch)     ▼                    (SYSTEMIC branch)▼
   Epidermal/superficial-dermal necrosis        Fever, headache, myalgia,
   → ESCHAR (tache noire) + regional            regional lymphadenopathy,
     lymphadenopathy                            variable maculopapular/
│                                       vesicular RASH
▼                                              │
   Barrier breach → occasional 2° cellulitis    Rare: myocarditis, CNS
                                 (mostly elderly)
                          ▼
     Relatively INTACT genome (low gene decay) →
     contained, self-limited course; doxycycline curative

Upstream vs downstream. Upstream = tick inoculation and endothelial invasion. Central = IL-1α–driven cytokine cascade and vasculitis. Downstream = eschar/necrosis, lymphadenopathy, systemic febrile illness, rash. The pathogen's genomic completeness is a "meta-upstream" determinant setting the ceiling on virulence.

Evidence Base

PMID Contribution Evidence type
34516408 Etiology: R. africae transmitted by A. hebraeum/A. variegatum; zoonotic importance Review
35537238 Meta-analysis: Amblyomma dominant competent vector (48% vs 1%) Meta-analysis (32 studies)
19379498 Genome (1.28 Mb + plasmid); low virulence ↔ minimal gene loss; benign to tick Genomics/computational
19327117 Endothelial tropism → "rickettsial vasculitis" Review
8675654 IL-1α–dependent IL-6/IL-8 from infected endothelium In vitro
40570043 pso/O-antigen modulates invasion + immune evasion; attenuated-vaccine concept In vitro + mouse
31955452 Eschar histopathology: lymphohistiocytic/granulomatous vasculitis + necrosis Human biopsy series
30537329 Hallmark cutaneous presentation (eschar + rash) Review
18558881 Phenotype frequencies; doxycycline favorable but slow recovery (elderly) Case series (n=8)
20233665 Eschar 53–100%, multiple 21–54%, rash 15–46%; multiple eschars pathognomonic Case series/review
38813598 Knowledge base skewed to travelers; endemic burden unknown Systematic review
20519590 SFG rickettsiosis = most common diagnosis in travelers to South Africa GeoSentinel
28544092 2nd cause of fever after malaria; pediatric cluster Case series/review
11939395 Mild, often spontaneously resolving course Outbreak (n=6)
27488618 Eschar-swab PCR positive post-doxycycline; clinical diagnosis Case report
21302476 Repellents/permethrin as PPM (prevention) Review
18503259 Eschar → secondary cellulitis complication Case series
36468449 R. africae in 46.9% A. hebraeum on cattle (reservoir ecology) Field survey
16572105 Doxycycline = drug of choice for tick-borne rickettsioses Guideline
25697742 Treatment delay drives severe SFG outcomes (contrast: RMSF) Case-control

Consistency. Findings are internally consistent — endothelial tropism, cytokine biology, and vasculitic histopathology converge on the eschar/febrile syndrome, while genomics explains the mild phenotype and epidemiology explains the traveler-centric evidence base. Caveat: several mechanistic details (endothelial cytokine assays, pso operon, eschar histopathology) derive from related SFG species (R. conorii, rickettsialpox), not R. africae directly, and are extrapolated on the basis of shared SFG biology.

Limitations and Knowledge Gaps

  1. Traveler-biased evidence base. Nearly all clinical data come from returning travelers; incidence/prevalence and disease spectrum among endemic residents are essentially unquantified (PMID: 38813598).
  2. Mechanistic extrapolation. Direct endothelial-infection cytokine data and eschar histopathology come from R. conorii/rickettsialpox, not R. africae specifically.
  3. No R. africae-specific animal model and no human host-genetic studies.
  4. Diagnostic gap. No sensitive early-illness test; serology is delayed and cross-reactive, and PCR/eschar sampling is not universally available.
  5. Quantitative QoL, long-term convalescence, and complication rates are imprecise (small series, older-patient skew).
  6. Formal epidemiologic metrics (cases/100,000) are lacking.

Proposed Follow-up Experiments / Actions

  1. Endemic-population cohort studies with active surveillance and eschar-swab PCR to establish true incidence, spectrum, and pediatric burden in sub-Saharan Africa.
  2. R. africae-specific endothelial and in-vivo studies (human microvascular endothelial cells; immunocompetent mouse/guinea-pig models) to confirm the IL-1α/IL-6/IL-8 cascade and pso-mediated immune evasion for this species specifically.
  3. Point-of-care molecular diagnostics (rapid gltA/ompA PCR or LAMP on eschar swabs) validated for field/travel-clinic use.
  4. Prospective evaluation of doxycycline regimens (duration, timing) and outcomes in older adults, plus systematic capture of complications (myocarditis, CNS, cellulitis).
  5. Vector-control / one-health interventions targeting Amblyomma on livestock to reduce transmission pressure, with pre/post pathogen-prevalence monitoring.
  6. Traveler prevention trials quantifying the protective efficacy of specific repellents/permethrin clothing against Amblyomma bites and ATBF incidence.

Report compiled from 12 confirmed findings and 39 reviewed papers across 5 investigation iterations. All mechanistic and clinical claims are cited to primary literature (PMID). Human host genetics, causal genes, and inherited risk are not applicable — ATBF is an infectious, vector-borne rickettsiosis.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 32
Resolved 32
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 20
Quoted claims found in source 19
Quoted claims not found in source 1
References weighed for topical relevance 32
On topic 26
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:19379498 (abstract only): "we speculate that in Rickettsia species virulence is mostly associated with gene loss"
  • closest text in source: "We also speculate that in Rickettsia species virulence is mostly associated with gene loss.The genome sequence was deposited in GenBank under accession number [GenBank: NZ_AAUY01000001]."

Term Validation

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

Outcome Count
Terms checked 24
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 10
Terms named correctly 7
Terms named as a different term 2
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:

  • HP:0012133 (1 mention) - the report calls it "Myocarditis"; HP calls it Erythroid hypoplasia
  • UBERON:0000029 (1 mention) - the report calls it "regional lymph nodes", "Lymphatic system: draining regional lymph nodes"; UBERON calls it lymph node

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:

  • CL:0000115 (2 mentions) - the report calls it "Cell/tissue level: vascular endothelial cells"; CL calls it endothelial cell**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • UBERON:0000029 - called "regional lymph nodes", "Lymphatic system: draining regional lymph nodes"