Boutonneuse fever

Infectious Disease MONDO:0024472 Pathograph 14 Rickettsia conorii infectious disease Spotted fever rickettsiosis

Boutonneuse fever, also called Mediterranean spotted fever, is an acute tick-borne spotted-fever-group rickettsiosis caused by Rickettsia conorii subsp. conorii. After an incubation period of about a week, infection causes fever, headache, myalgia or arthralgia, a centripetally spreading maculopapular rash that often involves palms and soles, and an inoculation eschar ("tache noire") at the tick-bite site. Disseminated infection of vascular endothelium can produce vasculitis, thrombocytopenia, renal injury, respiratory failure, and other severe multiorgan complications.

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1
Mappings
2
Definitions
5
Pathophys.
26
Phenotypes
14
Pathograph
3
Treatments
9
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0024472 boutonneuse fever
skos:exactMatch Orphanet ORPHA:83313
Orphanet ORPHA:83313 lists MONDO:0024472 as an exact cross-reference for Boutonneuse fever.
📘

Definitions

2
Orphanet Boutonneuse fever definition
Rare spotted fever rickettsiosis caused by the tick-borne bacterium Rickettsia conorii, with fever after about a week of incubation followed by maculopapular or petechial rash, headache, myalgia, arthralgia, and a possible tache noire at the tick-bite site.
OTHER
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"A rare spotted fever rickettsiosis caused by infection with the tick-borne bacterium <i>Rickettsia conorii</i>"
Orphanet defines Boutonneuse fever as tick-borne R. conorii rickettsiosis.
Molecular and clinical review definition
Modern molecular reviews define Mediterranean spotted fever as an emerging Mediterranean-basin spotted-fever-group rickettsiosis caused by Rickettsia conorii subsp. conorii and transmitted by the brown dog tick.
OTHER
Show evidence (1 reference)
PMID:34698275 SUPPORT Human Clinical
"the causative agent of MSF is Rickettsia conorii subspecies conorii. The arthropod vector of this bacterium is the brown dog tick Rhipicephalus sanguineus."
The review identifies the causative subspecies and vector.
⚙

Pathophysiology

5
Tick-borne Rickettsia conorii infection
Brown dog tick transmission introduces R. conorii subsp. conorii, an intracellular rickettsial bacterium, initiating acute spotted fever rickettsiosis.
response to bacterium link ⚠ ABNORMAL
Downstream
Endothelial infection and injury R. conorii disseminates to and injures vascular endothelium.
Show evidence (1 reference)
PMID:34698275 SUPPORT Human Clinical
"Mediterranean spotted fever (MSF) is an emerging tick-borne rickettsiosis of the spotted fever group (SFG)"
This directly supports the initiating tick-borne rickettsial infection.
Endothelial infection and injury
R. conorii targets vascular endothelial cells in vivo; endothelial damage is supported by circulating endothelial cells and elevated thrombomodulin and von Willebrand factor in patients.
endothelial cell link
inflammatory response link ↑ INCREASED
Downstream
Rickettsial vasculitis and vascular permeability Endothelial injury drives vasculitis and vascular leak.
Skin rash Endothelial infection contributes to the characteristic exanthem.
Maculopapular exanthema Endothelial infection contributes to the maculopapular rash pattern.
Show evidence (2 references)
PMID:7691249 SUPPORT Human Clinical
"The endothelial cell (EC) is the primary target for Rickettsia conorii (RC) in Mediterranean spotted fever (MSF)."
Human patient study identifies endothelial cells as the primary target.
PMID:34698275 SUPPORT Human Clinical
"All of these manifestations arise from the disseminated infection of the endothelium by R. conorii conorii."
Review links disseminated endothelial infection to clinical manifestations.
Rickettsial vasculitis and vascular permeability
Infected endothelial cells and systemic endothelial injury produce generalized vasculitis, microvascular injury, and vascular permeability changes that underlie severe organ manifestations.
endothelial cell link
positive regulation of vascular permeability link ↑ INCREASED inflammatory response link ↑ INCREASED
Downstream
Vasculitis Rickettsial endothelial injury directly manifests as vasculitis.
Petechiae Vascular injury can produce petechial rash.
Renal insufficiency Microvascular injury contributes to acute kidney involvement.
Respiratory failure Severe endothelial disease can involve the lungs.
Show evidence (2 references)
PMID:15109588 SUPPORT Human Clinical
"potentially life-threatening disease with disseminated vaculitis is occasionally seen."
Travel-medicine review supports disseminated vasculitis as a severe manifestation.
PMID:7691249 SUPPORT Human Clinical
"Clinical manifestations such as thrombosis and vasculitis are mediated by pathologic changes localized in blood vessels."
Human biomarker study links clinical disease to vascular pathology.
Endothelial cytokine activation
R. conorii-infected human endothelial cells secrete IL-6 and IL-8 through a cell-associated IL-1 alpha-dependent pathway, providing an inflammatory mechanism for vasculitis and systemic febrile symptoms.
endothelial cell link
cytokine production link ↑ INCREASED inflammatory response link ↑ INCREASED
Downstream
Rickettsial vasculitis and vascular permeability Cytokine activation amplifies rickettsial vasculitis.
Fever Endothelial inflammatory cytokines contribute to systemic fever.
Show evidence (2 references)
PMID:8675654 SUPPORT In Vitro
"human umbilical vein endothelial cells (HUVEC) infected with R. conorii actively secrete high levels of IL-8 and IL-6"
In vitro endothelial-cell infection supports increased cytokine secretion.
PMID:8675654 SUPPORT In Vitro
"providing a possible mechanism for the vasculitis observed in Mediterranean spotted fever."
The authors link the endothelial cytokine response to vasculitis.
Endothelial COX-2 prostaglandin activation
Spotted-fever-group rickettsial infection induces endothelial COX-2 and vasoactive prostaglandin release, which may regulate inflammatory responses and vascular permeability changes.
endothelial cell link
prostaglandin biosynthetic process link ↑ INCREASED positive regulation of vascular permeability link ↑ INCREASED
Downstream
Rickettsial vasculitis and vascular permeability Vasoactive prostaglandins modulate the vascular inflammatory phenotype.
Show evidence (2 references)
PMID:16926398 SUPPORT In Vitro
"Rocky Mountain spotted fever and boutonneuse fever, due to Rickettsia rickettsii and R. conorii, respectively, are characterized by widespread infection of the vascular endothelium, microvascular injury, and vasculitis."
The study frames boutonneuse fever as endothelial infection with microvascular injury and vasculitis.
PMID:16926398 SUPPORT In Vitro
"Induction of the endothelial COX-2 system and the resultant enhanced release of vasoactive PGs may contribute to the regulation of inflammatory responses and vascular permeability changes during spotted fever rickettsioses."
Infected endothelial-cell models support COX-2/prostaglandin contribution to vascular permeability.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Boutonneuse 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

26
Blood 3
Petechiae OCCASIONAL Petechiae (HP:0000967)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0000967 | Petechiae | Occasional (29-5%)"
Orphanet reports petechiae as occasional.
ORPHA:83313 SUPPORT Other
"maculopapular rash, which may evolve into a petechial form"
Orphanet definition describes petechial evolution of the rash.
Thrombocytopenia FREQUENT Thrombocytopenia (HP:0001873)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0001873 | Thrombocytopenia | Frequent (79-30%)"
Orphanet reports thrombocytopenia as frequent.
PMID:26090319 SUPPORT Human Clinical
"Most frequent blood test abnormalities were C-reactive protein, lactate dehydrogenase, aspartate aminotransferase and alanine transaminase elevations and thrombocytopenia."
A 250-patient case series identified thrombocytopenia among frequent blood-test abnormalities.
Decreased total leukocyte count OCCASIONAL Decreased total leukocyte count (HP:0001882)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0001882 | Leukopenia | Occasional (29-5%)"
Orphanet reports leukopenia as occasional.
Cardiovascular 3
Lymphadenopathy FREQUENT Lymphadenopathy (HP:0002716)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0002716 | Lymphadenopathy | Frequent (79-30%)"
Orphanet reports lymphadenopathy as frequent.
Cervical lymphadenopathy FREQUENT Cervical lymphadenopathy (HP:0025289)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0025289 | Cervical lymphadenopathy | Frequent (79-30%)"
Orphanet reports cervical lymphadenopathy as frequent.
Vasculitis VERY_RARE Vasculitis (HP:0002633)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0002633 | Vasculitis | Very rare (<4-1%)"
Orphanet reports vasculitis as very rare.
PMID:15109588 SUPPORT Human Clinical
"potentially life-threatening disease with disseminated vaculitis is occasionally seen."
Review supports disseminated vasculitis in occasional severe disease.
Digestive 2
Diarrhea OCCASIONAL Diarrhea (HP:0002014)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0002014 | Diarrhea | Occasional (29-5%)"
Orphanet reports diarrhea as occasional.
Nausea OCCASIONAL Nausea (HP:0002018)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0002018 | Nausea | Occasional (29-5%)"
Orphanet reports nausea as occasional.
Eye 1
Photophobia VERY_RARE Photophobia (HP:0000613)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0000613 | Photophobia | Very rare (<4-1%)"
Orphanet reports photophobia as very rare.
Genitourinary 1
Renal insufficiency FREQUENT Renal insufficiency (HP:0000083)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0000083 | Renal insufficiency | Frequent (79-30%)"
Orphanet reports renal insufficiency as frequent.
PMID:26090319 SUPPORT Human Clinical
"Most frequent complication was acute renal injury."
A 250-patient series identified acute renal injury as the most frequent complication.
Immune 2
Skin rash VERY_FREQUENT Skin rash (HP:0000988)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0000988 | Skin rash | Very frequent (99-80%)"
Orphanet reports skin rash as very frequent.
PMID:15109588 SUPPORT Human Clinical
"flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite"
Travel-medicine review supports rash with inoculation eschar.
Maculopapular exanthema FREQUENT Maculopapular exanthema (HP:0040186)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0040186 | Maculopapular exanthema | Frequent (79-30%)"
Orphanet reports maculopapular exanthema as frequent.
PMID:26090319 SUPPORT Human Clinical
"Maculopapular rash was noticed in 87%, affecting palms in 77% and soles in 69%."
A 250-patient series quantified maculopapular rash and palm/sole involvement.
Integument 2
Tache noire inoculation eschar FREQUENT Skin nodule (HP:0200036)
HPO lacks a specific inoculation-eschar term; the finding is mapped to the closest local skin nodule term while the preferred term preserves the clinically specific tache noire concept.
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0200036 | Skin nodule | Frequent (79-30%)"
Orphanet reports skin nodule as frequent; the disease definition specifies tache noire at the tick-bite site.
PMID:26090319 SUPPORT Human Clinical
"Inoculation eschar was found in 60%, mostly located on the trunk."
A 250-patient case series quantified inoculation eschar.
Skin detachment FREQUENT Skin detachment (HP:0032156)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0032156 | Skin detachment | Frequent (79-30%)"
Orphanet reports skin detachment as frequent.
Metabolism 2
Fever VERY_FREQUENT Fever (HP:0001945)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0001945 | Fever | Very frequent (99-80%)"
Orphanet reports fever as very frequent.
PMID:26090319 SUPPORT Human Clinical
"Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
A 250-patient series quantified fever in 98% of cases.
Elevated circulating hepatic transaminase concentration FREQUENT Elevated circulating hepatic transaminase concentration (HP:0002910)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0002910 | Elevated circulating hepatic transaminase concentration | Frequent (79-30%)"
Orphanet reports elevated circulating hepatic transaminases as frequent.
PMID:26090319 SUPPORT Human Clinical
"aspartate aminotransferase and alanine transaminase elevations and thrombocytopenia."
A 250-patient case series identifies AST and ALT elevations among frequent blood-test abnormalities.
Nervous System 1
Headache FREQUENT Headache (HP:0002315)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0002315 | Headache | Frequent (79-30%)"
Orphanet reports headache as frequent.
PMID:26090319 SUPPORT Human Clinical
"Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
A 250-patient case series quantified headache in 48%.
Respiratory 1
Respiratory failure VERY_RARE Respiratory failure (HP:0002878)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0002878 | Respiratory failure | Very rare (<4-1%)"
Orphanet reports respiratory failure as very rare.
Constitutional 3
Myalgia FREQUENT Myalgia (HP:0003326)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0003326 | Myalgia | Frequent (79-30%)"
Orphanet reports myalgia as frequent.
PMID:26090319 SUPPORT Human Clinical
"Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
A 250-patient case series quantified myo-arthralgia.
Arthralgia FREQUENT Arthralgia (HP:0002829)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0002829 | Arthralgia | Frequent (79-30%)"
Orphanet reports arthralgia as frequent.
PMID:26090319 SUPPORT Human Clinical
"Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
A 250-patient case series quantified myo-arthralgia.
Abdominal pain OCCASIONAL Abdominal pain (HP:0002027)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0002027 | Abdominal pain | Occasional (29-5%)"
Orphanet reports abdominal pain as occasional.
Other 5
Abnormal skin morphology of the palm VERY_FREQUENT Abnormal skin morphology of the palm (HP:0040211)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0040211 | Abnormality of the skin of the palm | Very frequent (99-80%)"
Orphanet reports palm skin involvement as very frequent.
PMID:26090319 SUPPORT Human Clinical
"affecting palms in 77% and soles in 69%."
A 250-patient case series quantified palm involvement.
Abnormality of the plantar skin of foot VERY_FREQUENT Abnormality of the plantar skin of foot (HP:0100872)
Show evidence (2 references)
ORPHA:83313 SUPPORT Other
"HP:0100872 | Abnormality of the plantar skin of foot | Very frequent (99-80%)"
Orphanet reports plantar skin involvement as very frequent.
PMID:26090319 SUPPORT Human Clinical
"affecting palms in 77% and soles in 69%."
A 250-patient case series quantified sole involvement.
Macule FREQUENT Macule (HP:0012733)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0012733 | Macule | Frequent (79-30%)"
Orphanet reports macules as frequent.
Increased circulating IgM level FREQUENT Increased circulating IgM level (HP:0003496)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0003496 | Increased circulating IgM level | Frequent (79-30%)"
Orphanet reports increased circulating IgM as frequent.
Increased circulating IgG concentration OCCASIONAL Increased circulating IgG concentration (HP:0003237)
Show evidence (1 reference)
ORPHA:83313 SUPPORT Other
"HP:0003237 | Increased circulating IgG level | Occasional (29-5%)"
Orphanet reports increased circulating IgG as occasional.
💊

Treatments

3
Doxycycline pharmacotherapy
Action: Pharmacotherapy NCIT:C15986
Agent: doxycycline ↗
Doxycycline is the treatment of choice for Mediterranean spotted fever and tick-borne rickettsioses.
Mechanism Target:
Tick-borne Rickettsia conorii infection — Antibacterial treatment of the causative rickettsial infection.
Show evidence (2 references)
PMID:34698275 SUPPORT Human Clinical
"Doxycycline remains the treatment of choice"
The current review identifies doxycycline as treatment of choice for MSF.
PMID:15109588 SUPPORT Human Clinical
"Doxycycline is the recommended treatment for tick-borne rickettsioses"
Travel-medicine review supports doxycycline treatment for tick-borne rickettsioses.
Tetracycline-class or chloramphenicol therapy
Action: Pharmacotherapy NCIT:C15986
Agent: tetracycline ↗ chloramphenicol ↗
Tetracyclines and chloramphenicol have historically been standard treatment options; doxycycline is preferred when appropriate.
Show evidence (1 reference)
PMID:16881414 SUPPORT Human Clinical
"Oral or parenteral administration of tetracyclines or chloramphenicol represent the standard treatment."
The Italian review supports tetracyclines or chloramphenicol as standard therapy.
Macrolide alternatives for children and pregnancy
Action: Pharmacotherapy NCIT:C15986
Agent: clarithromycin ↗ azithromycin ↗
Oral clarithromycin or azithromycin may be acceptable alternative treatment options, especially for children and during pregnancy.
Mechanism Target:
Tick-borne Rickettsia conorii infection — Macrolide antibacterial therapy targets the causative rickettsial infection.
Show evidence (1 reference)
PMID:16881414 SUPPORT Human Clinical
"Recent studies indicate that oral clarithromycin and azithromycin could constitute an acceptable alternative for the treatment of the disease in children; furthermore, they could be recommended during pregnancy."
The Italian clinical review identifies clarithromycin and azithromycin as acceptable alternatives in children and pregnancy.
{ }

Source YAML

click to show 
name: Boutonneuse fever
creation_date: "2026-05-09T22:40:00Z"
updated_date: "2026-05-10T00:34:49Z"
category: Infectious Disease
parents:
- Rickettsia conorii infectious disease
- Spotted fever rickettsiosis
synonyms:
- Mediterranean spotted fever
- Mediterranean tick fever
- Boutonneuse disease
- Marseilles fever
- Conor and Bruch's disease
description: >-
  Boutonneuse fever, also called Mediterranean spotted fever, is an acute
  tick-borne spotted-fever-group rickettsiosis caused by Rickettsia conorii
  subsp. conorii. After an incubation period of about a week, infection causes
  fever, headache, myalgia or arthralgia, a centripetally spreading
  maculopapular rash that often involves palms and soles, and an inoculation
  eschar ("tache noire") at the tick-bite site. Disseminated infection of
  vascular endothelium can produce vasculitis, thrombocytopenia, renal injury,
  respiratory failure, and other severe multiorgan complications.
disease_term:
  preferred_term: boutonneuse fever
  term:
    id: MONDO:0024472
    label: boutonneuse fever
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0024472
      label: boutonneuse fever
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:83313
    mapping_justification: >-
      Orphanet ORPHA:83313 lists MONDO:0024472 as an exact cross-reference for
      Boutonneuse fever.
external_assertions:
- name: Orphanet Boutonneuse fever disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:83313
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=83313
  description: >-
    Orphanet's ORPHA:83313 record provides the Rickettsia conorii disease
    definition, epidemiology, natural-history age of onset, exact MONDO mapping,
    and structured HPO phenotype rows used in this entry.
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0024472 | Exact"
    explanation: Orphanet maps ORPHA:83313 exactly to the MONDO term used by this entry.
- name: Orphanet African tick typhus record separated from phenotype transfer
  source: Orphanet
  assertion_type: related_structured_disease_record
  external_id: ORPHA:101334
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=101334
  description: >-
    MONDO also cross-references ORPHA:101334, but that Orphanet record is
    African tick typhus caused by Rickettsia africae rather than the R. conorii
    Mediterranean spotted fever record. This entry therefore does not transfer
    ORPHA:101334 phenotypes to boutonneuse fever.
  evidence:
  - reference: ORPHA:101334
    reference_title: "African tick typhus"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "caused by the tick-borne bacterium <i>Rickettsia africae</i>"
    explanation: The Orphanet African tick typhus record has a different etiologic agent.
definitions:
- name: Orphanet Boutonneuse fever definition
  definition_type: OTHER
  description: >-
    Rare spotted fever rickettsiosis caused by the tick-borne bacterium
    Rickettsia conorii, with fever after about a week of incubation followed by
    maculopapular or petechial rash, headache, myalgia, arthralgia, and a
    possible tache noire at the tick-bite site.
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare spotted fever rickettsiosis caused by infection with the tick-borne bacterium <i>Rickettsia conorii</i>"
    explanation: Orphanet defines Boutonneuse fever as tick-borne R. conorii rickettsiosis.
- name: Molecular and clinical review definition
  definition_type: OTHER
  description: >-
    Modern molecular reviews define Mediterranean spotted fever as an emerging
    Mediterranean-basin spotted-fever-group rickettsiosis caused by Rickettsia
    conorii subsp. conorii and transmitted by the brown dog tick.
  evidence:
  - reference: PMID:34698275
    reference_title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the causative agent of MSF is Rickettsia conorii subspecies conorii. The arthropod vector of this bacterium is the brown dog tick Rhipicephalus sanguineus."
    explanation: The review identifies the causative subspecies and vector.
references:
- reference: ORPHA:83313
  title: Boutonneuse fever
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      Orphanet defines Boutonneuse fever as Rickettsia conorii rickettsiosis and
      provides epidemiology, all-ages onset, exact MONDO mapping, and structured
      HPO phenotype frequencies.
    supporting_text: "MONDO:0024472 | Exact"
- reference: ORPHA:101334
  title: African tick typhus
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      The related Orphanet African tick typhus record is not used for phenotype
      transfer because it is caused by Rickettsia africae, not R. conorii.
    supporting_text: "caused by the tick-borne bacterium <i>Rickettsia africae</i>"
- reference: PMID:34698275
  title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      A modern review identifies R. conorii subsp. conorii and Rhipicephalus
      sanguineus, summarizes endothelial dissemination, diagnosis, and
      doxycycline treatment.
    supporting_text: "Doxycycline remains the treatment of choice"
- reference: PMID:26090319
  title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      A 250-patient case series quantifies fever, rash, palm and sole
      involvement, inoculation eschar, treatment use, blood-test abnormalities,
      acute renal injury, ICU admission, and mortality.
    supporting_text: "Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
- reference: PMID:15109588
  title: Tick-borne rickettsioses in international travellers.
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      A travel-medicine review supports rash, inoculation eschar, disseminated
      vasculitis, serology-supported diagnosis, doxycycline treatment, and tick
      bite prevention.
    supporting_text: "diagnosis must in most cases rely on clinical and epidemiological data supported by serology."
- reference: PMID:16881414
  title: Epidemiology and clinical features of Mediterranean spotted fever in Italy.
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      Italian clinical review supports the fever, exanthema, and tache noire
      triad, brown dog tick transmission, severe-risk groups, mortality,
      tetracycline or chloramphenicol treatment, and macrolide alternatives for
      children and pregnancy.
    supporting_text: "It is characterized by the symptomatologic triad: fever, exanthema and \"tache noire\""
- reference: PMID:7691249
  title: "Demonstration of Rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von Willebrand factor in patients with Mediterranean spotted fever."
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      Human patient biomarker data support endothelial injury as a central
      mechanism in Mediterranean spotted fever.
    supporting_text: "The endothelial cell (EC) is the primary target for Rickettsia conorii (RC) in Mediterranean spotted fever (MSF)."
- reference: PMID:8675654
  title: IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway.
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      Infected human endothelial cells secrete IL-6 and IL-8 through a
      cell-associated IL-1 alpha pathway, supporting an inflammatory mechanism
      for vasculitis.
    supporting_text: "R. conorii-infected HUVEC secrete IL-6 and IL-8"
- reference: PMID:16926398
  title: Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins.
  found_in:
  - Boutonneuse_Fever-deep-research-fallback.md
  findings:
  - statement: >-
      Infected endothelial cells upregulate COX-2 and vasoactive prostaglandins,
      providing a mechanism for inflammatory and vascular permeability changes.
    supporting_text: "enhanced release of vasoactive PGs may contribute to the regulation of inflammatory responses and vascular permeability changes"
prevalence:
- population: Europe
  percentage: 1-5 per 10,000
  notes: Orphanet records point prevalence of 1-5 per 10,000 in Europe.
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet provides the European point-prevalence band.
- population: France
  percentage: 1-5 per 10,000
  notes: Orphanet records point prevalence of 1-5 per 10,000 in France.
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | France | Point prevalence | ORPHANET"
    explanation: Orphanet provides the French point-prevalence band.
- population: Portugal
  percentage: 1-9 per 100,000
  notes: Orphanet records point prevalence of 1-9 per 100,000 in Portugal.
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Portugal | Point prevalence | ORPHANET"
    explanation: Orphanet provides the Portuguese point-prevalence band.
progression:
- phase: Incubation period
  incubation_days: "7"
  notes: Orphanet describes fever onset after an incubation period of about a week.
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "onset of fever after an incubation period of about a week"
    explanation: Orphanet supports the approximate one-week incubation phase.
- phase: Acute febrile exanthem
  notes: >-
    Acute disease begins with fever and systemic symptoms followed by a
    centripetally spreading maculopapular rash that can become petechial.
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "followed by a centripetally spreading maculopapular rash, which may evolve into a petechial form"
    explanation: Orphanet supports the acute rash progression.
epidemiology:
- name: Severe disease host comorbidity risk context
  description: >-
    Severe forms are reported in a minority of patients and are enriched among
    adults with diabetes, cardiac disease, chronic alcoholism, glucose-6-phosphate
    dehydrogenase deficiency, or end-stage kidney disease.
  factors:
  - adult age
  - diabetes
  - cardiac disease
  - chronic alcoholism
  - glucose-6-phosphate dehydrogenase deficiency
  - end stage kidney disease
  evidence:
  - reference: PMID:16881414
    reference_title: "Epidemiology and clinical features of Mediterranean spotted fever in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe forms of the disease have been reported in 6% of patients, especially adults with one of the following conditions: diabetes, cardiac disease, chronic alcoholism, glucose-6-phosphate dehydrogenase deficiency, end stage kidney disease."
    explanation: The Italian clinical review lists adult comorbidities associated with severe Mediterranean spotted fever.
infectious_agent:
- name: Rickettsia conorii subsp. conorii
  infectious_agent_term:
    preferred_term: Rickettsia conorii subsp. conorii
    term:
      id: NCBITaxon:319546
      label: Rickettsia conorii subsp. conorii
  description: >-
    Obligate intracellular spotted-fever-group rickettsial bacterium causing
    boutonneuse fever.
  evidence:
  - reference: PMID:34698275
    reference_title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the causative agent of MSF is Rickettsia conorii subspecies conorii"
    explanation: The review identifies the causative subspecies for Mediterranean spotted fever.
transmission:
- name: Brown dog tick bite transmission
  description: >-
    Rickettsia conorii subsp. conorii is transmitted to humans by the brown dog
    tick Rhipicephalus sanguineus; the inoculation site can produce a tache
    noire eschar.
  evidence:
  - reference: PMID:34698275
    reference_title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The arthropod vector of this bacterium is the brown dog tick Rhipicephalus sanguineus."
    explanation: The review identifies the tick vector.
  - reference: PMID:16881414
    reference_title: "Epidemiology and clinical features of Mediterranean spotted fever in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mediterranean Spotted Fever is caused by Rickettsia conorii and is transmitted to humans by Rhipicephalus sanguineus, the common dog tick."
    explanation: The Italian review independently supports brown dog tick transmission.
pathophysiology:
- name: Tick-borne Rickettsia conorii infection
  description: >-
    Brown dog tick transmission introduces R. conorii subsp. conorii, an
    intracellular rickettsial bacterium, initiating acute spotted fever
    rickettsiosis.
  biological_processes:
  - preferred_term: response to bacterium
    term:
      id: GO:0009617
      label: response to bacterium
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34698275
    reference_title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mediterranean spotted fever (MSF) is an emerging tick-borne rickettsiosis of the spotted fever group (SFG)"
    explanation: This directly supports the initiating tick-borne rickettsial infection.
  downstream:
  - target: Endothelial infection and injury
    description: R. conorii disseminates to and injures vascular endothelium.
    causal_link_type: DIRECT
- name: Endothelial infection and injury
  description: >-
    R. conorii targets vascular endothelial cells in vivo; endothelial damage is
    supported by circulating endothelial cells and elevated thrombomodulin and
    von Willebrand factor in patients.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:7691249
    reference_title: "Demonstration of Rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von Willebrand factor in patients with Mediterranean spotted fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The endothelial cell (EC) is the primary target for Rickettsia conorii (RC) in Mediterranean spotted fever (MSF)."
    explanation: Human patient study identifies endothelial cells as the primary target.
  - reference: PMID:34698275
    reference_title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of these manifestations arise from the disseminated infection of the endothelium by R. conorii conorii."
    explanation: Review links disseminated endothelial infection to clinical manifestations.
  downstream:
  - target: Rickettsial vasculitis and vascular permeability
    description: Endothelial injury drives vasculitis and vascular leak.
    causal_link_type: DIRECT
  - target: Skin rash
    description: Endothelial infection contributes to the characteristic exanthem.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Maculopapular exanthema
    description: Endothelial infection contributes to the maculopapular rash pattern.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Rickettsial vasculitis and vascular permeability
  description: >-
    Infected endothelial cells and systemic endothelial injury produce
    generalized vasculitis, microvascular injury, and vascular permeability
    changes that underlie severe organ manifestations.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: positive regulation of vascular permeability
    term:
      id: GO:0043117
      label: positive regulation of vascular permeability
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:15109588
    reference_title: "Tick-borne rickettsioses in international travellers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "potentially life-threatening disease with disseminated vaculitis is occasionally seen."
    explanation: Travel-medicine review supports disseminated vasculitis as a severe manifestation.
  - reference: PMID:7691249
    reference_title: "Demonstration of Rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von Willebrand factor in patients with Mediterranean spotted fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations such as thrombosis and vasculitis are mediated by pathologic changes localized in blood vessels."
    explanation: Human biomarker study links clinical disease to vascular pathology.
  downstream:
  - target: Vasculitis
    description: Rickettsial endothelial injury directly manifests as vasculitis.
    causal_link_type: DIRECT
  - target: Petechiae
    description: Vascular injury can produce petechial rash.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Renal insufficiency
    description: Microvascular injury contributes to acute kidney involvement.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Respiratory failure
    description: Severe endothelial disease can involve the lungs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Endothelial cytokine activation
  description: >-
    R. conorii-infected human endothelial cells secrete IL-6 and IL-8 through a
    cell-associated IL-1 alpha-dependent pathway, providing an inflammatory
    mechanism for vasculitis and systemic febrile symptoms.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:8675654
    reference_title: "IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "human umbilical vein endothelial cells (HUVEC) infected with R. conorii actively secrete high levels of IL-8 and IL-6"
    explanation: In vitro endothelial-cell infection supports increased cytokine secretion.
  - reference: PMID:8675654
    reference_title: "IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "providing a possible mechanism for the vasculitis observed in Mediterranean spotted fever."
    explanation: The authors link the endothelial cytokine response to vasculitis.
  downstream:
  - target: Rickettsial vasculitis and vascular permeability
    description: Cytokine activation amplifies rickettsial vasculitis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Fever
    description: Endothelial inflammatory cytokines contribute to systemic fever.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Endothelial COX-2 prostaglandin activation
  description: >-
    Spotted-fever-group rickettsial infection induces endothelial COX-2 and
    vasoactive prostaglandin release, which may regulate inflammatory responses
    and vascular permeability changes.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: prostaglandin biosynthetic process
    term:
      id: GO:0001516
      label: prostaglandin biosynthetic process
    modifier: INCREASED
  - preferred_term: positive regulation of vascular permeability
    term:
      id: GO:0043117
      label: positive regulation of vascular permeability
    modifier: INCREASED
  evidence:
  - reference: PMID:16926398
    reference_title: "Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rocky Mountain spotted fever and boutonneuse fever, due to Rickettsia rickettsii and R. conorii, respectively, are characterized by widespread infection of the vascular endothelium, microvascular injury, and vasculitis."
    explanation: The study frames boutonneuse fever as endothelial infection with microvascular injury and vasculitis.
  - reference: PMID:16926398
    reference_title: "Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Induction of the endothelial COX-2 system and the resultant enhanced release of vasoactive PGs may contribute to the regulation of inflammatory responses and vascular permeability changes during spotted fever rickettsioses."
    explanation: Infected endothelial-cell models support COX-2/prostaglandin contribution to vascular permeability.
  downstream:
  - target: Rickettsial vasculitis and vascular permeability
    description: Vasoactive prostaglandins modulate the vascular inflammatory phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- category: Infectious
  name: Fever
  frequency: VERY_FREQUENT
  diagnostic: true
  description: Fever is a core manifestation after the incubation period.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001945 | Fever | Very frequent (99-80%)"
    explanation: Orphanet reports fever as very frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
    explanation: A 250-patient series quantified fever in 98% of cases.
- category: Dermatological
  name: Skin rash
  frequency: VERY_FREQUENT
  diagnostic: true
  description: A generalized rash is a core clinical feature.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000988 | Skin rash | Very frequent (99-80%)"
    explanation: Orphanet reports skin rash as very frequent.
  - reference: PMID:15109588
    reference_title: "Tick-borne rickettsioses in international travellers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flu-like illness typically accompanied by a cutaneous rash and an inoculation eschar at the site of the tick bite"
    explanation: Travel-medicine review supports rash with inoculation eschar.
- category: Dermatological
  name: Maculopapular exanthema
  frequency: FREQUENT
  diagnostic: true
  description: The typical rash is maculopapular and spreads centripetally.
  phenotype_term:
    preferred_term: Maculopapular exanthema
    term:
      id: HP:0040186
      label: Maculopapular exanthema
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040186 | Maculopapular exanthema | Frequent (79-30%)"
    explanation: Orphanet reports maculopapular exanthema as frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maculopapular rash was noticed in 87%, affecting palms in 77% and soles in 69%."
    explanation: A 250-patient series quantified maculopapular rash and palm/sole involvement.
- category: Dermatological
  name: Abnormal skin morphology of the palm
  frequency: VERY_FREQUENT
  description: The rash commonly affects palms.
  phenotype_term:
    preferred_term: Palm rash involvement
    term:
      id: HP:0040211
      label: Abnormal skin morphology of the palm
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040211 | Abnormality of the skin of the palm | Very frequent (99-80%)"
    explanation: Orphanet reports palm skin involvement as very frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "affecting palms in 77% and soles in 69%."
    explanation: A 250-patient case series quantified palm involvement.
- category: Dermatological
  name: Abnormality of the plantar skin of foot
  frequency: VERY_FREQUENT
  description: The rash commonly affects soles.
  phenotype_term:
    preferred_term: Sole rash involvement
    term:
      id: HP:0100872
      label: Abnormality of the plantar skin of foot
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100872 | Abnormality of the plantar skin of foot | Very frequent (99-80%)"
    explanation: Orphanet reports plantar skin involvement as very frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "affecting palms in 77% and soles in 69%."
    explanation: A 250-patient case series quantified sole involvement.
- category: Dermatological
  name: Tache noire inoculation eschar
  frequency: FREQUENT
  diagnostic: true
  description: A dark inoculation eschar can occur at the tick-bite site.
  notes: >-
    HPO lacks a specific inoculation-eschar term; the finding is mapped to the
    closest local skin nodule term while the preferred term preserves the
    clinically specific tache noire concept.
  phenotype_term:
    preferred_term: Tache noire inoculation eschar
    term:
      id: HP:0200036
      label: Skin nodule
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200036 | Skin nodule | Frequent (79-30%)"
    explanation: Orphanet reports skin nodule as frequent; the disease definition specifies tache noire at the tick-bite site.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inoculation eschar was found in 60%, mostly located on the trunk."
    explanation: A 250-patient case series quantified inoculation eschar.
- category: Dermatological
  name: Petechiae
  frequency: OCCASIONAL
  description: The maculopapular rash may evolve into petechial lesions.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000967 | Petechiae | Occasional (29-5%)"
    explanation: Orphanet reports petechiae as occasional.
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "maculopapular rash, which may evolve into a petechial form"
    explanation: Orphanet definition describes petechial evolution of the rash.
- category: Dermatological
  name: Macule
  frequency: FREQUENT
  description: Macular skin lesions are part of the rickettsial exanthem.
  phenotype_term:
    preferred_term: Macule
    term:
      id: HP:0012733
      label: Macule
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012733 | Macule | Frequent (79-30%)"
    explanation: Orphanet reports macules as frequent.
- category: Dermatological
  name: Skin detachment
  frequency: FREQUENT
  description: Skin detachment can be recorded among cutaneous manifestations.
  phenotype_term:
    preferred_term: Skin detachment
    term:
      id: HP:0032156
      label: Skin detachment
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0032156 | Skin detachment | Frequent (79-30%)"
    explanation: Orphanet reports skin detachment as frequent.
- category: Neurological
  name: Headache
  frequency: FREQUENT
  description: Headache commonly accompanies the acute febrile illness.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002315 | Headache | Frequent (79-30%)"
    explanation: Orphanet reports headache as frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
    explanation: A 250-patient case series quantified headache in 48%.
- category: Musculoskeletal
  name: Myalgia
  frequency: FREQUENT
  description: Myalgia is a common systemic symptom.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003326 | Myalgia | Frequent (79-30%)"
    explanation: Orphanet reports myalgia as frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
    explanation: A 250-patient case series quantified myo-arthralgia.
- category: Musculoskeletal
  name: Arthralgia
  frequency: FREQUENT
  description: Arthralgia can accompany the acute febrile illness.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002829 | Arthralgia | Frequent (79-30%)"
    explanation: Orphanet reports arthralgia as frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
    explanation: A 250-patient case series quantified myo-arthralgia.
- category: Immune
  name: Lymphadenopathy
  frequency: FREQUENT
  description: Lymphadenopathy can accompany the acute infection.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002716 | Lymphadenopathy | Frequent (79-30%)"
    explanation: Orphanet reports lymphadenopathy as frequent.
- category: Immune
  name: Cervical lymphadenopathy
  frequency: FREQUENT
  description: Cervical lymphadenopathy can occur.
  phenotype_term:
    preferred_term: Cervical lymphadenopathy
    term:
      id: HP:0025289
      label: Cervical lymphadenopathy
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025289 | Cervical lymphadenopathy | Frequent (79-30%)"
    explanation: Orphanet reports cervical lymphadenopathy as frequent.
- category: Hematological
  name: Thrombocytopenia
  frequency: FREQUENT
  description: Thrombocytopenia is a common blood-test abnormality.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001873 | Thrombocytopenia | Frequent (79-30%)"
    explanation: Orphanet reports thrombocytopenia as frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most frequent blood test abnormalities were C-reactive protein, lactate dehydrogenase, aspartate aminotransferase and alanine transaminase elevations and thrombocytopenia."
    explanation: A 250-patient case series identified thrombocytopenia among frequent blood-test abnormalities.
- category: Hematological
  name: Decreased total leukocyte count
  frequency: OCCASIONAL
  description: Leukopenia can occur.
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001882 | Leukopenia | Occasional (29-5%)"
    explanation: Orphanet reports leukopenia as occasional.
- category: Renal
  name: Renal insufficiency
  frequency: FREQUENT
  description: Acute renal injury or insufficiency is the most frequent complication in one large series.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000083 | Renal insufficiency | Frequent (79-30%)"
    explanation: Orphanet reports renal insufficiency as frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most frequent complication was acute renal injury."
    explanation: A 250-patient series identified acute renal injury as the most frequent complication.
- category: Respiratory
  name: Respiratory failure
  frequency: VERY_RARE
  description: Severe disease can rarely include respiratory failure.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002878 | Respiratory failure | Very rare (<4-1%)"
    explanation: Orphanet reports respiratory failure as very rare.
- category: Cardiovascular
  name: Vasculitis
  frequency: VERY_RARE
  description: Vasculitis reflects endothelial tropism and injury in severe disease.
  phenotype_term:
    preferred_term: Vasculitis
    term:
      id: HP:0002633
      label: Vasculitis
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002633 | Vasculitis | Very rare (<4-1%)"
    explanation: Orphanet reports vasculitis as very rare.
  - reference: PMID:15109588
    reference_title: "Tick-borne rickettsioses in international travellers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "potentially life-threatening disease with disseminated vaculitis is occasionally seen."
    explanation: Review supports disseminated vasculitis in occasional severe disease.
- category: Biochemical
  name: Elevated circulating hepatic transaminase concentration
  frequency: FREQUENT
  description: Transaminase elevation is a common laboratory abnormality.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002910 | Elevated circulating hepatic transaminase concentration | Frequent (79-30%)"
    explanation: Orphanet reports elevated circulating hepatic transaminases as frequent.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aspartate aminotransferase and alanine transaminase elevations and thrombocytopenia."
    explanation: A 250-patient case series identifies AST and ALT elevations among frequent blood-test abnormalities.
- category: Immune
  name: Increased circulating IgM level
  frequency: FREQUENT
  diagnostic: true
  description: IgM elevation is part of serologic evidence of acute infection.
  phenotype_term:
    preferred_term: Increased circulating IgM level
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003496 | Increased circulating IgM level | Frequent (79-30%)"
    explanation: Orphanet reports increased circulating IgM as frequent.
- category: Immune
  name: Increased circulating IgG concentration
  frequency: OCCASIONAL
  diagnostic: true
  description: IgG elevation or seroconversion can support diagnosis.
  phenotype_term:
    preferred_term: Increased circulating IgG level
    term:
      id: HP:0003237
      label: Increased circulating IgG concentration
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003237 | Increased circulating IgG level | Occasional (29-5%)"
    explanation: Orphanet reports increased circulating IgG as occasional.
- category: Gastrointestinal
  name: Diarrhea
  frequency: OCCASIONAL
  description: Diarrhea can occur among gastrointestinal manifestations.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002014 | Diarrhea | Occasional (29-5%)"
    explanation: Orphanet reports diarrhea as occasional.
- category: Gastrointestinal
  name: Nausea
  frequency: OCCASIONAL
  description: Nausea can occur.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002018 | Nausea | Occasional (29-5%)"
    explanation: Orphanet reports nausea as occasional.
- category: Gastrointestinal
  name: Abdominal pain
  frequency: OCCASIONAL
  description: Abdominal pain can occur.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002027 | Abdominal pain | Occasional (29-5%)"
    explanation: Orphanet reports abdominal pain as occasional.
- category: Ophthalmological
  name: Photophobia
  frequency: VERY_RARE
  description: Photophobia is a rare ocular manifestation.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: ORPHA:83313
    reference_title: "Boutonneuse fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000613 | Photophobia | Very rare (<4-1%)"
    explanation: Orphanet reports photophobia as very rare.
diagnosis:
- name: Clinical-epidemiologic diagnosis with serology
  description: >-
    Diagnosis often relies on compatible clinical and epidemiologic findings
    supported by serologic testing.
  diagnosis_term:
    preferred_term: serology testing
    term:
      id: MAXO:0000609
      label: serology testing
  results: Serology supports suspected boutonneuse fever in a compatible tick-exposure syndrome.
  evidence:
  - reference: PMID:15109588
    reference_title: "Tick-borne rickettsioses in international travellers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diagnosis must in most cases rely on clinical and epidemiological data supported by serology."
    explanation: The review supports serology-backed clinical and epidemiologic diagnosis.
  - reference: PMID:26090319
    reference_title: "Mediterranean spotted fever: case series of 24 years (1989-2012)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "First serologic evaluation was positive in 37% (78/212), having seroconversion been documented in 85% (72/85)."
    explanation: The case series documents serologic confirmation and seroconversion.
- name: Serologic and molecular diagnostic testing
  description: >-
    Serology is widely used, and molecular methods have become increasingly
    available for confirming Mediterranean spotted fever.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  results: Serologic positivity, seroconversion, or molecular detection supports diagnosis.
  evidence:
  - reference: PMID:34698275
    reference_title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several methods exist for the diagnosis of MSF. Serological tests are widely used and molecular techniques have become increasingly available."
    explanation: The review supports both serologic and molecular diagnostic approaches.
treatments:
- name: Doxycycline pharmacotherapy
  description: >-
    Doxycycline is the treatment of choice for Mediterranean spotted fever and
    tick-borne rickettsioses.
  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: Tick-borne Rickettsia conorii infection
    description: Antibacterial treatment of the causative rickettsial infection.
  evidence:
  - reference: PMID:34698275
    reference_title: "Mediterranean Spotted Fever: Current Knowledge and Recent Advances."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Doxycycline remains the treatment of choice"
    explanation: The current review identifies doxycycline as treatment of choice for MSF.
  - reference: PMID:15109588
    reference_title: "Tick-borne rickettsioses in international travellers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Doxycycline is the recommended treatment for tick-borne rickettsioses"
    explanation: Travel-medicine review supports doxycycline treatment for tick-borne rickettsioses.
- name: Tetracycline-class or chloramphenicol therapy
  description: >-
    Tetracyclines and chloramphenicol have historically been standard treatment
    options; doxycycline is preferred when appropriate.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tetracycline
      term:
        id: CHEBI:27902
        label: tetracycline
    - preferred_term: chloramphenicol
      term:
        id: CHEBI:17698
        label: chloramphenicol
  evidence:
  - reference: PMID:16881414
    reference_title: "Epidemiology and clinical features of Mediterranean spotted fever in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral or parenteral administration of tetracyclines or chloramphenicol represent the standard treatment."
    explanation: The Italian review supports tetracyclines or chloramphenicol as standard therapy.
- name: Macrolide alternatives for children and pregnancy
  description: >-
    Oral clarithromycin or azithromycin may be acceptable alternative treatment
    options, especially for children and during pregnancy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clarithromycin
      term:
        id: CHEBI:3732
        label: clarithromycin
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
  target_mechanisms:
  - target: Tick-borne Rickettsia conorii infection
    description: Macrolide antibacterial therapy targets the causative rickettsial infection.
  evidence:
  - reference: PMID:16881414
    reference_title: "Epidemiology and clinical features of Mediterranean spotted fever in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies indicate that oral clarithromycin and azithromycin could constitute an acceptable alternative for the treatment of the disease in children; furthermore, they could be recommended during pregnancy."
    explanation: The Italian clinical review identifies clarithromycin and azithromycin as acceptable alternatives in children and pregnancy.
notes: >-
  Orphanet ORPHA:83313 is the disease-specific R. conorii Boutonneuse fever
  record used for phenotype transfer. ORPHA:101334 is an African tick typhus
  record caused by Rickettsia africae and is documented only to explain why its
  phenotype rows were not transferred into this R. conorii entry.
clinical_trials: []
datasets: []
📚

References & Deep Research

References

9
ORPHA:83313
Boutonneuse fever
1 finding
Orphanet defines Boutonneuse fever as Rickettsia conorii rickettsiosis and provides epidemiology, all-ages onset, exact MONDO mapping, and structured HPO phenotype frequencies.
"MONDO:0024472 | Exact"
ORPHA:101334
African tick typhus
1 finding
The related Orphanet African tick typhus record is not used for phenotype transfer because it is caused by Rickettsia africae, not R. conorii.
"caused by the tick-borne bacterium <i>Rickettsia africae</i>"
PMID:34698275
Mediterranean Spotted Fever: Current Knowledge and Recent Advances.
1 finding
A modern review identifies R. conorii subsp. conorii and Rhipicephalus sanguineus, summarizes endothelial dissemination, diagnosis, and doxycycline treatment.
"Doxycycline remains the treatment of choice"
PMID:26090319
Mediterranean spotted fever: case series of 24 years (1989-2012).
1 finding
A 250-patient case series quantifies fever, rash, palm and sole involvement, inoculation eschar, treatment use, blood-test abnormalities, acute renal injury, ICU admission, and mortality.
"Most common symptoms were: fever (98%), myo-arthralgia (64%) and headache (48%)."
PMID:15109588
Tick-borne rickettsioses in international travellers.
1 finding
A travel-medicine review supports rash, inoculation eschar, disseminated vasculitis, serology-supported diagnosis, doxycycline treatment, and tick bite prevention.
"diagnosis must in most cases rely on clinical and epidemiological data supported by serology."
PMID:16881414
Epidemiology and clinical features of Mediterranean spotted fever in Italy.
1 finding
Italian clinical review supports the fever, exanthema, and tache noire triad, brown dog tick transmission, severe-risk groups, mortality, tetracycline or chloramphenicol treatment, and macrolide alternatives for children and pregnancy.
"It is characterized by the symptomatologic triad: fever, exanthema and "tache noire""
PMID:7691249
Demonstration of Rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von Willebrand factor in patients with Mediterranean spotted fever.
1 finding
Human patient biomarker data support endothelial injury as a central mechanism in Mediterranean spotted fever.
"The endothelial cell (EC) is the primary target for Rickettsia conorii (RC) in Mediterranean spotted fever (MSF)."
PMID:8675654
IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway.
1 finding
Infected human endothelial cells secrete IL-6 and IL-8 through a cell-associated IL-1 alpha pathway, supporting an inflammatory mechanism for vasculitis.
"R. conorii-infected HUVEC secrete IL-6 and IL-8"
PMID:16926398
Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins.
1 finding
Infected endothelial cells upregulate COX-2 and vasoactive prostaglandins, providing a mechanism for inflammatory and vascular permeability changes.
"enhanced release of vasoactive PGs may contribute to the regulation of inflammatory responses and vascular permeability changes"

Deep Research

1
Boutonneuse fever deep-research fallback ▸

Boutonneuse fever deep-research fallback

Date: 2026-05-09

Provider attempts

  • timeout 240s just research-disorder falcon Boutonneuse_Fever timed out with exit code 124.
  • timeout 240s just research-disorder openai Boutonneuse_Fever timed out with exit code 124.

No provider output artifact was produced. Curation proceeded from locally cached Orphanet structured records and PubMed abstracts/full text fetched with just fetch-reference.

Scope used

  • ORPHA:83313 was used as the disease-specific Boutonneuse fever / Mediterranean spotted fever structured record. It supplies the definition, epidemiology, all-ages onset, exact MONDO mapping, and all 26 HPO phenotype rows used in the YAML.
  • ORPHA:101334 was checked because MONDO cross-references it, but it is the African tick typhus record caused by Rickettsia africae; its phenotypes were not transferred to the R. conorii Boutonneuse fever entry.
  • PMID:34698275 was used for the modern review summary of R. conorii subsp. conorii, brown dog tick vector, endothelial dissemination, diagnostic methods, and doxycycline treatment.
  • PMID:26090319 was used as a 250-patient case series for fever, rash, palm and sole involvement, inoculation eschar, blood-test abnormalities, acute renal injury, treatment use, ICU admission, and mortality.
  • PMID:15109588 and PMID:16881414 were used for clinical diagnosis, serology-supported confirmation, disseminated vasculitis, tick-bite prevention context, and antimicrobial treatment.
  • PMID:7691249, PMID:8675654, and PMID:16926398 were used for the endothelial-injury, cytokine, COX-2/prostaglandin, vasculitis, and vascular permeability mechanism chain.

Local audit summary

  • Schema and term validation passed for kb/disorders/Boutonneuse_Fever.yaml.
  • Local snippet audit found all quoted snippets/findings in cached references.
  • Graph-target audit found all downstream and treatment mechanism targets.
  • ORPHA phenotype coverage audit found 26/26 ORPHA:83313 HPO rows represented.