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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0019359 Rocky mountain spotted fever

Orphanet ORPHA:83311 lists MONDO:0019359 as an exact cross-reference for Rocky Mountain spotted fever.

📘

Definitions

2

Orphanet Rocky Mountain spotted fever definition

A rare, acquired, life-threatening infectious disease due to the tick-borne bacterium Rickettsia rickettsii, with acute fever, malaise, and severe headache, followed 2-5 days later by a maculopapular rash with petechiae beginning on the wrists and ankles.

OTHER

Show evidence (1 reference)

ORPHA:83311 SUPPORT Other

"A rare, acquired, life-threatening, infectious disease due to the tick-borne bacteria <i>Rickettsia rickettsii</i> characterized by an acute onset of fever, malaise, and severe headache"

Orphanet defines RMSF as a life-threatening tick-borne R. rickettsii infection.

CDC/MMWR clinical definition and pathophysiologic framing

The CDC national recommendations define RMSF as infection with the obligate intracellular pathogen R. rickettsii, which primarily infects vascular endothelial cells and produces a systemic vasculitis.

OTHER

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Infection with R. rickettsii leads to systemic vasculitis that manifests externally as characteristic petechial skin lesions."

The CDC recommendations define the disease by endothelial infection producing systemic vasculitis.

?

Discussions and Knowledge Gaps

1

Does the VE-cadherin phosphorylation mechanism of microvascular hyperpermeability, demonstrated with the non-pathogenic surrogate Rickettsia montanensis under BSL2 conditions, hold quantitatively for Rickettsia rickettsii in human microvasculature?

HUMAN MODEL MISMATCH OPEN rmsf_surrogate_species_permeability_mechanism

Attached to

pathophysiology#VE-Cadherin Phosphorylation and Adherens Junction Disruption pathophysiology#Increased Microvascular Permeability

The junctional mechanism curated on this entry is the best available molecular account of RMSF microvascular leak, but the biophysical and biochemical experiments were deliberately performed with R. montanensis, a genetically similar but non-pathogenic species chosen so the work could be done at biosafety level 2. Virulent R. rickettsii strains differ from avirulent relatives in outer-membrane protein expression, so the magnitude and kinetics of junctional disruption - and any pathogen-specific effector contribution - are not established for the disease-causing organism. The complementary in vivo permeability evidence comes from experimentally infected dogs rather than humans.

Proposed experiments

VE-cadherin phosphorylation assays with virulent R. rickettsii

exp_rmsf_ve_cadherin_bsl3

Repeat the atomic force microscopy and VE-cadherin phosphorylation assays using virulent R. rickettsii in human microvascular endothelial cells under BSL3 containment, to test whether the surrogate result holds for the pathogenic organism.

Virulent versus avirulent strain comparison of junctional disruption

exp_rmsf_virulent_vs_avirulent_junction

Compare adherens-junction disruption between the virulent Sheila Smith and avirulent Iowa strains of R. rickettsii to test whether the magnitude of the effect tracks with virulence.

Junctional integrity in human RMSF tissue

exp_rmsf_human_tissue_junction

Assess VE-cadherin phosphorylation and adherens-junction integrity in autopsy or skin-biopsy tissue from human RMSF cases to establish whether the in vitro mechanism is present in human disease.

Show evidence (1 reference)

PMID:22720111 SUPPORT In Vitro

"R. montanensis, which is genetically similar to R. rickettsii and R. conorii, and displays a similar ability to invade cells, but is non-pathogenic and can be experimentally manipulated under Biosafety Level 2 (BSL2) conditions"

The authors state explicitly that a non-pathogenic surrogate was used in place of R. rickettsii, which is the source of the translational uncertainty recorded here.

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Pathophysiology

11

Tick-Borne Rickettsia rickettsii Inoculation

A feeding Dermacentor or Rhipicephalus tick inoculates R. rickettsii into the skin, initiating acute spotted fever rickettsiosis after an incubation period of 3-12 days. Unlike most other spotted fever group rickettsioses, an inoculation eschar is rarely present.

response to bacterium GO:0009617 ⚠ ABNORMAL

Downstream

Endothelial Cell Invasion and Intracytoplasmic Replication Inoculated rickettsiae disseminate and invade vascular endothelium.

Rickettsial Ribosomal Translation The replicating organism depends on bacterial ribosomal translation.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Symptoms of RMSF typically appear 3-12 days after the bite of an infected tick"

The CDC report establishes tick-bite inoculation and the incubation interval.

PMID:27172113 SUPPORT Human Clinical

"Unlike some SFG rickettsioses, an inoculation eschar is rarely present with RMSF"

Supports the negative feature that distinguishes RMSF from eschar-forming spotted fever rickettsioses such as boutonneuse fever.

Endothelial Cell Invasion and Intracytoplasmic Replication

R. rickettsii is an obligate intracellular organism that primarily infects vascular endothelial cells, and less commonly the underlying smooth muscle cells of small and medium vessels. Adhesion and invasion are mediated by the conserved rOmpA and rOmpB surface autotransporters engaging host receptors (Ku70 identified for the closely related R. conorii); after entry the organism escapes into the cytoplasm and replicates. Individual adhesins are redundant - an isogenic rOmpA knockout in a virulent strain did not attenuate virulence in guinea pigs.

vascular endothelial cell CL:0000071 microvascular endothelial cell CL:2000008

symbiont entry into host GO:0044409 ↑ INCREASED

Downstream

VE-Cadherin Phosphorylation and Adherens Junction Disruption Infected endothelium loses adherens-junction integrity.

Disseminated Small-Vessel Vasculitis Widespread endothelial infection produces systemic vasculitis.

Cytotoxic T Lymphocyte Clearance of Infected Endothelium Infected endothelial cells become targets of CD8 T cell cytotoxicity.

Obligate Intracellular Niche (Cell-Penetrant Drug Requirement) Cytoplasmic residence gates which antimicrobials can reach the organism.

Show evidence (3 references)

PMID:27172113 SUPPORT Human Clinical

"R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells, and, less commonly, underlying smooth muscle cells of small and medium vessels"

The CDC report establishes the endothelial tropism that defines RMSF pathophysiology.

PMID:16360032 SUPPORT In Vitro

"Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii."

Identifies a host receptor for rickettsial entry. Marked PARTIAL because the receptor was characterized for the closely related spotted fever group agent R. conorii rather than R. rickettsii directly.

PMID:25827414 SUPPORT Model Organism

"no significant difference in either fever peak (40.5 C) or duration (8 days) were shown between the wild type and the knockout"

Guinea pig challenge with an isogenic rOmpA knockout shows that this immunodominant adhesin is not individually required for virulence, supporting redundancy among invasion factors.

VE-Cadherin Phosphorylation and Adherens Junction Disruption

Spotted fever group rickettsial infection of microvascular endothelial cells activates tyrosine phosphorylation of VE-cadherin, attenuating homophilic adherens-junction protein-protein interactions and producing paracellular barrier dysfunction. This is the best-characterized molecular route from endothelial infection to microvascular leak.

adherens junction organization GO:0034332 ↓ DECREASED

Downstream

Increased Microvascular Permeability Loss of junctional integrity permits paracellular leak.

Show evidence (1 reference)

PMID:22720111 SUPPORT In Vitro

"upon infection by SFG rickettsiae, phosphorylation of VE-cadherin directly attenuates homophilic protein-protein interactions at the endothelial adherens junctions, and may lead to endothelial paracellular barrier dysfunction causing microvascular hyperpermeability"

Atomic force microscopy and biochemical assays establish the VE-cadherin-phosphorylation mechanism. The experiments used the non-pathogenic surrogate R. montanensis under BSL2 conditions, so the inference to R. rickettsii is by genetic and phenotypic similarity (see the HUMAN_MODEL_MISMATCH discussion on this entry).

Disseminated Small-Vessel Vasculitis

Infection of endothelium throughout the body produces a systemic small-vessel vasculitis. Cutaneously this is visible as the characteristic macular-to-petechial rash; systemically it is the substrate for end-organ injury. Infected human endothelial cells upregulate cyclooxygenase 2 and release vasoactive prostaglandins, contributing to the inflammatory and permeability changes.

vascular endothelial cell CL:0000071

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Increased Microvascular Permeability Vasculitic injury increases microvascular leak.

Platelet Consumption and Coagulation Activation Endothelial injury triggers platelet adhesion and consumption.

Skin rash Cutaneous small-vessel vasculitis produces the characteristic rash.

Petechiae Progressive vascular injury produces petechial lesions.

Vasculitis The systemic lesion is itself a clinically recognized vasculitis.

Gangrene Severe vasculitic and thrombotic injury can produce cutaneous necrosis and gangrene.

Show evidence (3 references)

PMID:27172113 SUPPORT Human Clinical

"Infection with R. rickettsii leads to systemic vasculitis that manifests externally as characteristic petechial skin lesions."

The CDC report identifies systemic vasculitis as the central lesion.

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 RMSF explicitly as endothelial infection with microvascular injury and vasculitis.

PMID:2105679 SUPPORT Model Organism

"multifocal areas of retinal vasculitis were evident, which corresponded to areas of altered vascular permeability demonstrated by fluorescein angiography"

Experimental canine infection directly visualizes rickettsial vasculitic foci and the corresponding permeability defect.

Increased Microvascular Permeability

Pathogen-mediated injury to the vascular endothelium produces increased capillary permeability and microhemorrhage. The late-stage manifestations of noncardiogenic pulmonary edema (ARDS) and cerebral edema are direct consequences of this microvascular leakage, and hypovolemia from leak drives appropriate antidiuretic hormone secretion and hyponatremia.

positive regulation of vascular permeability GO:0043117 ↑ INCREASED

Downstream

Cerebral edema Vasogenic cerebral edema follows CNS microvascular leak.

Acute respiratory distress syndrome Noncardiogenic pulmonary edema follows pulmonary microvascular leak.

Hyponatremia Hypovolemia from leak drives appropriate antidiuretic hormone secretion.

Multiorgan End-Organ Injury Sustained leak and vasculopathy injure brain, kidney, lung, and skin.

Show evidence (3 references)

PMID:27172113 SUPPORT Human Clinical

"Pathogen-mediated injury to the vascular endothelium results in increased capillary permeability, microhemorrhage, and platelet consumption"

The CDC report gives the causal step from endothelial injury to microvascular leak.

PMID:27172113 SUPPORT Human Clinical

"and cerebral edema, are consequences of microvascular leakage."

The CDC report attributes ARDS and cerebral edema to microvascular leakage.

PMID:22720111 SUPPORT In Vitro

"The most prominent pathophysiological effect of spotted fever group (SFG) rickettsial infection of microvascular endothelial cells (ECs) is an enhanced vascular permeability, promoting vasogenic cerebral edema and non-cardiogenic pulmonary edema"

Independently identifies enhanced vascular permeability as the dominant pathophysiologic effect.

Platelet Consumption and Coagulation Activation

Injured endothelium consumes platelets intravascularly and activates the coagulation system. In experimental canine infection, retinal vasculitic foci developed together with thrombocytopenia, increased circulating fibrinogen, and slight prolongation of the activated partial thromboplastin time - a mild consumptive coagulopathy that can progress to disseminated intravascular coagulation in severe disease.

platelet CL:0000233

blood coagulation GO:0007596 ↑ INCREASED

Downstream

Thrombocytopenia Intravascular platelet consumption lowers the platelet count.

Disseminated intravascular coagulation Severe consumptive coagulopathy can progress to DIC.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Pathogen-mediated injury to the vascular endothelium results in increased capillary permeability, microhemorrhage, and platelet consumption"

The CDC report attributes platelet consumption to endothelial injury.

PMID:2105679 SUPPORT Model Organism

"Development of retinal vasculitic foci was associated with thrombocytopenia, increased concentrations of circulating fibrinogen, and slight prolongation of activated partial thromboplastin time."

The canine model links rickettsial vasculitis directly to thrombocytopenia and coagulation activation.

Cytotoxic T Lymphocyte Clearance of Infected Endothelium

Recovery depends on cell-mediated immunity: interferon-gamma- and TNF-alpha-activated endothelial cells kill intracellular rickettsiae by nitric-oxide-dependent mechanisms, and CD8 T lymphocyte cytotoxicity eliminates the remaining infected cells. MHC class I knockout mice are dramatically more susceptible to lethal rickettsial infection than wild-type animals, establishing CTL activity as the critical effector arm.

CD8-positive T lymphocyte CL:0000625 macrophage CL:0000235

T cell mediated cytotoxicity GO:0001913 ↑ INCREASED

Show evidence (2 references)

PMID:11179362 SUPPORT Model Organism

"Our results for rickettsial infection differ from these chlamydial models in that immune clearance of rickettsial infection was more dependent on CD8 T lymphocytes, and there is evidence that CTL activity is a critical factor."

Knockout-mouse experiments establish CD8 T lymphocyte cytotoxicity as the critical clearance mechanism for rickettsial infection of endothelium.

PMID:11179362 SUPPORT Model Organism

"nitric oxide-dependent killing of rickettsiae in endothelial cells activated by IFN-gamma and TNF-alpha followed by the elimination of the remaining rickettsia-infected cells by CTL activity"

Describes the cytokine-activated intracellular killing that complements CTL-mediated elimination of infected endothelial cells.

Multiorgan End-Organ Injury

Sustained vasculopathy and microvascular leak injure the brain, kidney, lung, and skin, producing meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure. Survivors of severe disease may be left with long-term neurologic sequelae that are most likely the result of R. rickettsii-induced vasculopathy.

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Bacterial encephalitis CNS vasculitis produces meningoencephalitis.

Acute kidney injury Renal microvascular injury produces acute renal failure.

Cognitive impairment Vasculopathic CNS injury leaves long-term cognitive sequelae.

Hearing impairment Vasculopathic injury can leave persistent hearing loss.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."

The CDC report enumerates the end-organ consequences of untreated RMSF.

PMID:27172113 SUPPORT Human Clinical

"These complications are observed most frequently in persons recovering from severe, life-threatening disease, often after lengthy hospitalizations, and are most likely the result of R. rickettsii"

The CDC report attributes long-term sequelae to severe disease and rickettsial vasculopathy.

Fulminant Thrombotic Course in G6PD Deficiency

A minority of patients follow a hyperacute course with death on or before day 5 of illness. In the described fulminant cases, thrombosis was more extensive than in classic RMSF with fibrin thrombi at foci of rickettsial infection, rash was absent or only preterminal, and there was minimal mononuclear leukocytic response - a thrombotic rather than classically vasculitic pathology. All described patients were G6PD-deficient, and the CDC recommendations list G6PD deficiency as a risk factor for fulminant RMSF.

blood coagulation GO:0007596 ↑ INCREASED

Downstream

Disseminated intravascular coagulation Extensive fibrin thrombosis manifests as consumptive coagulopathy.

Show evidence (3 references)

PMID:6687526 SUPPORT Human Clinical

"Thrombosis was more extensive than in classic RMSF, with fibrin thrombi located in foci of rickettsial infection."

Autopsy series describing the thrombotic pathology of fulminant RMSF.

PMID:6687526 SUPPORT Human Clinical

"had severe multisystemic injury as shown by clinical signs and laboratory data, but on microscopic examination showed minimal evidence of the typical mononuclear leukocytic response to rickettsial vascular infection and injury"

Documents the absent inflammatory infiltrate that distinguishes the fulminant course from classic vasculitic RMSF.

PMID:27172113 SUPPORT Human Clinical

"Glucose-6-phosphate dehydrogenase deficiency is a risk factor for fulminant RMSF, with death occurring in <=5 days"

Independent national guidance confirming G6PD deficiency as a fulminant-disease risk factor.

Rickettsial Ribosomal Translation

R. rickettsii, like other bacteria, depends on 70S-ribosome translation of its mRNA. Doxycycline, a tetracycline, binds the 30S ribosomal subunit and blocks aminoacyl-tRNA delivery to the A site, arresting bacterial protein synthesis. This ribosomal target - not a cell-wall target - is why a tetracycline rather than a beta-lactam is the drug of choice.

Translation GO:0006412

Show evidence (1 reference)

PMID:24336183 SUPPORT Other

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

Review establishing the bacterial ribosome as the target of tetracyclines and other protein-synthesis inhibitors, the step this node represents. Evidence source is OTHER as this is a review article.

Obligate Intracellular Niche (Cell-Penetrant Drug Requirement)

R. rickettsii is an obligate intracellular bacterium that replicates within host endothelial cells. Effective therapy therefore requires an antibiotic that accumulates inside host cells; doxycycline does, whereas beta-lactams cannot reach the intracellular organism - the lifestyle gating that further constrains drug choice beyond the ribosomal target.

Biological Process Involved in Interaction with Host GO:0051701

Show evidence (2 references)

PMID:18611821 SUPPORT Other

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

Review stating that the intracellular niche confers resistance to poorly cell-penetrant antibiotics such as beta-lactams, the gating principle this node represents. Evidence source is OTHER as this is a review article.

PMID:27172113 SUPPORT Human Clinical

"R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells, and, less commonly, underlying smooth muscle cells of small and medium vessels"

Confirms the obligate intracellular lifestyle for this specific organism.

✶

Histopathology

4

Lymphohistiocytic capillaritis and venulitis

The main histopathologic feature of RMSF skin lesions is a lymphohistiocytic small-vessel capillaritis and venulitis with erythrocyte extravasation, edema, and a predominantly perivascular with some interstitial infiltrate. This is the tissue-level correlate of the disseminated small-vessel vasculitis node in the pathograph, and it is the earlier lesion in a sequence that progresses to leukocytoclastic vasculitis.

Show evidence (1 reference)

PMID:9449487 SUPPORT Human Clinical

"The main histopathologic feature was lymphohistiocytic capillaritis and venulitis with extravasation of erythrocytes, edema, predominantly perivascular and some interstitial infiltrate."

Directly reports the dominant cutaneous histopathologic pattern in a 26-case series.

Leukocytoclastic vasculitis with nuclear dust FREQUENT

Leukocytoclastic vasculitis with a neutrophilic infiltrate and nuclear dust was present in 11 of 15 involved-skin specimens. It represents progression from the earlier lymphohistiocytic lesion, and the authors classify the vasculitis of RMSF as a septic vasculitis caused by direct rickettsial endothelial damage rather than an immune-complex process - a distinction that matters for the differential against idiopathic cutaneous vasculitis.

Show evidence (2 references)

PMID:9449487 SUPPORT Human Clinical

"Leukocytoclastic vasculitis (LCV) with neutrophilic infiltrate and nuclear dust was seen in 11 of 15 (73%) specimens from involved skin."

Quantifies the finding at 73 percent of involved-skin specimens, which maps to the FREQUENT band.

PMID:9449487 SUPPORT Human Clinical

"The vasculitis in RMSF is, therefore, considered to be a form of septic vasculitis."

Supports the septic rather than immune-complex classification of the vasculitis.

Focal fibrin thrombi and capillary wall necrosis FREQUENT

Six leukocytoclastic lesions showed focal fibrin thrombi and capillary wall necrosis - the histologic counterpart of the platelet consumption and microvascular occlusion recorded in the pathograph, and the lesion that becomes extensive in fulminant G6PD-associated disease.

Show evidence (1 reference)

PMID:9449487 SUPPORT Human Clinical

"Six lesions with LCV displayed focal fibrin thrombi and capillary wall necrosis."

Reports fibrin thrombi and capillary wall necrosis in six of the leukocytoclastic vasculitis lesions, the count behind the FREQUENT band.

Rickettsial antigen in affected endothelial cells

Immunohistologic staining with polyclonal rabbit anti-Rickettsia rickettsii demonstrated organisms in the affected endothelial cells in all 12 cases tested, confirming at tissue level the endothelial tropism that initiates the pathograph. This is the histopathologic basis of the skin-biopsy immunohistochemistry diagnostic entry.

Show evidence (1 reference)

PMID:9449487 SUPPORT Human Clinical

"Immunohistologic (IH) staining using polyclonal rabbit anti-Rickettsia rickettsii demonstrated positive staining of the organisms in the affected endothelial cells in all 12 cases tested."

Confirms endothelial localization of the organism in stained tissue.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

25

Blood 3

Petechiae HP:0000967

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"The classic spotted or generalized petechial rash, including involvement of the palms and soles, usually appears by day 5 or 6 and is indicative of advanced disease."

The CDC report describes the petechial evolution as a late, severity-associated sign.

Thrombocytopenia FREQUENT HP:0001873

Show evidence (2 references)

PMID:17236897 SUPPORT Human Clinical

"Platelet counts were <150,000/mm3 in 59% of children, and serum sodium concentrations were <135 mEq/dL in 52%."

Thrombocytopenia occurred in 59% of children, supporting the FREQUENT band.

PMID:27172113 SUPPORT Human Clinical

"Thrombocytopenia, slight elevations in hepatic transaminases (aspartate transaminase and alanine transaminase), and hyponatremia might be present, particularly as the disease advances"

The CDC report lists thrombocytopenia among the characteristic laboratory findings.

Disseminated intravascular coagulation HP:0005521

Show evidence (2 references)

PMID:6687526 SUPPORT Human Clinical

"Thrombosis was more extensive than in classic RMSF, with fibrin thrombi located in foci of rickettsial infection."

Autopsy findings document extensive fibrin thrombosis in fulminant RMSF.

PMID:2105679 SUPPORT Model Organism

"Increased concentrations of fibrin/fibrinogen degradation products were detected in 4 of 9 dogs."

The canine model shows consumptive coagulopathy markers; marked PARTIAL as it is animal evidence for a human clinical phenotype.

Cardiovascular 2

Vasculitis HP:0002633

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"RMSF-associated vasculitis has been confused with idiopathic, acute vasculitides, such as Kawasaki disease in pediatric patients."

The CDC report records vasculitis as a recognized clinical manifestation.

Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"calf pain; acute transient hearing loss; hepatomegaly; and splenomegaly"

The CDC report lists splenomegaly among observed clinical features.

Digestive 4

Anorexia HP:0002039

Show evidence (1 reference)

ORPHA:83311 SUPPORT Other

"variably accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain, and photophobia"

Orphanet lists anorexia among the variable accompanying features.

Nausea and vomiting FREQUENT HP:0002017

Show evidence (2 references)

PMID:17236897 SUPPORT Human Clinical

"which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"

Nausea and/or vomiting occurred in 73% of children, supporting the FREQUENT band.

PMID:25697742 SUPPORT Human Clinical

"Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea"

Early gastrointestinal symptoms were associated with doxycycline delay and fatal outcome.

Diarrhea HP:0002014

Show evidence (1 reference)

PMID:25697742 SUPPORT Human Clinical

"Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea"

The Arizona case review documents diarrhea as an early RMSF symptom associated with treatment delay.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"conjunctival suffusion; periorbital and peripheral edema (more common in children); calf pain; acute transient hearing loss; hepatomegaly; and splenomegaly"

The CDC report lists hepatomegaly among observed clinical features.

Ear 1

Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Long-term neurologic sequelae of RMSF include cognitive impairment; paraparesis; hearing loss; blindness; peripheral neuropathy; bowel and bladder incontinence; cerebellar, vestibular, and motor dysfunction; and speech disorders"

The CDC report lists hearing loss among long-term neurologic sequelae.

Eye 1

Photophobia HP:0000613

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Other early symptoms might include nausea or vomiting, abdominal pain, anorexia, and photophobia."

The CDC report lists photophobia among early symptoms.

Genitourinary 1

Acute kidney injury HP:0001919

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."

The CDC report lists acute renal failure among severe manifestations.

Immune 1

Skin rash VERY_FREQUENT HP:0000988

Show evidence (2 references)

PMID:17236897 SUPPORT Human Clinical

"fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"

Rash was documented in 97% of children in the multicenter series, supporting the VERY_FREQUENT band.

PMID:27172113 SUPPORT Human Clinical

"Absence of rash should not preclude consideration of RMSF; <50% of patients have a rash in the first 3 days of illness, and a smaller percentage of patients never develop a rash"

The CDC report qualifies rash timing and its unreliability as an early sign.

Metabolism 4

Fever VERY_FREQUENT HP:0001945

Temporal: ACUTE

Show evidence (2 references)

PMID:17236897 SUPPORT Human Clinical

"which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"

A 92-patient pediatric series quantifies fever in 98% of children, supporting the VERY_FREQUENT band.

PMID:27172113 SUPPORT Human Clinical

"Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia."

The CDC report lists fever among the initial symptoms.

Hyponatremia FREQUENT HP:0002902

Show evidence (2 references)

PMID:17236897 SUPPORT Human Clinical

"Platelet counts were <150,000/mm3 in 59% of children, and serum sodium concentrations were <135 mEq/dL in 52%."

Hyponatremia occurred in 52% of children, supporting the FREQUENT band.

PMID:27172113 SUPPORT Human Clinical

"Hyponatremia occurs as a result of appropriate secretion of antidiuretic hormone in response to hypovolemia"

The CDC report gives the mechanism of hyponatremia in RMSF.

Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Thrombocytopenia, slight elevations in hepatic transaminases (aspartate transaminase and alanine transaminase), and hyponatremia might be present, particularly as the disease advances"

The CDC report lists transaminase elevation among characteristic laboratory findings.

PMID:25697742 SUPPORT Human Clinical

"abnormal laboratory results such as elevated liver aminotransferases. Rash, history of tick bite, thrombocytopenia, and hyponatremia were often absent at initial presentation."

Elevated aminotransferases were among the abnormal findings in the Arizona case review.

Cerebral edema HP:0002181

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Late-stage manifestations, such as noncardiogenic pulmonary edema (acute respiratory distress syndrome ARDS) and cerebral edema, are consequences of microvascular leakage."

The CDC report attributes cerebral edema to microvascular leakage.

Nervous System 2

Headache FREQUENT HP:0002315

Show evidence (1 reference)

PMID:17236897 SUPPORT Human Clinical

"which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"

Headache was documented in 61% of children, supporting the FREQUENT band.

Cognitive impairment HP:0100543

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Long-term neurologic sequelae of RMSF include cognitive impairment; paraparesis; hearing loss; blindness; peripheral neuropathy"

The CDC report enumerates long-term neurologic sequelae including cognitive impairment.

Respiratory 1

Acute respiratory distress syndrome HP:0033677

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Late-stage manifestations, such as noncardiogenic pulmonary edema (acute respiratory distress syndrome ARDS) and cerebral edema, are consequences of microvascular leakage."

The CDC report identifies ARDS as a late-stage manifestation.

Constitutional 4

Myalgia HP:0003326

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia."

The CDC report lists myalgia among initial symptoms.

Malaise HP:0033834

Show evidence (1 reference)

ORPHA:83311 SUPPORT Other

"characterized by an acute onset of fever, malaise, and severe headache, variably accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain, and photophobia"

Orphanet lists malaise as part of the acute presentation.

Abdominal pain HP:0002027

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"abdominal pain that mimics acute appendicitis (102), cholecystitis (103), or gastroenteritis"

The CDC report records abdominal pain as a recognized and misleading feature.

Gangrene HP:0100758

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Cutaneous necrosis and gangrene (Figure 23) might result in amputation of digits or limbs"

The CDC report documents gangrene requiring amputation as a severe complication.

Other 1

Bacterial encephalitis HP:0034387

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."

The CDC report lists meningoencephalitis as a severe late manifestation.

🧬

Genetic Associations

1

G6PD deficiency as a fulminant-disease modifier (Glucose-6-phosphate dehydrogenase deficiency does not cause RMSF but is a recognized host modifier of severity. It is a risk factor for the fulminant form, in which death occurs on or before day 5 of illness with extensive fibrin thrombosis and minimal inflammatory response.)

Gene: G6PD hgnc:4057 relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (2 references)

PMID:6687526 SUPPORT Human Clinical

"All three patients were male blacks with glucose-6-phosphate dehydrogenase deficiency, a condition recently associated with severity of RMSF."

The autopsy series links G6PD deficiency to the fulminant RMSF phenotype.

PMID:27172113 SUPPORT Human Clinical

"Glucose-6-phosphate dehydrogenase deficiency is a risk factor for fulminant RMSF, with death occurring in <=5 days"

National guidance independently records G6PD deficiency as a fulminant-disease risk factor.

🗃️

External Assertions

1

Orphanet Rocky Mountain spotted fever disease record

Orphanet structured disease record ORPHA:83311

Orphanet's ORPHA:83311 record provides the Rickettsia rickettsii disease definition, the clinical description of rash evolution and systemic features, and the exact MONDO cross-reference used by this entry.

Show evidence (1 reference)

ORPHA:83311 SUPPORT Other

"MONDO:0019359 | Exact"

Orphanet maps ORPHA:83311 exactly to the MONDO term used by this entry.

💊

Medical Actions

5

Empiric doxycycline for patients of all ages

Action: Pharmacotherapy NCIT:C15986

Agent: doxycycline CHEBI:50845

Doxycycline is the drug of choice for RMSF in patients of all ages, including children under 8 years, and should be started immediately on clinical suspicion without waiting for laboratory confirmation. Patients treated after the fifth day of illness are more likely to die. The historical reluctance to use doxycycline in young children is not supported: children who received courses of doxycycline before age 8 showed no tetracycline-like dental staining and no difference in tooth shade or enamel hypoplasia. Agents to avoid - sulfonamide antimicrobials can result in increased disease severity and death in RMSF.

Mechanism Target:

INHIBITS Rickettsial Ribosomal Translation — Doxycycline binds the bacterial 30S ribosomal subunit and arrests rickettsial protein synthesis.

BYPASSES Obligate Intracellular Niche (Cell-Penetrant Drug Requirement) — Doxycycline accumulates intracellularly and so reaches the cytoplasmic organism that beta-lactams cannot.

Show evidence (4 references)

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 national recommendation establishes doxycycline as first-line for all ages.

PMID:27172113 SUPPORT Human Clinical

"Patients treated after the fifth day of illness are more likely to die than those treated earlier in the course of illness"

Supports the day-5 treatment window that governs outcome.

PMID:25794784 SUPPORT Human Clinical

"No tetracycline-like staining was observed in any of the exposed children's teeth (0/58, 95% CI 0%-5%), and no significant difference in tooth shade (P=.20) or hypoplasia (P=1.0) was found between the 2 groups."

Directly supports the safety statement that removed the age barrier to doxycycline in young children.

+ 1 more reference

Chloramphenicol as second-line therapy

Action: Pharmacotherapy NCIT:C15986

Agent: chloramphenicol CHEBI:17698

Chloramphenicol is the only alternative drug that has been used to treat RMSF, and it is clearly inferior to doxycycline - CDC case-report data show higher mortality in chloramphenicol-treated patients. It is no longer available orally in the United States, requires monitoring of blood indices for hematologic toxicity, and does not cover ehrlichiosis or anaplasmosis, so empiric substitution leaves those co-endemic infections untreated. In pregnancy it is a potential alternative to doxycycline, but administration late in the third trimester carries a theoretical risk of gray baby syndrome. Because doxycycline has been used successfully in pregnant women and RMSF is potentially fatal, doxycycline remains preferred for suspected RMSF in pregnancy; chloramphenicol is reserved for true doxycycline intolerance.

Mechanism Target:

INHIBITS Rickettsial Ribosomal Translation — Chloramphenicol binds the bacterial 50S ribosomal subunit and blocks rickettsial protein synthesis, acting on the same translational target that doxycycline inhibits from the 30S side.

Show evidence (3 references)

PMID:27172113 SUPPORT Human Clinical

"Chloramphenicol is the only alternative drug that has been used to treat RMSF; however, epidemiologic studies using CDC case report data suggest that patients with RMSF treated with chloramphenicol are at higher risk for death than persons who received a tetracycline"

Supports chloramphenicol as the sole alternative agent while documenting its inferior mortality outcome relative to tetracyclines.

PMID:27172113 SUPPORT Human Clinical

"Chloramphenicol is a potential alternative treatment for RMSF during pregnancy; however, care must be used when administering the drug late during the third trimester of pregnancy because of the theoretical risk for gray baby syndrome"

Supports the pregnancy positioning and the third-trimester gray baby syndrome caveat.

PMID:27172113 SUPPORT Human Clinical

"Doxycycline has been used successfully to treat tickborne rickettsial diseases in several pregnant women without adverse effects to the mother"

Supports retaining doxycycline as the preferred agent in pregnancy.

Tick-bite prevention counseling

Category: Counseling / Informational Action: tick-bite prevention counseling Ontology label: Behavioral Counseling NCIT:C181743

No vaccine is licensed against tickborne rickettsial diseases, so primary prevention rests entirely on interrupting the tick-inoculation step that triggers the pathograph. Personal protective measures are DEET at 20-30 percent on skin, with IR3535 or picaridin above 15 percent as alternatives; permethrin applied to outer clothing but never to skin, which reduces tick bites by more than 80 percent among outdoor workers; protective clothing; and prompt tick checks and bathing after time in tick habitat, since several hours may elapse before an attached tick transmits the organism. Prophylactic doxycycline after a tick bite is explicitly not recommended, and asymptomatic seropositive persons should not be treated - antibody can persist for months to years, so serology cannot be used to monitor treatment response.

Show evidence (4 references)

PMID:27172113 SUPPORT Human Clinical

"No vaccine is licensed for the prevention of tickborne rickettsial diseases in the United States. Avoiding tick bites and promptly removing attached ticks remain the best disease prevention strategies."

Establishes the absence of a vaccine and that bite avoidance is the primary prevention strategy.

PMID:27172113 SUPPORT Human Clinical

"Permethrin-impregnated clothing can reduce tick bites by >80% among outdoor workers"

Quantifies the protective effect of permethrin-treated clothing.

PMID:27172113 SUPPORT Human Clinical

"Several hours might elapse before ticks attach and transmit pathogens; therefore, timely tick checks increase the likelihood of finding and removing ticks before they can transmit an infectious agent."

Supports the mechanistic rationale for prompt tick checks.

+ 1 more reference

Pet acaricide use and peridomestic tick control

Category: Therapeutic Action: pet ectoparasite control Ontology label: Preventive Intervention NCIT:C15843

Because dogs are the primary host of Rhipicephalus sanguineus, the brown dog tick that drives the epidemic RMSF foci in Arizona tribal communities and northern Mexico, controlling ticks on dogs is a population-level intervention against the same inoculation step. Monthly topical acaricides, acaricidal tick collars, oral acaricidal products, and acaricidal shampoos reduce human exposure to ticks carried by pets. This is the intervention that maps onto the peridomestic transmission cycle recorded in this entry's environmental risk factors, and it addresses a route that individual repellent use does not.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Regular use of pet ectoparasite control products (e.g., monthly topical acaricide products, acaricidal tick collars, oral acaricidal products, and acaricidal shampoos) can help reduce the risk for human exposure to ticks on pets."

Supports acaricidal pet treatment as a measure that reduces human tick exposure.

PMID:27172113 SUPPORT Human Clinical

"dogs serve as the primary host for Rh. sanguineus, which is known to transmit R. rickettsii both to humans and dogs in certain geographic areas"

Establishes the dog-brown dog tick reservoir that makes pet acaricide use a human-disease intervention.

Supportive and intensive care for severe disease

Action: Supportive Care NCIT:C15747

Severe RMSF requires supportive management of the vasculitic complications - fluid and electrolyte correction for hyponatremia, transfusion support for coagulopathy, and intensive care for ARDS, shock, and renal failure - alongside, never instead of, doxycycline.

Mechanism Target:

MODULATES Multiorgan End-Organ Injury — Organ support mitigates the consequences of established vasculopathy.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."

Establishes the complications that require organ support. Marked PARTIAL because the source enumerates the complications rather than evaluating supportive-care efficacy.

PMID:17236897 SUPPORT INDIRECT Human Clinical

"Coma and need for inotropic support and intravenous fluid boluses were independently associated with adverse outcomes."

Documents the intensive-care interventions used in severe pediatric RMSF; INDIRECT because these markers of severity are not evidence of benefit.

🌍

Environmental Factors

2

Tick exposure in endemic habitat

Exposure to questing Dermacentor ticks in wooded, shrubby, and grassy areas, including residential areas and city parks, is the proximate environmental risk. Adult Dermacentor ticks are active from spring through autumn with maximum activity in late spring through early summer.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"D. variabilis ticks often are encountered in wooded, shrubby, and grassy areas and tend to congregate along walkways and trails."

The CDC report describes the habitat in which vector exposure occurs.

PMID:27172113 SUPPORT Human Clinical

"Adult Dermacentor ticks are active from spring through autumn, with maximum activity during late spring through early summer."

The CDC report gives the seasonality of vector activity.

Mechanism Target:

TRIGGERS Tick-Borne Rickettsia rickettsii Inoculation — Entering the wooded, shrubby and grassy habitat where questing Dermacentor ticks congregate is what brings a person within reach of an attaching, infected tick.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"D. variabilis ticks often are encountered in wooded, shrubby, and grassy areas and tend to congregate along walkways and trails."

Describes where these ticks are encountered and that they congregate along walkways and trails, the habitat contact that precedes inoculation.

Domestic dog and peridomestic brown dog tick exposure

Domestic dogs are the preferred host of Rhipicephalus sanguineus at all life stages, and free-roaming dogs with peridomestic tick infestation drive the high-incidence epidemic foci in Arizona and northern Mexico. Dogs are also susceptible to R. rickettsii and can serve as sentinels for human risk.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Canids, especially domestic dogs, are the preferred hosts for the brown dog tick at all life stages."

The CDC report identifies dogs as the tick host driving peridomestic transmission.

PMID:28365226 SUPPORT Human Clinical

"These investigators also described the pivotal roles of domesticated dogs and Rhipicephalus sanguineus sensu lato (brown dog ticks) as drivers of epidemic levels of Rocky Mountain spotted fever."

The Lancet review identifies dogs and brown dog ticks as epidemic drivers.

Mechanism Target:

TRIGGERS Tick-Borne Rickettsia rickettsii Inoculation — Dogs are not themselves the source of infection: they maintain and amplify brown dog tick populations around dwellings, and those ticks then bite people. The intermediates are known, which is why this is indirect rather than direct.

Show evidence (1 reference)

PMID:28365226 SUPPORT Human Clinical

"These investigators also described the pivotal roles of domesticated dogs and Rhipicephalus sanguineus sensu lato (brown dog ticks) as drivers of epidemic levels of Rocky Mountain spotted fever."

Identifies domestic dogs and brown dog ticks as drivers of epidemic transmission, the amplification step between dog contact and human inoculation.

🔬

Diagnosis

5

Empiric clinical diagnosis without waiting for confirmation

Because diagnostic tests are usually not helpful during the initial stages of illness and the classic triad of fever, rash, and reported tick bite is present in only a minority of patients at presentation, RMSF is treated empirically on clinical and epidemiologic suspicion.

clinical diagnosis NCIT:C18020

Results: Compatible acute febrile illness with tick exposure in an endemic area warrants immediate empiric doxycycline regardless of test results.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Diagnostic tests for rickettsial diseases, particularly for RMSF, are usually not helpful in making a timely diagnosis during the initial stages of illness."

The CDC report establishes that acute testing cannot guide initial treatment.

PMID:27172113 SUPPORT Human Clinical

"The classic triad of fever, rash, and reported tick bite is present in only a minority of patients during initial presentation to health care"

The CDC report documents the low sensitivity of the classic triad at presentation.

Paired-serum indirect immunofluorescence antibody assay

The standard confirmatory test is the indirect immunofluorescence antibody (IFA) assay on paired acute and convalescent sera; at least a fourfold rise in antibody titer is confirmatory. IFA assays are insensitive during the first week of illness and therefore confirm the diagnosis retrospectively.

serologic testing NCIT:C25294

Results: A fourfold or greater rise in R. rickettsii antibody titer between paired sera confirms infection.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"A diagnosis of tickborne rickettsial disease is confirmed with a fourfold or greater increase in antibody titer in samples collected at appropriately timed intervals in patients with a clinically compatible acute illness"

The CDC report defines the serologic confirmation criterion.

PMID:27172113 SUPPORT Human Clinical

"Indirect immunofluorescence antibody (IFA) assays using paired acute and convalescent sera are the reference standard for serologic confirmation of rickettsial infection"

The CDC report identifies IFA as the standard serologic assay.

Supportive laboratory pattern

Thrombocytopenia, slight transaminase elevation, hyponatremia, and a normal or slightly increased white blood cell count with increased immature neutrophils together form a suggestive but non-specific pattern that cannot be relied on to guide early treatment.

clinical laboratory testing NCIT:C25294

Results: Suggestive but non-diagnostic haematologic, hepatic, and electrolyte abnormalities.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"however, laboratory values cannot be relied on to guide early treatment decisions"

The CDC report cautions against using laboratory findings to gate early therapy.

Whole-blood PCR for Rickettsia rickettsii

Real-time PCR amplification of R. rickettsii DNA from whole blood can confirm infection during the acute stage, but sensitivity is low because few rickettsiae circulate before advanced disease; tissue specimens are a better source of spotted fever group rickettsial DNA than acute blood. Blood should be drawn before antibacterial agents are given, because doxycycline reduces PCR sensitivity. A negative PCR result therefore never excludes RMSF and must not delay empiric doxycycline.

polymerase chain reaction NCIT:C17003

Results: A positive result confirms rickettsial infection and identifies the species; a negative result is uninformative in early or mild disease.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"PCR detection of R. rickettsii in whole blood is possible but less sensitive because low numbers of rickettsiae typically circulate in the blood in the absence of advanced disease"

The CDC report documents the low sensitivity of whole-blood PCR for R. rickettsii.

PMID:27172113 SUPPORT Human Clinical

"obtaining blood for molecular testing before antibacterial agents are administered is recommended to minimize the likelihood of a false-negative result"

The CDC report recommends collecting molecular-testing specimens before therapy is started.

Immunohistochemical staining of a skin punch biopsy

Immunostaining (immunohistochemistry or immunofluorescence) for rickettsial antigen in formalin-fixed, paraffin-embedded skin punch biopsy of a rash lesion or eschar is a rapid confirmatory technique that, unlike serology, can establish the diagnosis during acute illness. It is highly specific but only moderately sensitive, so a negative stain does not exclude RMSF.

skin biopsy immunohistochemistry NCIT:C23020

Results: Detection of spotted fever group rickettsial antigen in dermal microvascular endothelium; approximately 100% specific and 70% sensitive.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"For patients with a rash or eschar, immunohistochemical staining of a skin punch biopsy is a useful diagnostic technique"

The CDC report endorses skin punch biopsy immunohistochemistry for rash or eschar.

PMID:27172113 SUPPORT Human Clinical

"Immunostaining of skin biopsy specimens is 100% specific and 70% sensitive in diagnosing RMSF"

The CDC report quantifies the specificity and sensitivity of skin biopsy immunostaining.

📈

Progression

4

Incubation period

Incubation: 3-12 days

Symptoms appear 3-12 days after the bite of an infected tick; a shorter incubation (5 days or less) is associated with severe disease.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Symptoms of RMSF typically appear 3-12 days after the bite of an infected tick"

The CDC report gives the incubation window.

Nonspecific febrile prodrome

Illness begins abruptly with fever, headache, chills, malaise, and myalgia, often with gastrointestinal symptoms and before any rash is visible.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia."

The CDC report describes the initial nonspecific febrile phase.

Rash onset and centripetal spread

A rash typically appears 2-4 days after fever onset, beginning as blanching macules on the ankles, wrists, or forearms and spreading to the palms, soles, limbs, and trunk, usually sparing the face.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"A rash typically appears 2-4 days after the onset of fever"

The CDC report gives rash timing relative to fever onset.

PMID:27172113 SUPPORT Human Clinical

"blanching, pink macules on the ankles, wrists, or forearms that subsequently spread to the palms, soles, arms, legs, and trunk, usually sparing the face"

The CDC report describes the characteristic acral-onset centripetal spread.

Late-stage multiorgan disease

Untreated or late-treated disease progresses to meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."

The CDC report enumerates the late-stage complications of untreated disease.

📊

Prevalence

2

United States

Annual Incidence 0.89 per 100,000 1–9 per 1,000,000

CDC passive surveillance estimate of 8.9 cases per million persons per year for spotted fever group rickettsiosis (the surveillance category that includes RMSF), 2008-2012, normalized to 0.89 per 100,000.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"the estimated average annual incidence of SFG rickettsiosis was 8.9 cases per million persons in the United States"

Supports the national incidence figure. Marked PARTIAL because the surveillance category is spotted fever group rickettsiosis rather than laboratory-confirmed RMSF alone.

Highly affected American Indian reservations, Arizona

Annual Incidence 136.0 per 100,000 >1 in 1,000

Approximately 1,360 cases per million persons per year during 2009-2012 on the three most affected reservations, normalized to 136 per 100,000 - a focal, brown-dog-tick-driven epidemic far above the national rate.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"the average annual incidence rate for 2009-2012 was approximately 1,360 cases per million persons"

The CDC report gives the focal Arizona incidence rate used here.

🌍

Epidemiology

4

Treatment delay as the dominant determinant of death

Delay in diagnosis and treatment is the most important factor associated with death. Patients treated after the fifth day of illness are more likely to die, and in a high-incidence Arizona region doxycycline was started a median of four days later in fatal than in nonfatal cases.

delayed doxycycline initiation late-onset or absent rash atypical or gastrointestinal early manifestations absence of a reported tick bite

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Delay in diagnosis and treatment is the most important factor associated with increased likelihood of death, and early empiric therapy is the best way to prevent RMSF progression."

The CDC report identifies treatment delay as the dominant modifiable determinant of mortality.

PMID:25697742 SUPPORT Human Clinical

"Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3)"

The Arizona case review quantifies the treatment-timing difference between fatal and nonfatal cases.

Host risk factors for fatal outcome

Additional risk factors for fatal RMSF include age 40 years or older, age under 10 years, alcohol abuse, and glucose-6-phosphate dehydrogenase deficiency (a risk factor specifically for the fulminant form).

age 40 years or older age under 10 years alcohol abuse glucose-6-phosphate dehydrogenase deficiency

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"Additional risk factors for fatal RMSF include age >=40 years, age <10 years, and alcohol abuse"

The CDC report enumerates host risk factors for fatal outcome.

PMID:25697742 SUPPORT Human Clinical

"Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea, history of alcoholism or chronic lung disease, and abnormal laboratory results such as elevated liver aminotransferases."

The Arizona review found alcoholism and chronic lung disease among factors increasing risk of doxycycline delay and fatal outcome.

Case fatality before and after antimicrobial therapy

RMSF is the most frequently fatal rickettsial illness in the United States. Case fatality was approximately 25% in the preantibiotic era; present-day estimates are 5%-10% overall and depend heavily on the timing of treatment, with rates of 40%-50% reported among patients treated on days 8 or 9.

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"RMSF is the most frequently fatal rickettsial illness in the United States; the case-fatality rate in the preantibiotic era was approximately 25%"

The CDC report gives the historical and present-day case-fatality estimates.

Brown dog tick driven re-emergence in Mexico

RMSF re-emerged in Sonora and Baja California in the early 21st century, driven by the same environmental circumstances - domesticated dogs and Rhipicephalus sanguineus brown dog ticks - that produced devastating Mexican outbreaks in the 1940s.

free-roaming domestic dogs peridomestic brown dog tick infestation

Show evidence (1 reference)

PMID:28365226 SUPPORT Human Clinical

"These investigators also described the pivotal roles of domesticated dogs and Rhipicephalus sanguineus sensu lato (brown dog ticks) as drivers of epidemic levels of Rocky Mountain spotted fever."

The Lancet review identifies dogs and brown dog ticks as drivers of epidemic RMSF in Mexico.

🦠

Infectious Agent

1

Rickettsia rickettsii

Obligate intracellular, Gram-negative spotted-fever-group rickettsial bacterium that primarily infects vascular endothelial cells and is the sole etiologic agent of Rocky Mountain spotted fever.

Rickettsia rickettsii NCBITaxon:783

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells"

The CDC report identifies the etiologic agent and its cellular tropism.

↔️

Transmission

2

Dermacentor tick bite transmission

In the United States R. rickettsii is transmitted most frequently by the American dog tick Dermacentor variabilis, and in the western states by the Rocky Mountain wood tick Dermacentor andersoni.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"the tick species that is most frequently associated with transmission of R. rickettsii is the American dog tick, Dermacentor variabilis (Figure 2). This tick is found primarily in the eastern, central, and Pacific coastal United States"

The CDC report names the principal United States vector.

PMID:27172113 SUPPORT Human Clinical

"The Rocky Mountain wood tick, Dermacentor andersoni (Figure 4), is associated with transmission in the western United States"

The CDC report names the western United States vector.

Brown dog tick transmission in peridomestic epidemic foci

Rhipicephalus sanguineus, the brown dog tick, is a recognized R. rickettsii vector in parts of Arizona and along the United States-Mexico border, where domestic dogs are the preferred host at all life stages and drive a peridomestic transmission cycle with unusually high incidence.

Show evidence (2 references)

PMID:27172113 SUPPORT Human Clinical

"recognized as an important vector in parts of Arizona (16) and along the U.S.-Mexico border"

The CDC report identifies the brown dog tick as an emergent vector in Arizona.

PMID:28365226 SUPPORT Human Clinical

"Rocky Mountain spotted fever, a tick-borne zoonosis caused by Rickettsia rickettsii, is among the most lethal of all infectious diseases in the Americas."

The Lancet review frames RMSF as a tick-borne zoonosis of the Americas.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Rocky Mountain spotted fever:

Meningococcemia

Overlapping Features RMSF-associated cutaneous necrosis and gangrene can be difficult to distinguish clinically from purpura fulminans associated with meningococcemia.

Distinguishing Features

Purpura fulminans of meningococcemia closely mimics RMSF cutaneous necrosis
Tick exposure history and acral-onset rash favour RMSF
Both warrant concurrent empiric therapy while awaiting diagnostic information

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"RMSF-associated cutaneous necrosis and gangrene might be difficult to distinguish clinically from purpura fulminans associated with meningococcemia"

The CDC report names meningococcemia as a key clinical mimic.

Thrombotic thrombocytopenic purpura

Overlapping Features RMSF-associated neurologic manifestations, renal failure, and thrombocytopenia have led to confusion with thrombotic thrombocytopenic purpura.

Distinguishing Features

Neurologic signs, renal failure, and thrombocytopenia overlap between the two
Tick exposure history and response to doxycycline favour RMSF

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"RMSF-associated neurologic manifestations, renal failure, and thrombocytopenia have led to confusion with the diagnosis of thrombotic thrombocytopenic purpura (TTP)"

The CDC report records TTP as a recognized diagnostic confusion.

Kawasaki disease

Overlapping Features RMSF-associated vasculitis in children has been confused with idiopathic acute vasculitides such as Kawasaki disease.

Distinguishing Features

Both present with fever and rash in children
RMSF follows tick exposure in an endemic area and responds to doxycycline

Show evidence (1 reference)

PMID:27172113 SUPPORT Human Clinical

"RMSF-associated vasculitis has been confused with idiopathic, acute vasculitides, such as Kawasaki disease in pediatric patients."

The CDC report names Kawasaki disease as a pediatric mimic.

Acute gastroenteritis

Overlapping Features Prominent early nausea, vomiting, abdominal pain, and diarrhea commonly lead to an initial diagnosis of gastroenteritis, which delays doxycycline and increases the risk of fatal outcome.

Distinguishing Features

Gastrointestinal symptoms in RMSF accompany high fever and severe headache
Gastrointestinal symptoms often precede any rash
Misattribution to gastroenteritis is a documented cause of treatment delay and death

Show evidence (1 reference)

PMID:25697742 SUPPORT Human Clinical

"Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea"

The Arizona review links early gastrointestinal symptoms to treatment delay and death.

🐁

Animal Models

3

Dog

Experimental intradermal R. rickettsii inoculation of dogs reproduces the vasculitic and coagulopathic core of human RMSF, with retinal vasculitic foci corresponding to fluorescein-demonstrated permeability defects, thrombocytopenia, and coagulation activation. The dog is also a natural host and a sentinel for human risk.

Species

Dog

Show evidence (1 reference)

PMID:2105679 SUPPORT Model Organism

"The vascular permeability of the ocular fundus, alterations in the coagulation system, and plasma concentrations of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were studied in dogs following intradermal inoculation with 5 x 10(5) TCID50 of Rickettsia rickettsii."

The canine model was used to measure permeability and coagulation during R. rickettsii infection.

Guinea pig

Guinea pig challenge is the standard virulence readout for R. rickettsii mutants; it was used to show that an isogenic rOmpA knockout in the virulent Sheila Smith strain is not attenuated.

Species

Guinea pig

Show evidence (1 reference)

PMID:25827414 SUPPORT Model Organism

"Virulence was assessed in a guinea pig model by challenge with 100 PFU of either ompA::int312 Sheila Smith or the wild type"

Establishes the guinea pig as the virulence model used for R. rickettsii genetics.

MHC class I knockout Mouse

MHC class I knockout mice are dramatically more susceptible to lethal rickettsial infection than wild-type animals, defining the CD8 T lymphocyte requirement for clearance. This is an immunologic-mechanism model rather than a faithful clinical model of RMSF.

Species

Mouse

Genotype

MHC class I knockout

Show evidence (1 reference)

PMID:11179362 SUPPORT Model Organism

"immune clearance of rickettsial infection was more dependent on CD8 T lymphocytes, and there is evidence that CTL activity is a critical factor."

Knockout mice establish the CD8 T lymphocyte requirement for rickettsial clearance.

{ }

Source YAML

click to show

name: Rocky Mountain spotted fever
creation_date: "2026-08-02T14:15:00Z"
category: Infectious Disease
parents:
- Spotted fever rickettsiosis
- Rickettsial disease
- Tick-borne disease
synonyms:
- RMSF
- Rickettsia rickettsii infection
- Sao Paulo fever
- Brazilian spotted fever
- Tick typhus
description: >-
  Rocky Mountain spotted fever is an acute, life-threatening tick-borne
  rickettsiosis caused by the obligate intracellular bacterium Rickettsia
  rickettsii. After inoculation by a feeding Dermacentor or Rhipicephalus tick,
  the organism disseminates and infects vascular endothelial cells throughout the
  body, producing a systemic small-vessel vasculitis with adherens-junction
  disruption, increased microvascular permeability, platelet consumption, and
  end-organ injury. Illness begins nonspecifically 3-12 days after the tick bite
  with fever, headache, myalgia, and gastrointestinal symptoms; a macular rash
  typically appears 2-4 days after fever onset, begins on the wrists and ankles,
  and may become petechial. It is the most frequently fatal rickettsiosis in the
  United States, and outcome is dominated by the timing of empiric doxycycline:
  patients treated after the fifth day of illness are substantially more likely
  to die.
disease_term:
  preferred_term: Rocky mountain spotted fever
  term:
    id: MONDO:0019359
    label: Rocky mountain spotted fever
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019359
      label: Rocky mountain spotted fever
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:83311
    mapping_justification: >-
      Orphanet ORPHA:83311 lists MONDO:0019359 as an exact cross-reference for
      Rocky Mountain spotted fever.
external_assertions:
- name: Orphanet Rocky Mountain spotted fever disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:83311
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=83311
  description: >-
    Orphanet's ORPHA:83311 record provides the Rickettsia rickettsii disease
    definition, the clinical description of rash evolution and systemic
    features, and the exact MONDO cross-reference used by this entry.
  evidence:
  - reference: ORPHA:83311
    reference_title: "Rocky Mountain spotted fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0019359 | Exact"
    explanation: Orphanet maps ORPHA:83311 exactly to the MONDO term used by this entry.
definitions:
- name: Orphanet Rocky Mountain spotted fever definition
  definition_type: OTHER
  description: >-
    A rare, acquired, life-threatening infectious disease due to the tick-borne
    bacterium Rickettsia rickettsii, with acute fever, malaise, and severe
    headache, followed 2-5 days later by a maculopapular rash with petechiae
    beginning on the wrists and ankles.
  evidence:
  - reference: ORPHA:83311
    reference_title: "Rocky Mountain spotted fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, acquired, life-threatening, infectious disease due to the tick-borne bacteria <i>Rickettsia rickettsii</i> characterized by an acute onset of fever, malaise, and severe headache"
    explanation: Orphanet defines RMSF as a life-threatening tick-borne R. rickettsii infection.
- name: CDC/MMWR clinical definition and pathophysiologic framing
  definition_type: OTHER
  description: >-
    The CDC national recommendations define RMSF as infection with the obligate
    intracellular pathogen R. rickettsii, which primarily infects vascular
    endothelial cells and produces a systemic vasculitis.
  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: "Infection with R. rickettsii leads to systemic vasculitis that manifests externally as characteristic petechial skin lesions."
    explanation: The CDC recommendations define the disease by endothelial infection producing systemic vasculitis.
references:
- reference: ORPHA:83311
  title: Rocky Mountain spotted fever
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      Orphanet defines Rocky Mountain spotted fever as a life-threatening
      tick-borne Rickettsia rickettsii infection and provides the exact MONDO
      cross-reference used by this entry.
    supporting_text: "MONDO:0019359 | Exact"
- reference: PMID:27172113
  title: "Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      The CDC national recommendations provide the authoritative account of RMSF
      pathophysiology, tick vectors, incubation and rash timing, laboratory
      findings, case-fatality, sequelae, diagnostic testing, and doxycycline
      treatment for patients of all ages.
    supporting_text: "Doxycycline is the drug of choice for treatment of all tickborne rickettsial diseases in patients of all ages, including children aged <8 years"
- reference: PMID:17236897
  title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      A 92-patient multicenter pediatric series quantifies the frequency of
      fever, rash, nausea/vomiting, headache, thrombocytopenia, and
      hyponatremia, and documents death or neurologic deficits at discharge.
    supporting_text: "which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"
- reference: PMID:25697742
  title: "Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      A 205-case review in a high-incidence Arizona region shows that
      doxycycline was started significantly later in fatal than nonfatal cases
      and identifies clinical risk factors for treatment delay.
    supporting_text: "Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3)"
- reference: PMID:22720111
  title: "Rickettsiae induce microvascular hyperpermeability via phosphorylation of VE-cadherins: evidence from atomic force microscopy and biochemical studies."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      Spotted fever group rickettsial infection of microvascular endothelial
      cells phosphorylates VE-cadherin and attenuates adherens-junction
      interactions, giving a molecular mechanism for hyperpermeability. The
      experiments used the non-pathogenic surrogate R. montanensis at BSL2.
    supporting_text: "phosphorylation of VE-cadherin directly attenuates homophilic protein-protein interactions at the endothelial adherens junctions"
- reference: PMID:6687526
  title: "Fulminant Rocky Mountain spotted fever. Its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      Fulminant RMSF (death on or before day 5) in G6PD-deficient patients shows
      extensive fibrin thrombosis with minimal mononuclear inflammatory
      response, a hyperacute thrombotic variant of the classic vasculitic course.
    supporting_text: "Thrombosis was more extensive than in classic RMSF, with fibrin thrombi located in foci of rickettsial infection."
- reference: PMID:2105679
  title: "Vascular permeability and coagulation during Rickettsia rickettsii infection in dogs."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      Experimental canine R. rickettsii infection links retinal vasculitic foci
      to altered vascular permeability and to thrombocytopenia with coagulation
      activation.
    supporting_text: "Twenty-four to 48 hours after the onset of fever and rickettsemia, multifocal areas of retinal vasculitis were evident, which corresponded to areas of altered vascular permeability demonstrated by fluorescein angiography."
- reference: PMID:11179362
  title: "Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      MHC class I knockout mice are dramatically more susceptible to lethal
      rickettsial infection, establishing CD8 T lymphocyte cytotoxicity as
      critical for clearing rickettsia-infected endothelium.
    supporting_text: "immune clearance of rickettsial infection was more dependent on CD8 T lymphocytes, and there is evidence that CTL activity is a critical factor."
- reference: PMID:25827414
  title: "Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence in a mammalian model system."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      An isogenic rOmpA knockout in the virulent Sheila Smith strain did not
      attenuate virulence in guinea pigs, indicating redundancy among
      rickettsial adhesins rather than a single essential invasion factor.
    supporting_text: "no significant difference in either fever peak (40.5 C) or duration (8 days) were shown between the wild type and the knockout"
- reference: PMID:28365226
  title: "Rocky Mountain spotted fever in Mexico: past, present, and future."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      A Lancet review documents the re-emergence of RMSF in Sonora and Baja
      California driven by domesticated dogs and brown dog ticks.
    supporting_text: "Rocky Mountain spotted fever, a tick-borne zoonosis caused by Rickettsia rickettsii, is among the most lethal of all infectious diseases in the Americas."
- reference: PMID:25794784
  title: "No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      Children who received doxycycline before 8 years of age showed no
      tetracycline-like staining and no difference in tooth shade or enamel
      hypoplasia, removing the historical barrier to doxycycline in young
      children.
    supporting_text: "No tetracycline-like staining was observed in any of the exposed children's teeth (0/58, 95% CI 0%-5%), and no significant difference in tooth shade (P=.20) or hypoplasia (P=1.0) was found between the 2 groups."
- 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:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      Spotted fever group infection of human endothelial cells upregulates COX-2
      and vasoactive prostaglandins, a mechanism contributing to inflammatory
      and vascular permeability changes in RMSF.
    supporting_text: "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."
- reference: PMID:16360032
  title: "Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii."
  found_in:
  - Rocky_Mountain_Spotted_Fever-deep-research-claude_code.md
  findings:
  - statement: >-
      Ku70 was identified as a mammalian receptor engaged by rickettsial OmpB
      for host-cell entry, characterized for the closely related spotted fever
      group agent R. conorii.
    supporting_text: "Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii."
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    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: "R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells"
      explanation: >-
        RMSF is an acute bacterial (rickettsial) infection acquired from a tick
        bite, placing it in Harrison's Infectious Diseases Part.
prevalence:
- population: United States
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.89
  notes: >-
    CDC passive surveillance estimate of 8.9 cases per million persons per year
    for spotted fever group rickettsiosis (the surveillance category that
    includes RMSF), 2008-2012, normalized to 0.89 per 100,000.
  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: "the estimated average annual incidence of SFG rickettsiosis was 8.9 cases per million persons in the United States"
    explanation: >-
      Supports the national incidence figure. Marked PARTIAL because the
      surveillance category is spotted fever group rickettsiosis rather than
      laboratory-confirmed RMSF alone.
- population: Highly affected American Indian reservations, Arizona
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 136.0
  notes: >-
    Approximately 1,360 cases per million persons per year during 2009-2012 on
    the three most affected reservations, normalized to 136 per 100,000 - a
    focal, brown-dog-tick-driven epidemic far above the national rate.
  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: "the average annual incidence rate for 2009-2012 was approximately 1,360 cases per million persons"
    explanation: The CDC report gives the focal Arizona incidence rate used here.
progression:
- phase: Incubation period
  incubation_days: "3-12"
  notes: >-
    Symptoms appear 3-12 days after the bite of an infected tick; a shorter
    incubation (5 days or less) is associated with severe disease.
  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: "Symptoms of RMSF typically appear 3-12 days after the bite of an infected tick"
    explanation: The CDC report gives the incubation window.
- phase: Nonspecific febrile prodrome
  notes: >-
    Illness begins abruptly with fever, headache, chills, malaise, and myalgia,
    often with gastrointestinal symptoms and before any rash is visible.
  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: "Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia."
    explanation: The CDC report describes the initial nonspecific febrile phase.
- phase: Rash onset and centripetal spread
  notes: >-
    A rash typically appears 2-4 days after fever onset, beginning as blanching
    macules on the ankles, wrists, or forearms and spreading to the palms,
    soles, limbs, and trunk, usually sparing the face.
  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: "A rash typically appears 2-4 days after the onset of fever"
    explanation: The CDC report gives rash timing relative to fever onset.
  - 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: "blanching, pink macules on the ankles, wrists, or forearms that subsequently spread to the palms, soles, arms, legs, and trunk, usually sparing the face"
    explanation: The CDC report describes the characteristic acral-onset centripetal spread.
- phase: Late-stage multiorgan disease
  notes: >-
    Untreated or late-treated disease progresses to meningoencephalitis, acute
    renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure.
  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: "Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."
    explanation: The CDC report enumerates the late-stage complications of untreated disease.
epidemiology:
- name: Treatment delay as the dominant determinant of death
  description: >-
    Delay in diagnosis and treatment is the most important factor associated
    with death. Patients treated after the fifth day of illness are more likely
    to die, and in a high-incidence Arizona region doxycycline was started a
    median of four days later in fatal than in nonfatal cases.
  factors:
  - delayed doxycycline initiation
  - late-onset or absent rash
  - atypical or gastrointestinal early manifestations
  - absence of a reported tick bite
  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: "Delay in diagnosis and treatment is the most important factor associated with increased likelihood of death, and early empiric therapy is the best way to prevent RMSF progression."
    explanation: The CDC report identifies treatment delay as the dominant modifiable determinant of mortality.
  - reference: PMID:25697742
    reference_title: "Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3)"
    explanation: The Arizona case review quantifies the treatment-timing difference between fatal and nonfatal cases.
- name: Host risk factors for fatal outcome
  description: >-
    Additional risk factors for fatal RMSF include age 40 years or older, age
    under 10 years, alcohol abuse, and glucose-6-phosphate dehydrogenase
    deficiency (a risk factor specifically for the fulminant form).
  factors:
  - age 40 years or older
  - age under 10 years
  - alcohol abuse
  - glucose-6-phosphate dehydrogenase deficiency
  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: "Additional risk factors for fatal RMSF include age >=40 years, age <10 years, and alcohol abuse"
    explanation: The CDC report enumerates host risk factors for fatal outcome.
  - reference: PMID:25697742
    reference_title: "Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea, history of alcoholism or chronic lung disease, and abnormal laboratory results such as elevated liver aminotransferases."
    explanation: The Arizona review found alcoholism and chronic lung disease among factors increasing risk of doxycycline delay and fatal outcome.
- name: Case fatality before and after antimicrobial therapy
  description: >-
    RMSF is the most frequently fatal rickettsial illness in the United States.
    Case fatality was approximately 25% in the preantibiotic era; present-day
    estimates are 5%-10% overall and depend heavily on the timing of treatment,
    with rates of 40%-50% reported among patients treated on days 8 or 9.
  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: "RMSF is the most frequently fatal rickettsial illness in the United States; the case-fatality rate in the preantibiotic era was approximately 25%"
    explanation: The CDC report gives the historical and present-day case-fatality estimates.
- name: Brown dog tick driven re-emergence in Mexico
  description: >-
    RMSF re-emerged in Sonora and Baja California in the early 21st century,
    driven by the same environmental circumstances - domesticated dogs and
    Rhipicephalus sanguineus brown dog ticks - that produced devastating
    Mexican outbreaks in the 1940s.
  factors:
  - free-roaming domestic dogs
  - peridomestic brown dog tick infestation
  evidence:
  - reference: PMID:28365226
    reference_title: "Rocky Mountain spotted fever in Mexico: past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These investigators also described the pivotal roles of domesticated dogs and Rhipicephalus sanguineus sensu lato (brown dog ticks) as drivers of epidemic levels of Rocky Mountain spotted fever."
    explanation: The Lancet review identifies dogs and brown dog ticks as drivers of epidemic RMSF in Mexico.
infectious_agent:
- name: Rickettsia rickettsii
  infectious_agent_term:
    preferred_term: Rickettsia rickettsii
    term:
      id: NCBITaxon:783
      label: Rickettsia rickettsii
  description: >-
    Obligate intracellular, Gram-negative spotted-fever-group rickettsial
    bacterium that primarily infects vascular endothelial cells and is the sole
    etiologic agent of Rocky Mountain spotted fever.
  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: "R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells"
    explanation: The CDC report identifies the etiologic agent and its cellular tropism.
transmission:
- name: Dermacentor tick bite transmission
  description: >-
    In the United States R. rickettsii is transmitted most frequently by the
    American dog tick Dermacentor variabilis, and in the western states by the
    Rocky Mountain wood tick Dermacentor andersoni.
  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: "the tick species that is most frequently associated with transmission of R. rickettsii is the American dog tick, Dermacentor variabilis (Figure 2). This tick is found primarily in the eastern, central, and Pacific coastal United States"
    explanation: The CDC report names the principal United States vector.
  - 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: "The Rocky Mountain wood tick, Dermacentor andersoni (Figure 4), is associated with transmission in the western United States"
    explanation: The CDC report names the western United States vector.
- name: Brown dog tick transmission in peridomestic epidemic foci
  description: >-
    Rhipicephalus sanguineus, the brown dog tick, is a recognized R. rickettsii
    vector in parts of Arizona and along the United States-Mexico border, where
    domestic dogs are the preferred host at all life stages and drive a
    peridomestic transmission cycle with unusually high incidence.
  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: "recognized as an important vector in parts of Arizona (16) and along the U.S.-Mexico border"
    explanation: The CDC report identifies the brown dog tick as an emergent vector in Arizona.
  - reference: PMID:28365226
    reference_title: "Rocky Mountain spotted fever in Mexico: past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rocky Mountain spotted fever, a tick-borne zoonosis caused by Rickettsia rickettsii, is among the most lethal of all infectious diseases in the Americas."
    explanation: The Lancet review frames RMSF as a tick-borne zoonosis of the Americas.
pathophysiology:
- name: Tick-Borne Rickettsia rickettsii Inoculation
  biological_scale: ORGANISM
  description: >-
    A feeding Dermacentor or Rhipicephalus tick inoculates R. rickettsii into
    the skin, initiating acute spotted fever rickettsiosis after an incubation
    period of 3-12 days. Unlike most other spotted fever group rickettsioses, an
    inoculation eschar is rarely present.
  biological_processes:
  - preferred_term: response to bacterium
    term:
      id: GO:0009617
      label: response to bacterium
    modifier: ABNORMAL
  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: "Symptoms of RMSF typically appear 3-12 days after the bite of an infected tick"
    explanation: The CDC report establishes tick-bite inoculation and the incubation interval.
  - 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: "Unlike some SFG rickettsioses, an inoculation eschar is rarely present with RMSF"
    explanation: >-
      Supports the negative feature that distinguishes RMSF from eschar-forming
      spotted fever rickettsioses such as boutonneuse fever.
  downstream:
  - target: Endothelial Cell Invasion and Intracytoplasmic Replication
    description: Inoculated rickettsiae disseminate and invade vascular endothelium.
    causal_link_type: DIRECT
  - target: Rickettsial Ribosomal Translation
    description: The replicating organism depends on bacterial ribosomal translation.
    causal_link_type: DIRECT
- name: Endothelial Cell Invasion and Intracytoplasmic Replication
  biological_scale: CELLULAR
  description: >-
    R. rickettsii is an obligate intracellular organism that primarily infects
    vascular endothelial cells, and less commonly the underlying smooth muscle
    cells of small and medium vessels. Adhesion and invasion are mediated by
    the conserved rOmpA and rOmpB surface autotransporters engaging host
    receptors (Ku70 identified for the closely related R. conorii); after entry
    the organism escapes into the cytoplasm and replicates. Individual adhesins
    are redundant - an isogenic rOmpA knockout in a virulent strain did not
    attenuate virulence in guinea pigs.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  - preferred_term: microvascular endothelial cell
    term:
      id: CL:2000008
      label: microvascular endothelial cell
  biological_processes:
  - preferred_term: symbiont entry into host
    term:
      id: GO:0044409
      label: symbiont entry into host
    modifier: INCREASED
  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: "R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells, and, less commonly, underlying smooth muscle cells of small and medium vessels"
    explanation: The CDC report establishes the endothelial tropism that defines RMSF pathophysiology.
  - reference: PMID:16360032
    reference_title: "Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii."
    explanation: >-
      Identifies a host receptor for rickettsial entry. Marked PARTIAL because
      the receptor was characterized for the closely related spotted fever group
      agent R. conorii rather than R. rickettsii directly.
  - reference: PMID:25827414
    reference_title: "Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence in a mammalian model system."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "no significant difference in either fever peak (40.5 C) or duration (8 days) were shown between the wild type and the knockout"
    explanation: >-
      Guinea pig challenge with an isogenic rOmpA knockout shows that this
      immunodominant adhesin is not individually required for virulence,
      supporting redundancy among invasion factors.
  downstream:
  - target: VE-Cadherin Phosphorylation and Adherens Junction Disruption
    description: Infected endothelium loses adherens-junction integrity.
    causal_link_type: DIRECT
  - target: Disseminated Small-Vessel Vasculitis
    description: Widespread endothelial infection produces systemic vasculitis.
    causal_link_type: DIRECT
  - target: Cytotoxic T Lymphocyte Clearance of Infected Endothelium
    description: Infected endothelial cells become targets of CD8 T cell cytotoxicity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Obligate Intracellular Niche (Cell-Penetrant Drug Requirement)
    description: Cytoplasmic residence gates which antimicrobials can reach the organism.
    causal_link_type: DIRECT
- name: VE-Cadherin Phosphorylation and Adherens Junction Disruption
  biological_scale: MOLECULAR
  description: >-
    Spotted fever group rickettsial infection of microvascular endothelial cells
    activates tyrosine phosphorylation of VE-cadherin, attenuating homophilic
    adherens-junction protein-protein interactions and producing paracellular
    barrier dysfunction. This is the best-characterized molecular route from
    endothelial infection to microvascular leak.
  biological_processes:
  - preferred_term: adherens junction organization
    term:
      id: GO:0034332
      label: adherens junction organization
    modifier: DECREASED
  evidence:
  - reference: PMID:22720111
    reference_title: "Rickettsiae induce microvascular hyperpermeability via phosphorylation of VE-cadherins: evidence from atomic force microscopy and biochemical studies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "upon infection by SFG rickettsiae, phosphorylation of VE-cadherin directly attenuates homophilic protein-protein interactions at the endothelial adherens junctions, and may lead to endothelial paracellular barrier dysfunction causing microvascular hyperpermeability"
    explanation: >-
      Atomic force microscopy and biochemical assays establish the
      VE-cadherin-phosphorylation mechanism. The experiments used the
      non-pathogenic surrogate R. montanensis under BSL2 conditions, so the
      inference to R. rickettsii is by genetic and phenotypic similarity (see
      the HUMAN_MODEL_MISMATCH discussion on this entry).
  downstream:
  - target: Increased Microvascular Permeability
    description: Loss of junctional integrity permits paracellular leak.
    causal_link_type: DIRECT
- name: Disseminated Small-Vessel Vasculitis
  biological_scale: TISSUE
  description: >-
    Infection of endothelium throughout the body produces a systemic
    small-vessel vasculitis. Cutaneously this is visible as the characteristic
    macular-to-petechial rash; systemically it is the substrate for end-organ
    injury. Infected human endothelial cells upregulate cyclooxygenase 2 and
    release vasoactive prostaglandins, contributing to the inflammatory and
    permeability changes.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  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: "Infection with R. rickettsii leads to systemic vasculitis that manifests externally as characteristic petechial skin lesions."
    explanation: The CDC report identifies systemic vasculitis as the central lesion.
  - 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 RMSF explicitly as endothelial infection with microvascular injury and vasculitis.
  - reference: PMID:2105679
    reference_title: "Vascular permeability and coagulation during Rickettsia rickettsii infection in dogs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "multifocal areas of retinal vasculitis were evident, which corresponded to areas of altered vascular permeability demonstrated by fluorescein angiography"
    explanation: >-
      Experimental canine infection directly visualizes rickettsial vasculitic
      foci and the corresponding permeability defect.
  downstream:
  - target: Increased Microvascular Permeability
    description: Vasculitic injury increases microvascular leak.
    causal_link_type: DIRECT
  - target: Platelet Consumption and Coagulation Activation
    description: Endothelial injury triggers platelet adhesion and consumption.
    causal_link_type: DIRECT
  - target: Skin rash
    description: Cutaneous small-vessel vasculitis produces the characteristic rash.
    causal_link_type: DIRECT
  - target: Petechiae
    description: Progressive vascular injury produces petechial lesions.
    causal_link_type: DIRECT
  - target: Vasculitis
    description: The systemic lesion is itself a clinically recognized vasculitis.
    causal_link_type: DIRECT
  - target: Gangrene
    description: Severe vasculitic and thrombotic injury can produce cutaneous necrosis and gangrene.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Increased Microvascular Permeability
  biological_scale: TISSUE
  description: >-
    Pathogen-mediated injury to the vascular endothelium produces increased
    capillary permeability and microhemorrhage. The late-stage manifestations of
    noncardiogenic pulmonary edema (ARDS) and cerebral edema are direct
    consequences of this microvascular leakage, and hypovolemia from leak drives
    appropriate antidiuretic hormone secretion and hyponatremia.
  biological_processes:
  - preferred_term: positive regulation of vascular permeability
    term:
      id: GO:0043117
      label: positive regulation of vascular permeability
    modifier: INCREASED
  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: "Pathogen-mediated injury to the vascular endothelium results in increased capillary permeability, microhemorrhage, and platelet consumption"
    explanation: The CDC report gives the causal step from endothelial injury to microvascular leak.
  - 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: "and cerebral edema, are consequences of microvascular leakage."
    explanation: The CDC report attributes ARDS and cerebral edema to microvascular leakage.
  - reference: PMID:22720111
    reference_title: "Rickettsiae induce microvascular hyperpermeability via phosphorylation of VE-cadherins: evidence from atomic force microscopy and biochemical studies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The most prominent pathophysiological effect of spotted fever group (SFG) rickettsial infection of microvascular endothelial cells (ECs) is an enhanced vascular permeability, promoting vasogenic cerebral edema and non-cardiogenic pulmonary edema"
    explanation: Independently identifies enhanced vascular permeability as the dominant pathophysiologic effect.
  downstream:
  - target: Cerebral edema
    description: Vasogenic cerebral edema follows CNS microvascular leak.
    causal_link_type: DIRECT
  - target: Acute respiratory distress syndrome
    description: Noncardiogenic pulmonary edema follows pulmonary microvascular leak.
    causal_link_type: DIRECT
  - target: Hyponatremia
    description: Hypovolemia from leak drives appropriate antidiuretic hormone secretion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Multiorgan End-Organ Injury
    description: Sustained leak and vasculopathy injure brain, kidney, lung, and skin.
    causal_link_type: DIRECT
- name: Platelet Consumption and Coagulation Activation
  biological_scale: CELLULAR
  description: >-
    Injured endothelium consumes platelets intravascularly and activates the
    coagulation system. In experimental canine infection, retinal vasculitic
    foci developed together with thrombocytopenia, increased circulating
    fibrinogen, and slight prolongation of the activated partial thromboplastin
    time - a mild consumptive coagulopathy that can progress to disseminated
    intravascular coagulation in severe disease.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  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: "Pathogen-mediated injury to the vascular endothelium results in increased capillary permeability, microhemorrhage, and platelet consumption"
    explanation: The CDC report attributes platelet consumption to endothelial injury.
  - reference: PMID:2105679
    reference_title: "Vascular permeability and coagulation during Rickettsia rickettsii infection in dogs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Development of retinal vasculitic foci was associated with thrombocytopenia, increased concentrations of circulating fibrinogen, and slight prolongation of activated partial thromboplastin time."
    explanation: >-
      The canine model links rickettsial vasculitis directly to thrombocytopenia
      and coagulation activation.
  downstream:
  - target: Thrombocytopenia
    description: Intravascular platelet consumption lowers the platelet count.
    causal_link_type: DIRECT
  - target: Disseminated intravascular coagulation
    description: Severe consumptive coagulopathy can progress to DIC.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Cytotoxic T Lymphocyte Clearance of Infected Endothelium
  biological_scale: CELLULAR
  description: >-
    Recovery depends on cell-mediated immunity: interferon-gamma- and
    TNF-alpha-activated endothelial cells kill intracellular rickettsiae by
    nitric-oxide-dependent mechanisms, and CD8 T lymphocyte cytotoxicity
    eliminates the remaining infected cells. MHC class I knockout mice are
    dramatically more susceptible to lethal rickettsial infection than wild-type
    animals, establishing CTL activity as the critical effector arm.
  cell_types:
  - preferred_term: CD8-positive T lymphocyte
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
    modifier: INCREASED
  evidence:
  - reference: PMID:11179362
    reference_title: "Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results for rickettsial infection differ from these chlamydial models in that immune clearance of rickettsial infection was more dependent on CD8 T lymphocytes, and there is evidence that CTL activity is a critical factor."
    explanation: >-
      Knockout-mouse experiments establish CD8 T lymphocyte cytotoxicity as the
      critical clearance mechanism for rickettsial infection of endothelium.
  - reference: PMID:11179362
    reference_title: "Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "nitric oxide-dependent killing of rickettsiae in endothelial cells activated by IFN-gamma and TNF-alpha followed by the elimination of the remaining rickettsia-infected cells by CTL activity"
    explanation: >-
      Describes the cytokine-activated intracellular killing that complements
      CTL-mediated elimination of infected endothelial cells.
- name: Multiorgan End-Organ Injury
  biological_scale: ORGANISM
  description: >-
    Sustained vasculopathy and microvascular leak injure the brain, kidney,
    lung, and skin, producing meningoencephalitis, acute renal failure, ARDS,
    cutaneous necrosis, shock, arrhythmia, and seizure. Survivors of severe
    disease may be left with long-term neurologic sequelae that are most likely
    the result of R. rickettsii-induced vasculopathy.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  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: "Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."
    explanation: The CDC report enumerates the end-organ consequences of untreated RMSF.
  - 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: "These complications are observed most frequently in persons recovering from severe, life-threatening disease, often after lengthy hospitalizations, and are most likely the result of R. rickettsii"
    explanation: The CDC report attributes long-term sequelae to severe disease and rickettsial vasculopathy.
  downstream:
  - target: Bacterial encephalitis
    description: CNS vasculitis produces meningoencephalitis.
    causal_link_type: DIRECT
  - target: Acute kidney injury
    description: Renal microvascular injury produces acute renal failure.
    causal_link_type: DIRECT
  - target: Cognitive impairment
    description: Vasculopathic CNS injury leaves long-term cognitive sequelae.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hearing impairment
    description: Vasculopathic injury can leave persistent hearing loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Fulminant Thrombotic Course in G6PD Deficiency
  biological_scale: ORGANISM
  description: >-
    A minority of patients follow a hyperacute course with death on or before
    day 5 of illness. In the described fulminant cases, thrombosis was more
    extensive than in classic RMSF with fibrin thrombi at foci of rickettsial
    infection, rash was absent or only preterminal, and there was minimal
    mononuclear leukocytic response - a thrombotic rather than classically
    vasculitic pathology. All described patients were G6PD-deficient, and the
    CDC recommendations list G6PD deficiency as a risk factor for fulminant
    RMSF.
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  evidence:
  - reference: PMID:6687526
    reference_title: "Fulminant Rocky Mountain spotted fever. Its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombosis was more extensive than in classic RMSF, with fibrin thrombi located in foci of rickettsial infection."
    explanation: Autopsy series describing the thrombotic pathology of fulminant RMSF.
  - reference: PMID:6687526
    reference_title: "Fulminant Rocky Mountain spotted fever. Its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had severe multisystemic injury as shown by clinical signs and laboratory data, but on microscopic examination showed minimal evidence of the typical mononuclear leukocytic response to rickettsial vascular infection and injury"
    explanation: >-
      Documents the absent inflammatory infiltrate that distinguishes the
      fulminant course from classic vasculitic RMSF.
  - 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: "Glucose-6-phosphate dehydrogenase deficiency is a risk factor for fulminant RMSF, with death occurring in <=5 days"
    explanation: Independent national guidance confirming G6PD deficiency as a fulminant-disease risk factor.
  downstream:
  - target: Disseminated intravascular coagulation
    description: Extensive fibrin thrombosis manifests as consumptive coagulopathy.
    causal_link_type: DIRECT
- name: Rickettsial Ribosomal Translation
  role: therapeutic_vulnerability
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  biological_scale: MOLECULAR
  description: >-
    R. rickettsii, like other bacteria, depends on 70S-ribosome translation of
    its mRNA. Doxycycline, a tetracycline, binds the 30S ribosomal subunit and
    blocks aminoacyl-tRNA delivery to the A site, arresting bacterial protein
    synthesis. This ribosomal target - not a cell-wall target - is why a
    tetracycline rather than a beta-lactam is the drug of choice.
  biological_processes:
  - preferred_term: Translation
    term:
      id: GO:0006412
      label: translation
  evidence:
  - reference: PMID:24336183
    reference_title: "Ribosome-targeting antibiotics and mechanisms of bacterial resistance."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The ribosome is one of the main antibiotic targets in the bacterial cell.
    explanation: >-
      Review establishing the bacterial ribosome as the target of tetracyclines
      and other protein-synthesis inhibitors, the step this node represents.
      Evidence source is OTHER as this is a review article.
- name: Obligate Intracellular Niche (Cell-Penetrant Drug Requirement)
  role: intrinsic_resistance
  conforms_to: "intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion"
  biological_scale: CELLULAR
  description: >-
    R. rickettsii is an obligate intracellular bacterium that replicates within
    host endothelial cells. Effective therapy therefore requires an antibiotic
    that accumulates inside host cells; doxycycline does, whereas beta-lactams
    cannot reach the intracellular organism - the lifestyle gating that further
    constrains drug choice beyond the ribosomal target.
  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:18611821
    reference_title: "Intracellular organisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The intracellular location of some microorganisms allow them to resist
      antibiotics with poor ability to penetrate eukaryotic cell membranes, such
      as the beta-lactam compounds.
    explanation: >-
      Review stating that the intracellular niche confers resistance to poorly
      cell-penetrant antibiotics such as beta-lactams, the gating principle this
      node represents. Evidence source is OTHER as this is a review article.
  - 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: "R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells, and, less commonly, underlying smooth muscle cells of small and medium vessels"
    explanation: Confirms the obligate intracellular lifestyle for this specific organism.
phenotypes:
- category: Infectious
  name: Fever
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Sudden-onset fever is the earliest and most consistent manifestation, and
    is present in nearly all children with laboratory-diagnosed RMSF.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
    temporality: ACUTE
  evidence:
  - reference: PMID:17236897
    reference_title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"
    explanation: A 92-patient pediatric series quantifies fever in 98% of children, supporting the VERY_FREQUENT band.
  - 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: "Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia."
    explanation: The CDC report lists fever among the initial symptoms.
- category: Dermatological
  name: Skin rash
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    A rash typically appears 2-4 days after fever onset as small blanching pink
    macules on the ankles, wrists, or forearms, spreading to palms, soles,
    limbs, and trunk while usually sparing the face. Fewer than half of patients
    have a rash in the first three days of illness, and a smaller proportion
    never develop one, so its absence must not delay treatment.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:17236897
    reference_title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"
    explanation: Rash was documented in 97% of children in the multicenter series, supporting the VERY_FREQUENT band.
  - 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: "Absence of rash should not preclude consideration of RMSF; <50% of patients have a rash in the first 3 days of illness, and a smaller percentage of patients never develop a rash"
    explanation: The CDC report qualifies rash timing and its unreliability as an early sign.
- category: Dermatological
  name: Petechiae
  description: >-
    The rash typically becomes maculopapular and then petechial; the classic
    generalized petechial rash involving palms and soles usually appears by day
    5 or 6 and indicates advanced disease.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  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: "The classic spotted or generalized petechial rash, including involvement of the palms and soles, usually appears by day 5 or 6 and is indicative of advanced disease."
    explanation: The CDC report describes the petechial evolution as a late, severity-associated sign.
- category: Vascular
  name: Vasculitis
  description: >-
    RMSF is fundamentally a systemic small-vessel vasculitis produced by
    endothelial infection; the clinically recognized vasculitis has been
    confused with idiopathic acute vasculitides such as Kawasaki disease.
  phenotype_term:
    preferred_term: Vasculitis
    term:
      id: HP:0002633
      label: Vasculitis
  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: "RMSF-associated vasculitis has been confused with idiopathic, acute vasculitides, such as Kawasaki disease in pediatric patients."
    explanation: The CDC report records vasculitis as a recognized clinical manifestation.
- category: Neurological
  name: Headache
  frequency: FREQUENT
  description: Severe headache is a cardinal early symptom and part of the classic triad.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:17236897
    reference_title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"
    explanation: Headache was documented in 61% of children, supporting the FREQUENT band.
- category: Constitutional
  name: Myalgia
  description: Myalgia is among the initial symptoms of acute RMSF.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  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: "Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia."
    explanation: The CDC report lists myalgia among initial symptoms.
- category: Constitutional
  name: Malaise
  description: Malaise accompanies the abrupt febrile onset.
  phenotype_term:
    preferred_term: Malaise
    term:
      id: HP:0033834
      label: Malaise
  evidence:
  - reference: ORPHA:83311
    reference_title: "Rocky Mountain spotted fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by an acute onset of fever, malaise, and severe headache, variably accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain, and photophobia"
    explanation: Orphanet lists malaise as part of the acute presentation.
- category: Constitutional
  name: Anorexia
  description: >-
    Loss of appetite is a variable accompaniment of the acute febrile
    presentation, part of the non-specific prodrome that makes early RMSF hard
    to distinguish from other acute febrile illnesses.
  phenotype_term:
    preferred_term: Anorexia
    term:
      id: HP:0002039
      label: Anorexia
  evidence:
  - reference: ORPHA:83311
    reference_title: "Rocky Mountain spotted fever"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "variably accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain, and photophobia"
    explanation: Orphanet lists anorexia among the variable accompanying features.
- category: Gastrointestinal
  name: Nausea and vomiting
  frequency: FREQUENT
  description: >-
    Nausea and vomiting are common early symptoms and a recognized cause of
    misdiagnosis as gastroenteritis, which delays doxycycline.
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  evidence:
  - reference: PMID:17236897
    reference_title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"
    explanation: Nausea and/or vomiting occurred in 73% of children, supporting the FREQUENT band.
  - reference: PMID:25697742
    reference_title: "Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea"
    explanation: Early gastrointestinal symptoms were associated with doxycycline delay and fatal outcome.
- category: Gastrointestinal
  name: Abdominal pain
  description: >-
    Abdominal pain occurs early and can mimic acute appendicitis, cholecystitis,
    or gastroenteritis.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  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: "abdominal pain that mimics acute appendicitis (102), cholecystitis (103), or gastroenteritis"
    explanation: The CDC report records abdominal pain as a recognized and misleading feature.
- category: Gastrointestinal
  name: Diarrhea
  description: Diarrhea is a recognized feature that contributes to misdiagnosis as gastroenteritis.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:25697742
    reference_title: "Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea"
    explanation: The Arizona case review documents diarrhea as an early RMSF symptom associated with treatment delay.
- category: Ophthalmological
  name: Photophobia
  description: Photophobia is among the early symptoms of RMSF.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  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: "Other early symptoms might include nausea or vomiting, abdominal pain, anorexia, and photophobia."
    explanation: The CDC report lists photophobia among early symptoms.
- category: Laboratory
  name: Thrombocytopenia
  frequency: FREQUENT
  description: >-
    Thrombocytopenia reflects intravascular platelet consumption at sites of
    endothelial injury and is a supportive but not early-reliable laboratory
    finding.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:17236897
    reference_title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet counts were <150,000/mm3 in 59% of children, and serum sodium concentrations were <135 mEq/dL in 52%."
    explanation: Thrombocytopenia occurred in 59% of children, supporting the FREQUENT band.
  - 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: "Thrombocytopenia, slight elevations in hepatic transaminases (aspartate transaminase and alanine transaminase), and hyponatremia might be present, particularly as the disease advances"
    explanation: The CDC report lists thrombocytopenia among the characteristic laboratory findings.
- category: Laboratory
  name: Hyponatremia
  frequency: FREQUENT
  description: >-
    Hyponatremia results from appropriate secretion of antidiuretic hormone in
    response to hypovolemia caused by microvascular leak.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:17236897
    reference_title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet counts were <150,000/mm3 in 59% of children, and serum sodium concentrations were <135 mEq/dL in 52%."
    explanation: Hyponatremia occurred in 52% of children, supporting the FREQUENT band.
  - 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: "Hyponatremia occurs as a result of appropriate secretion of antidiuretic hormone in response to hypovolemia"
    explanation: The CDC report gives the mechanism of hyponatremia in RMSF.
- category: Laboratory
  name: Elevated circulating hepatic transaminase concentration
  description: Slight elevations in aspartate and alanine transaminase accompany advancing disease.
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  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: "Thrombocytopenia, slight elevations in hepatic transaminases (aspartate transaminase and alanine transaminase), and hyponatremia might be present, particularly as the disease advances"
    explanation: The CDC report lists transaminase elevation among characteristic laboratory findings.
  - reference: PMID:25697742
    reference_title: "Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal laboratory results such as elevated liver aminotransferases. Rash, history of tick bite, thrombocytopenia, and hyponatremia were often absent at initial presentation."
    explanation: Elevated aminotransferases were among the abnormal findings in the Arizona case review.
- category: Neurological
  name: Bacterial encephalitis
  description: >-
    Meningoencephalitis is a severe late manifestation reflecting CNS
    small-vessel vasculitis, and may mimic bacterial or viral
    meningoencephalitis.
  phenotype_term:
    preferred_term: Meningoencephalitis
    term:
      id: HP:0034387
      label: Bacterial encephalitis
  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: "Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."
    explanation: The CDC report lists meningoencephalitis as a severe late manifestation.
- category: Neurological
  name: Cerebral edema
  description: Vasogenic cerebral edema is a consequence of CNS microvascular leakage.
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  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: "Late-stage manifestations, such as noncardiogenic pulmonary edema (acute respiratory distress syndrome ARDS) and cerebral edema, are consequences of microvascular leakage."
    explanation: The CDC report attributes cerebral edema to microvascular leakage.
- category: Respiratory
  name: Acute respiratory distress syndrome
  description: >-
    Noncardiogenic pulmonary edema presenting as ARDS is a severe late
    manifestation of microvascular leak.
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
  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: "Late-stage manifestations, such as noncardiogenic pulmonary edema (acute respiratory distress syndrome ARDS) and cerebral edema, are consequences of microvascular leakage."
    explanation: The CDC report identifies ARDS as a late-stage manifestation.
- category: Renal
  name: Acute kidney injury
  description: Acute renal failure is among the severe late-stage manifestations.
  phenotype_term:
    preferred_term: Acute renal failure
    term:
      id: HP:0001919
      label: Acute kidney injury
  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: "Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."
    explanation: The CDC report lists acute renal failure among severe manifestations.
- category: Hematological
  name: Disseminated intravascular coagulation
  description: >-
    Severe consumptive coagulopathy with extensive fibrin thrombosis occurs in
    fulminant disease and has led to diagnostic confusion with thrombotic
    thrombocytopenic purpura.
  phenotype_term:
    preferred_term: Disseminated intravascular coagulation
    term:
      id: HP:0005521
      label: Disseminated intravascular coagulation
  evidence:
  - reference: PMID:6687526
    reference_title: "Fulminant Rocky Mountain spotted fever. Its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombosis was more extensive than in classic RMSF, with fibrin thrombi located in foci of rickettsial infection."
    explanation: Autopsy findings document extensive fibrin thrombosis in fulminant RMSF.
  - reference: PMID:2105679
    reference_title: "Vascular permeability and coagulation during Rickettsia rickettsii infection in dogs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Increased concentrations of fibrin/fibrinogen degradation products were detected in 4 of 9 dogs."
    explanation: >-
      The canine model shows consumptive coagulopathy markers; marked PARTIAL as
      it is animal evidence for a human clinical phenotype.
- category: Dermatological
  name: Gangrene
  description: >-
    Cutaneous necrosis and gangrene from severe vasculitic and thrombotic injury
    may result in amputation of digits or limbs.
  phenotype_term:
    preferred_term: Gangrene
    term:
      id: HP:0100758
      label: Gangrene
  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: "Cutaneous necrosis and gangrene (Figure 23) might result in amputation of digits or limbs"
    explanation: The CDC report documents gangrene requiring amputation as a severe complication.
- category: Neurological
  name: Cognitive impairment
  description: >-
    Cognitive impairment is among the long-term neurologic sequelae in survivors
    of severe disease, attributed to rickettsial vasculopathy.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  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: "Long-term neurologic sequelae of RMSF include cognitive impairment; paraparesis; hearing loss; blindness; peripheral neuropathy"
    explanation: The CDC report enumerates long-term neurologic sequelae including cognitive impairment.
- category: Otolaryngological
  name: Hearing impairment
  description: >-
    Hearing loss occurs both as acute transient hearing loss during illness and
    as a long-term neurologic sequela.
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  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: "Long-term neurologic sequelae of RMSF include cognitive impairment; paraparesis; hearing loss; blindness; peripheral neuropathy; bowel and bladder incontinence; cerebellar, vestibular, and motor dysfunction; and speech disorders"
    explanation: The CDC report lists hearing loss among long-term neurologic sequelae.
- category: Gastrointestinal
  name: Hepatomegaly
  description: Hepatomegaly has been observed in association with RMSF.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  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: "conjunctival suffusion; periorbital and peripheral edema (more common in children); calf pain; acute transient hearing loss; hepatomegaly; and splenomegaly"
    explanation: The CDC report lists hepatomegaly among observed clinical features.
- category: Hematological
  name: Splenomegaly
  description: Splenomegaly has been observed in association with RMSF.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  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: "calf pain; acute transient hearing loss; hepatomegaly; and splenomegaly"
    explanation: The CDC report lists splenomegaly among observed clinical features.
genetic:
- name: G6PD deficiency as a fulminant-disease modifier
  gene_term:
    preferred_term: G6PD
    term:
      id: hgnc:4057
      label: G6PD
  association: >-
    Glucose-6-phosphate dehydrogenase deficiency does not cause RMSF but is a
    recognized host modifier of severity. It is a risk factor for the fulminant
    form, in which death occurs on or before day 5 of illness with extensive
    fibrin thrombosis and minimal inflammatory response.
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:6687526
    reference_title: "Fulminant Rocky Mountain spotted fever. Its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients were male blacks with glucose-6-phosphate dehydrogenase deficiency, a condition recently associated with severity of RMSF."
    explanation: The autopsy series links G6PD deficiency to the fulminant RMSF phenotype.
  - 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: "Glucose-6-phosphate dehydrogenase deficiency is a risk factor for fulminant RMSF, with death occurring in <=5 days"
    explanation: National guidance independently records G6PD deficiency as a fulminant-disease risk factor.
  notes: >-
    No specific G6PD allele has been implicated beyond G6PD deficiency broadly,
    and no RMSF-specific GWAS or additional host susceptibility locus has been
    reported.
environmental:
- name: Tick exposure in endemic habitat
  influences_mechanisms:
  - target: Tick-Borne Rickettsia rickettsii Inoculation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Entering the wooded, shrubby and grassy habitat where questing
      Dermacentor ticks congregate is what brings a person within reach of an
      attaching, infected tick.
    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: "D. variabilis ticks often are encountered in wooded, shrubby, and grassy areas and tend to congregate along walkways and trails."
      explanation: >-
        Describes where these ticks are encountered and that they congregate
        along walkways and trails, the habitat contact that precedes
        inoculation.
  description: >-
    Exposure to questing Dermacentor ticks in wooded, shrubby, and grassy areas,
    including residential areas and city parks, is the proximate environmental
    risk. Adult Dermacentor ticks are active from spring through autumn with
    maximum activity in late spring through early summer.
  effect: Increases the probability of an infectious tick bite and therefore of acquiring RMSF.
  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: "D. variabilis ticks often are encountered in wooded, shrubby, and grassy areas and tend to congregate along walkways and trails."
    explanation: The CDC report describes the habitat in which vector exposure occurs.
  - 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: "Adult Dermacentor ticks are active from spring through autumn, with maximum activity during late spring through early summer."
    explanation: The CDC report gives the seasonality of vector activity.
- name: Domestic dog and peridomestic brown dog tick exposure
  influences_mechanisms:
  - target: Tick-Borne Rickettsia rickettsii Inoculation
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Dogs are not themselves the source of infection: they maintain and
      amplify brown dog tick populations around dwellings, and those ticks
      then bite people. The intermediates are known, which is why this is
      indirect rather than direct.
    evidence:
    - reference: PMID:28365226
      reference_title: "Rocky Mountain spotted fever in Mexico: past, present, and future."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These investigators also described the pivotal roles of domesticated dogs and Rhipicephalus sanguineus sensu lato (brown dog ticks) as drivers of epidemic levels of Rocky Mountain spotted fever."
      explanation: >-
        Identifies domestic dogs and brown dog ticks as drivers of epidemic
        transmission, the amplification step between dog contact and human
        inoculation.
  description: >-
    Domestic dogs are the preferred host of Rhipicephalus sanguineus at all life
    stages, and free-roaming dogs with peridomestic tick infestation drive the
    high-incidence epidemic foci in Arizona and northern Mexico. Dogs are also
    susceptible to R. rickettsii and can serve as sentinels for human risk.
  effect: Sustains a peridomestic transmission cycle that raises human exposure to infected brown dog ticks.
  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: "Canids, especially domestic dogs, are the preferred hosts for the brown dog tick at all life stages."
    explanation: The CDC report identifies dogs as the tick host driving peridomestic transmission.
  - reference: PMID:28365226
    reference_title: "Rocky Mountain spotted fever in Mexico: past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These investigators also described the pivotal roles of domesticated dogs and Rhipicephalus sanguineus sensu lato (brown dog ticks) as drivers of epidemic levels of Rocky Mountain spotted fever."
    explanation: The Lancet review identifies dogs and brown dog ticks as epidemic drivers.
diagnosis:
- name: Empiric clinical diagnosis without waiting for confirmation
  description: >-
    Because diagnostic tests are usually not helpful during the initial stages
    of illness and the classic triad of fever, rash, and reported tick bite is
    present in only a minority of patients at presentation, RMSF is treated
    empirically on clinical and epidemiologic suspicion.
  diagnosis_term:
    preferred_term: clinical diagnosis
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    Compatible acute febrile illness with tick exposure in an endemic area
    warrants immediate empiric doxycycline regardless of test results.
  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: "Diagnostic tests for rickettsial diseases, particularly for RMSF, are usually not helpful in making a timely diagnosis during the initial stages of illness."
    explanation: The CDC report establishes that acute testing cannot guide initial treatment.
  - 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: "The classic triad of fever, rash, and reported tick bite is present in only a minority of patients during initial presentation to health care"
    explanation: The CDC report documents the low sensitivity of the classic triad at presentation.
- name: Paired-serum indirect immunofluorescence antibody assay
  description: >-
    The standard confirmatory test is the indirect immunofluorescence antibody
    (IFA) assay on paired acute and convalescent sera; at least a fourfold rise
    in antibody titer is confirmatory. IFA assays are insensitive during the
    first week of illness and therefore confirm the diagnosis retrospectively.
  diagnosis_term:
    preferred_term: serologic testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: A fourfold or greater rise in R. rickettsii antibody titer between paired sera confirms infection.
  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: "A diagnosis of tickborne rickettsial disease is confirmed with a fourfold or greater increase in antibody titer in samples collected at appropriately timed intervals in patients with a clinically compatible acute illness"
    explanation: The CDC report defines the serologic confirmation criterion.
  - 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: "Indirect immunofluorescence antibody (IFA) assays using paired acute and convalescent sera are the reference standard for serologic confirmation of rickettsial infection"
    explanation: The CDC report identifies IFA as the standard serologic assay.
- name: Supportive laboratory pattern
  description: >-
    Thrombocytopenia, slight transaminase elevation, hyponatremia, and a normal
    or slightly increased white blood cell count with increased immature
    neutrophils together form a suggestive but non-specific pattern that cannot
    be relied on to guide early treatment.
  diagnosis_term:
    preferred_term: clinical laboratory testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: Suggestive but non-diagnostic haematologic, hepatic, and electrolyte abnormalities.
  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: "however, laboratory values cannot be relied on to guide early treatment decisions"
    explanation: The CDC report cautions against using laboratory findings to gate early therapy.
- name: Whole-blood PCR for Rickettsia rickettsii
  description: >-
    Real-time PCR amplification of R. rickettsii DNA from whole blood can
    confirm infection during the acute stage, but sensitivity is low because
    few rickettsiae circulate before advanced disease; tissue specimens are a
    better source of spotted fever group rickettsial DNA than acute blood.
    Blood should be drawn before antibacterial agents are given, because
    doxycycline reduces PCR sensitivity. A negative PCR result therefore never
    excludes RMSF and must not delay empiric doxycycline.
  diagnosis_term:
    preferred_term: polymerase chain reaction
    term:
      id: NCIT:C17003
      label: Polymerase Chain Reaction
  results: >-
    A positive result confirms rickettsial infection and identifies the
    species; a negative result is uninformative in early or mild disease.
  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: "PCR detection of R. rickettsii in whole blood is possible but less sensitive because low numbers of rickettsiae typically circulate in the blood in the absence of advanced disease"
    explanation: The CDC report documents the low sensitivity of whole-blood PCR for R. rickettsii.
  - 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: "obtaining blood for molecular testing before antibacterial agents are administered is recommended to minimize the likelihood of a false-negative result"
    explanation: The CDC report recommends collecting molecular-testing specimens before therapy is started.
- name: Immunohistochemical staining of a skin punch biopsy
  description: >-
    Immunostaining (immunohistochemistry or immunofluorescence) for
    rickettsial antigen in formalin-fixed, paraffin-embedded skin punch biopsy
    of a rash lesion or eschar is a rapid confirmatory technique that, unlike
    serology, can establish the diagnosis during acute illness. It is highly
    specific but only moderately sensitive, so a negative stain does not
    exclude RMSF.
  diagnosis_term:
    preferred_term: skin biopsy immunohistochemistry
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  results: >-
    Detection of spotted fever group rickettsial antigen in dermal
    microvascular endothelium; approximately 100% specific and 70% sensitive.
  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: "For patients with a rash or eschar, immunohistochemical staining of a skin punch biopsy is a useful diagnostic technique"
    explanation: The CDC report endorses skin punch biopsy immunohistochemistry for rash or eschar.
  - 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: "Immunostaining of skin biopsy specimens is 100% specific and 70% sensitive in diagnosing RMSF"
    explanation: The CDC report quantifies the specificity and sensitivity of skin biopsy immunostaining.
differential_diagnoses:
- name: Meningococcemia
  description: >-
    RMSF-associated cutaneous necrosis and gangrene can be difficult to
    distinguish clinically from purpura fulminans associated with
    meningococcemia.
  distinguishing_features:
  - Purpura fulminans of meningococcemia closely mimics RMSF cutaneous necrosis
  - Tick exposure history and acral-onset rash favour RMSF
  - Both warrant concurrent empiric therapy while awaiting diagnostic information
  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: "RMSF-associated cutaneous necrosis and gangrene might be difficult to distinguish clinically from purpura fulminans associated with meningococcemia"
    explanation: The CDC report names meningococcemia as a key clinical mimic.
- name: Thrombotic thrombocytopenic purpura
  description: >-
    RMSF-associated neurologic manifestations, renal failure, and
    thrombocytopenia have led to confusion with thrombotic thrombocytopenic
    purpura.
  distinguishing_features:
  - Neurologic signs, renal failure, and thrombocytopenia overlap between the two
  - Tick exposure history and response to doxycycline favour RMSF
  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: "RMSF-associated neurologic manifestations, renal failure, and thrombocytopenia have led to confusion with the diagnosis of thrombotic thrombocytopenic purpura (TTP)"
    explanation: The CDC report records TTP as a recognized diagnostic confusion.
- name: Kawasaki disease
  description: >-
    RMSF-associated vasculitis in children has been confused with idiopathic
    acute vasculitides such as Kawasaki disease.
  distinguishing_features:
  - Both present with fever and rash in children
  - RMSF follows tick exposure in an endemic area and responds to doxycycline
  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: "RMSF-associated vasculitis has been confused with idiopathic, acute vasculitides, such as Kawasaki disease in pediatric patients."
    explanation: The CDC report names Kawasaki disease as a pediatric mimic.
- name: Acute gastroenteritis
  description: >-
    Prominent early nausea, vomiting, abdominal pain, and diarrhea commonly lead
    to an initial diagnosis of gastroenteritis, which delays doxycycline and
    increases the risk of fatal outcome.
  distinguishing_features:
  - Gastrointestinal symptoms in RMSF accompany high fever and severe headache
  - Gastrointestinal symptoms often precede any rash
  - Misattribution to gastroenteritis is a documented cause of treatment delay and death
  evidence:
  - reference: PMID:25697742
    reference_title: "Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea"
    explanation: The Arizona review links early gastrointestinal symptoms to treatment delay and death.
treatments:
- name: Empiric doxycycline for patients of all ages
  description: >-
    Doxycycline is the drug of choice for RMSF in patients of all ages,
    including children under 8 years, and should be started immediately on
    clinical suspicion without waiting for laboratory confirmation. Patients
    treated after the fifth day of illness are more likely to die. The
    historical reluctance to use doxycycline in young children is not supported:
    children who received courses of doxycycline before age 8 showed no
    tetracycline-like dental staining and no difference in tooth shade or enamel
    hypoplasia. Agents to avoid - sulfonamide antimicrobials can result in
    increased disease severity and death in RMSF.
  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
    treatment_effect: INHIBITS
    description: >-
      Doxycycline binds the bacterial 30S ribosomal subunit and arrests
      rickettsial protein synthesis.
  - target: Obligate Intracellular Niche (Cell-Penetrant Drug Requirement)
    treatment_effect: BYPASSES
    description: >-
      Doxycycline accumulates intracellularly and so reaches the cytoplasmic
      organism that beta-lactams cannot.
  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 national recommendation establishes doxycycline as first-line for all ages.
  - 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 treated after the fifth day of illness are more likely to die than those treated earlier in the course of illness"
    explanation: Supports the day-5 treatment window that governs outcome.
  - reference: PMID:25794784
    reference_title: "No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No tetracycline-like staining was observed in any of the exposed children's teeth (0/58, 95% CI 0%-5%), and no significant difference in tooth shade (P=.20) or hypoplasia (P=1.0) was found between the 2 groups."
    explanation: >-
      Directly supports the safety statement that removed the age barrier to
      doxycycline in young children.
  - 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: "treatment of patients with RMSF using a sulfonamide antimicrobial can result in increased disease severity and death"
    explanation: Supports the agents-to-avoid warning recorded in this treatment description.
- name: Chloramphenicol as second-line therapy
  description: >-
    Chloramphenicol is the only alternative drug that has been used to treat
    RMSF, and it is clearly inferior to doxycycline - CDC case-report data show
    higher mortality in chloramphenicol-treated patients. It is no longer
    available orally in the United States, requires monitoring of blood indices
    for hematologic toxicity, and does not cover ehrlichiosis or anaplasmosis,
    so empiric substitution leaves those co-endemic infections untreated. In
    pregnancy it is a potential alternative to doxycycline, but administration
    late in the third trimester carries a theoretical risk of gray baby
    syndrome. Because doxycycline has been used successfully in pregnant women
    and RMSF is potentially fatal, doxycycline remains preferred for suspected
    RMSF in pregnancy; chloramphenicol is reserved for true doxycycline
    intolerance.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: chloramphenicol
      term:
        id: CHEBI:17698
        label: chloramphenicol
  target_mechanisms:
  - target: Rickettsial Ribosomal Translation
    treatment_effect: INHIBITS
    description: >-
      Chloramphenicol binds the bacterial 50S ribosomal subunit and blocks
      rickettsial protein synthesis, acting on the same translational target
      that doxycycline inhibits from the 30S side.
  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: "Chloramphenicol is the only alternative drug that has been used to treat RMSF; however, epidemiologic studies using CDC case report data suggest that patients with RMSF treated with chloramphenicol are at higher risk for death than persons who received a tetracycline"
    explanation: >-
      Supports chloramphenicol as the sole alternative agent while documenting
      its inferior mortality outcome relative to tetracyclines.
  - 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: "Chloramphenicol is a potential alternative treatment for RMSF during pregnancy; however, care must be used when administering the drug late during the third trimester of pregnancy because of the theoretical risk for gray baby syndrome"
    explanation: Supports the pregnancy positioning and the third-trimester gray baby syndrome caveat.
  - 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 has been used successfully to treat tickborne rickettsial diseases in several pregnant women without adverse effects to the mother"
    explanation: Supports retaining doxycycline as the preferred agent in pregnancy.
- name: Tick-bite prevention counseling
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  description: >-
    No vaccine is licensed against tickborne rickettsial diseases, so primary
    prevention rests entirely on interrupting the tick-inoculation step that
    triggers the pathograph. Personal protective measures are DEET at 20-30
    percent on skin, with IR3535 or picaridin above 15 percent as alternatives;
    permethrin applied to outer clothing but never to skin, which reduces tick
    bites by more than 80 percent among outdoor workers; protective clothing;
    and prompt tick checks and bathing after time in tick habitat, since
    several hours may elapse before an attached tick transmits the organism.
    Prophylactic doxycycline after a tick bite is explicitly not recommended,
    and asymptomatic seropositive persons should not be treated - antibody can
    persist for months to years, so serology cannot be used to monitor
    treatment response.
  treatment_term:
    preferred_term: tick-bite prevention counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  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: "No vaccine is licensed for the prevention of tickborne rickettsial diseases in the United States. Avoiding tick bites and promptly removing attached ticks remain the best disease prevention strategies."
    explanation: Establishes the absence of a vaccine and that bite avoidance is the primary prevention strategy.
  - 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: "Permethrin-impregnated clothing can reduce tick bites by >80% among outdoor workers"
    explanation: Quantifies the protective effect of permethrin-treated clothing.
  - 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: "Several hours might elapse before ticks attach and transmit pathogens; therefore, timely tick checks increase the likelihood of finding and removing ticks before they can transmit an infectious agent."
    explanation: Supports the mechanistic rationale for prompt tick checks.
  - 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: "Prophylactic use of doxycycline after a tick bite is not recommended for the prevention of tickborne rickettsial diseases."
    explanation: Supports the explicit recommendation against post-bite antibiotic prophylaxis.
- name: Pet acaricide use and peridomestic tick control
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    Because dogs are the primary host of Rhipicephalus sanguineus, the brown
    dog tick that drives the epidemic RMSF foci in Arizona tribal communities
    and northern Mexico, controlling ticks on dogs is a population-level
    intervention against the same inoculation step. Monthly topical acaricides,
    acaricidal tick collars, oral acaricidal products, and acaricidal shampoos
    reduce human exposure to ticks carried by pets. This is the intervention
    that maps onto the peridomestic transmission cycle recorded in this entry's
    environmental risk factors, and it addresses a route that individual
    repellent use does not.
  treatment_term:
    preferred_term: pet ectoparasite control
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  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: "Regular use of pet ectoparasite control products (e.g., monthly topical acaricide products, acaricidal tick collars, oral acaricidal products, and acaricidal shampoos) can help reduce the risk for human exposure to ticks on pets."
    explanation: Supports acaricidal pet treatment as a measure that reduces human tick exposure.
  - 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: "dogs serve as the primary host for Rh. sanguineus, which is known to transmit R. rickettsii both to humans and dogs in certain geographic areas"
    explanation: Establishes the dog-brown dog tick reservoir that makes pet acaricide use a human-disease intervention.
- name: Supportive and intensive care for severe disease
  description: >-
    Severe RMSF requires supportive management of the vasculitic complications -
    fluid and electrolyte correction for hyponatremia, transfusion support for
    coagulopathy, and intensive care for ARDS, shock, and renal failure -
    alongside, never instead of, doxycycline.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Multiorgan End-Organ Injury
    treatment_effect: MODULATES
    description: Organ support mitigates the consequences of established vasculopathy.
  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: "Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure."
    explanation: >-
      Establishes the complications that require organ support. Marked PARTIAL
      because the source enumerates the complications rather than evaluating
      supportive-care efficacy.
  - reference: PMID:17236897
    reference_title: "Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coma and need for inotropic support and intravenous fluid boluses were independently associated with adverse outcomes."
    explanation: >-
      Documents the intensive-care interventions used in severe pediatric RMSF;
      INDIRECT because these markers of severity are not evidence of benefit.
histopathology:
- name: Lymphohistiocytic capillaritis and venulitis
  description: >-
    The main histopathologic feature of RMSF skin lesions is a lymphohistiocytic
    small-vessel capillaritis and venulitis with erythrocyte extravasation,
    edema, and a predominantly perivascular with some interstitial infiltrate.
    This is the tissue-level correlate of the disseminated small-vessel
    vasculitis node in the pathograph, and it is the earlier lesion in a
    sequence that progresses to leukocytoclastic vasculitis.
  finding_term:
    preferred_term: lymphohistiocytic capillaritis and venulitis
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  context: Skin biopsy and autopsy specimens; series of 26 RMSF cases.
  evidence:
  - reference: PMID:9449487
    reference_title: "Cutaneous histopathology of Rocky Mountain spotted fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main histopathologic feature was lymphohistiocytic capillaritis and venulitis with extravasation of erythrocytes, edema, predominantly perivascular and some interstitial infiltrate."
    explanation: Directly reports the dominant cutaneous histopathologic pattern in a 26-case series.
- name: Leukocytoclastic vasculitis with nuclear dust
  description: >-
    Leukocytoclastic vasculitis with a neutrophilic infiltrate and nuclear dust
    was present in 11 of 15 involved-skin specimens. It represents progression
    from the earlier lymphohistiocytic lesion, and the authors classify the
    vasculitis of RMSF as a septic vasculitis caused by direct rickettsial
    endothelial damage rather than an immune-complex process - a distinction
    that matters for the differential against idiopathic cutaneous vasculitis.
  finding_term:
    preferred_term: leukocytoclastic vasculitis
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  frequency: FREQUENT
  context: Involved skin specimens; 11 of 15 (73 percent).
  evidence:
  - reference: PMID:9449487
    reference_title: "Cutaneous histopathology of Rocky Mountain spotted fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leukocytoclastic vasculitis (LCV) with neutrophilic infiltrate and nuclear dust was seen in 11 of 15 (73%) specimens from involved skin."
    explanation: >-
      Quantifies the finding at 73 percent of involved-skin specimens, which
      maps to the FREQUENT band.
  - reference: PMID:9449487
    reference_title: "Cutaneous histopathology of Rocky Mountain spotted fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The vasculitis in RMSF is, therefore, considered to be a form of septic vasculitis."
    explanation: Supports the septic rather than immune-complex classification of the vasculitis.
- name: Focal fibrin thrombi and capillary wall necrosis
  description: >-
    Six leukocytoclastic lesions showed focal fibrin thrombi and capillary wall
    necrosis - the histologic counterpart of the platelet consumption and
    microvascular occlusion recorded in the pathograph, and the lesion that
    becomes extensive in fulminant G6PD-associated disease.
  finding_term:
    preferred_term: fibrin thrombi with capillary wall necrosis
    term:
      id: NCIT:C48903
      label: Intravascular Fibrin Thrombus Formation
  frequency: FREQUENT
  context: >-
    Six of the leukocytoclastic vasculitis lesions in the series, against the
    11 of 15 involved-skin specimens that showed leukocytoclastic vasculitis.
  notes: >-
    The FREQUENT band holds under either denominator the source actually
    states - 6 of 11 leukocytoclastic lesions or 6 of 15 involved-skin
    specimens. It would fall to OCCASIONAL only against all 26 cases, a
    denominator the paper does not report for this finding.
  evidence:
  - reference: PMID:9449487
    reference_title: "Cutaneous histopathology of Rocky Mountain spotted fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six lesions with LCV displayed focal fibrin thrombi and capillary wall necrosis."
    explanation: >-
      Reports fibrin thrombi and capillary wall necrosis in six of the
      leukocytoclastic vasculitis lesions, the count behind the FREQUENT band.
- name: Rickettsial antigen in affected endothelial cells
  description: >-
    Immunohistologic staining with polyclonal rabbit anti-Rickettsia rickettsii
    demonstrated organisms in the affected endothelial cells in all 12 cases
    tested, confirming at tissue level the endothelial tropism that initiates
    the pathograph. This is the histopathologic basis of the skin-biopsy
    immunohistochemistry diagnostic entry.
  finding_term:
    preferred_term: rickettsial antigen in endothelium
    term:
      id: NCIT:C40998
      label: Immunophenotypic Finding
  diagnostic: true
  context: 12 cases tested by polyclonal anti-R. rickettsii immunohistology.
  evidence:
  - reference: PMID:9449487
    reference_title: "Cutaneous histopathology of Rocky Mountain spotted fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistologic (IH) staining using polyclonal rabbit anti-Rickettsia rickettsii demonstrated positive staining of the organisms in the affected endothelial cells in all 12 cases tested."
    explanation: Confirms endothelial localization of the organism in stained tissue.
animal_models:
- species: Dog
  description: >-
    Experimental intradermal R. rickettsii inoculation of dogs reproduces the
    vasculitic and coagulopathic core of human RMSF, with retinal vasculitic
    foci corresponding to fluorescein-demonstrated permeability defects,
    thrombocytopenia, and coagulation activation. The dog is also a natural host
    and a sentinel for human risk.
  evidence:
  - reference: PMID:2105679
    reference_title: "Vascular permeability and coagulation during Rickettsia rickettsii infection in dogs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The vascular permeability of the ocular fundus, alterations in the coagulation system, and plasma concentrations of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were studied in dogs following intradermal inoculation with 5 x 10(5) TCID50 of Rickettsia rickettsii."
    explanation: The canine model was used to measure permeability and coagulation during R. rickettsii infection.
- species: Guinea pig
  description: >-
    Guinea pig challenge is the standard virulence readout for R. rickettsii
    mutants; it was used to show that an isogenic rOmpA knockout in the virulent
    Sheila Smith strain is not attenuated.
  evidence:
  - reference: PMID:25827414
    reference_title: "Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence in a mammalian model system."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Virulence was assessed in a guinea pig model by challenge with 100 PFU of either ompA::int312 Sheila Smith or the wild type"
    explanation: Establishes the guinea pig as the virulence model used for R. rickettsii genetics.
- species: Mouse
  genotype: MHC class I knockout
  description: >-
    MHC class I knockout mice are dramatically more susceptible to lethal
    rickettsial infection than wild-type animals, defining the CD8 T lymphocyte
    requirement for clearance. This is an immunologic-mechanism model rather
    than a faithful clinical model of RMSF.
  evidence:
  - reference: PMID:11179362
    reference_title: "Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "immune clearance of rickettsial infection was more dependent on CD8 T lymphocytes, and there is evidence that CTL activity is a critical factor."
    explanation: Knockout mice establish the CD8 T lymphocyte requirement for rickettsial clearance.
discussions:
- discussion_id: rmsf_surrogate_species_permeability_mechanism
  prompt: >-
    Does the VE-cadherin phosphorylation mechanism of microvascular
    hyperpermeability, demonstrated with the non-pathogenic surrogate Rickettsia
    montanensis under BSL2 conditions, hold quantitatively for Rickettsia
    rickettsii in human microvasculature?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#VE-Cadherin Phosphorylation and Adherens Junction Disruption
  - pathophysiology#Increased Microvascular Permeability
  rationale: >-
    The junctional mechanism curated on this entry is the best available
    molecular account of RMSF microvascular leak, but the biophysical and
    biochemical experiments were deliberately performed with R. montanensis, a
    genetically similar but non-pathogenic species chosen so the work could be
    done at biosafety level 2. Virulent R. rickettsii strains differ from
    avirulent relatives in outer-membrane protein expression, so the magnitude
    and kinetics of junctional disruption - and any pathogen-specific effector
    contribution - are not established for the disease-causing organism. The
    complementary in vivo permeability evidence comes from experimentally
    infected dogs rather than humans.
  proposed_experiments:
  - experiment_id: exp_rmsf_ve_cadherin_bsl3
    name: VE-cadherin phosphorylation assays with virulent R. rickettsii
    description: >-
      Repeat the atomic force microscopy and VE-cadherin phosphorylation assays
      using virulent R. rickettsii in human microvascular endothelial cells
      under BSL3 containment, to test whether the surrogate result holds for the
      pathogenic organism.
  - experiment_id: exp_rmsf_virulent_vs_avirulent_junction
    name: Virulent versus avirulent strain comparison of junctional disruption
    description: >-
      Compare adherens-junction disruption between the virulent Sheila Smith and
      avirulent Iowa strains of R. rickettsii to test whether the magnitude of
      the effect tracks with virulence.
  - experiment_id: exp_rmsf_human_tissue_junction
    name: Junctional integrity in human RMSF tissue
    description: >-
      Assess VE-cadherin phosphorylation and adherens-junction integrity in
      autopsy or skin-biopsy tissue from human RMSF cases to establish whether
      the in vitro mechanism is present in human disease.
  evidence:
  - reference: PMID:22720111
    reference_title: "Rickettsiae induce microvascular hyperpermeability via phosphorylation of VE-cadherins: evidence from atomic force microscopy and biochemical studies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "R. montanensis, which is genetically similar to R. rickettsii and R. conorii, and displays a similar ability to invade cells, but is non-pathogenic and can be experimentally manipulated under Biosafety Level 2 (BSL2) conditions"
    explanation: >-
      The authors state explicitly that a non-pathogenic surrogate was used in
      place of R. rickettsii, which is the source of the translational
      uncertainty recorded here.
notes: >-
  Scope note: this entry models RMSF as caused by Rickettsia rickettsii and is
  deliberately distinct from the other spotted fever group rickettsioses already
  in the knowledge base. Boutonneuse fever (R. conorii) is the closest sibling
  entry and shares the endothelial-infection mechanism, but differs clinically in
  that an inoculation eschar is characteristic there and rare in RMSF.
  Frequency bands are taken from a pediatric multicenter series (PMID:17236897)
  and therefore reflect hospitalized children; adult frequencies may differ, and
  frequency was omitted wherever a quantitative or mappable qualitative source
  was not available. The United States incidence record is marked PARTIAL because
  the surveillance category is spotted fever group rickettsiosis rather than
  laboratory-confirmed RMSF alone. No GeneReviews chapter exists for RMSF, which
  is expected for an acquired infectious disease.
clinical_trials: []
datasets: []

📚

References & Deep Research

References

13

ORPHA:83311

Rocky Mountain spotted fever

1 finding

Orphanet defines Rocky Mountain spotted fever as a life-threatening tick-borne Rickettsia rickettsii infection and provides the exact MONDO cross-reference used by this entry.

"MONDO:0019359 | Exact"

PMID:27172113

Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States.

1 finding

The CDC national recommendations provide the authoritative account of RMSF pathophysiology, tick vectors, incubation and rash timing, laboratory findings, case-fatality, sequelae, diagnostic testing, and doxycycline treatment for patients of all ages.

"Doxycycline is the drug of choice for treatment of all tickborne rickettsial diseases in patients of all ages, including children aged <8 years"

PMID:17236897

Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children.

1 finding

A 92-patient multicenter pediatric series quantifies the frequency of fever, rash, nausea/vomiting, headache, thrombocytopenia, and hyponatremia, and documents death or neurologic deficits at discharge.

"which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%)"

PMID:25697742

Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011.

1 finding

A 205-case review in a high-incidence Arizona region shows that doxycycline was started significantly later in fatal than nonfatal cases and identifies clinical risk factors for treatment delay.

"Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3)"

PMID:22720111

Rickettsiae induce microvascular hyperpermeability via phosphorylation of VE-cadherins: evidence from atomic force microscopy and biochemical studies.

1 finding

Spotted fever group rickettsial infection of microvascular endothelial cells phosphorylates VE-cadherin and attenuates adherens-junction interactions, giving a molecular mechanism for hyperpermeability. The experiments used the non-pathogenic surrogate R. montanensis at BSL2.

"phosphorylation of VE-cadherin directly attenuates homophilic protein-protein interactions at the endothelial adherens junctions"

PMID:6687526

Fulminant Rocky Mountain spotted fever. Its pathologic characteristics associated with glucose-6-phosphate dehydrogenase deficiency.

1 finding

Fulminant RMSF (death on or before day 5) in G6PD-deficient patients shows extensive fibrin thrombosis with minimal mononuclear inflammatory response, a hyperacute thrombotic variant of the classic vasculitic course.

"Thrombosis was more extensive than in classic RMSF, with fibrin thrombi located in foci of rickettsial infection."

PMID:2105679

Vascular permeability and coagulation during Rickettsia rickettsii infection in dogs.

1 finding

Experimental canine R. rickettsii infection links retinal vasculitic foci to altered vascular permeability and to thrombocytopenia with coagulation activation.

"Twenty-four to 48 hours after the onset of fever and rickettsemia, multifocal areas of retinal vasculitis were evident, which corresponded to areas of altered vascular permeability demonstrated by fluorescein angiography."

PMID:11179362

Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection.

1 finding

MHC class I knockout mice are dramatically more susceptible to lethal rickettsial infection, establishing CD8 T lymphocyte cytotoxicity as critical for clearing rickettsia-infected endothelium.

"immune clearance of rickettsial infection was more dependent on CD8 T lymphocytes, and there is evidence that CTL activity is a critical factor."

PMID:25827414

Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence in a mammalian model system.

1 finding

An isogenic rOmpA knockout in the virulent Sheila Smith strain did not attenuate virulence in guinea pigs, indicating redundancy among rickettsial adhesins rather than a single essential invasion factor.

"no significant difference in either fever peak (40.5 C) or duration (8 days) were shown between the wild type and the knockout"

PMID:28365226

Rocky Mountain spotted fever in Mexico: past, present, and future.

1 finding

A Lancet review documents the re-emergence of RMSF in Sonora and Baja California driven by domesticated dogs and brown dog ticks.

"Rocky Mountain spotted fever, a tick-borne zoonosis caused by Rickettsia rickettsii, is among the most lethal of all infectious diseases in the Americas."

PMID:25794784

No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever.

1 finding

Children who received doxycycline before 8 years of age showed no tetracycline-like staining and no difference in tooth shade or enamel hypoplasia, removing the historical barrier to doxycycline in young children.

"No tetracycline-like staining was observed in any of the exposed children's teeth (0/58, 95% CI 0%-5%), and no significant difference in tooth shade (P=.20) or hypoplasia (P=1.0) was found between the 2 groups."

PMID:16926398

Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins.

1 finding

Spotted fever group infection of human endothelial cells upregulates COX-2 and vasoactive prostaglandins, a mechanism contributing to inflammatory and vascular permeability changes in RMSF.

"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."

PMID:16360032

Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii.

1 finding

Ku70 was identified as a mammalian receptor engaged by rickettsial OmpB for host-cell entry, characterized for the closely related spotted fever group agent R. conorii.

"Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii."

Deep Research

1

Claude Code ▸

Rocky Mountain Spotted Fever (RMSF): Comprehensive Disease Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 28 citations 2026-08-02T14:22:09.406702

Rocky Mountain Spotted Fever (RMSF): Comprehensive Disease Research Report

1. Disease Information

Overview: Rocky Mountain spotted fever (RMSF) is a rare, acquired, life-threatening tick-borne infectious disease caused by Rickettsia rickettsii, an obligate intracellular, Gram-negative bacterium of the spotted fever group (SFG) rickettsiae. It is characterized by an acute onset of fever, malaise, and severe headache, followed in most patients by a characteristic centripetally-spreading petechial rash. It is the most severe and most frequently fatal rickettsial illness in the United States Orphanet: Rocky Mountain spotted fever.

Key Identifiers: - Orphanet ID: ORPHA:83311 - MONDO ID: MONDO:0019359 - ICD-10-CM: A77.0 - ICD-11: 1C31.0 - UMLS CUI: C0035793 - MeSH: D012373 (Rocky Mountain Spotted Fever) - No dedicated OMIM entry exists (RMSF is an acquired infectious disease, not a classically Mendelian OMIM phenotype)

Synonyms/alternative names: Tick typhus (Americas); "spotted fever" (historical, non-specific); São Paulo fever / febre maculosa brasileira (Brazilian form, caused by the same organism); New World spotted fever. Note: "spotted fever" as a general term (Wikidata Q9274700) also covers other SFG rickettsioses (Mediterranean spotted fever/R. conorii, etc.) and should not be conflated with RMSF specifically.

Data source type: Information is derived from aggregated disease-level resources (CDC national surveillance case counts, MMWR clinical guidelines, Orphanet/GARD rare disease summaries) and primary/case-series literature (individual patient case reports and cohort studies), rather than large-scale structured EHR datasets — consistent with a notifiable infectious disease under public health surveillance.

Sources: CDC – About RMSF, GARD, NORD, StatPearls

2. Etiology

Disease causal factor: RMSF is caused exclusively by infection with Rickettsia rickettsii (an obligate intracellular alphaproteobacterium, order Rickettsiales, family Rickettsiaceae), transmitted to humans via the bite of an infected hard tick. This is a purely infectious etiology — there is no known genetic disease-causing mutation; rather, host genetics modulates severity (see below), not occurrence.

Risk factors — environmental/exposure: - Tick exposure through outdoor occupational or recreational activity in endemic regions (camping, hiking, gardening, dog ownership) CDC Data & Statistics - Age >40 years is associated with highest reported incidence CDC - Male sex and possibly alcohol abuse are associated with increased risk of severe/fatal outcomes - Geographic residence in high-incidence states (North Carolina, Oklahoma, Arkansas, Tennessee, Missouri — >60% of U.S. cases) and in Arizona/northern Mexico border regions where Rhipicephalus sanguineus (brown dog tick)-associated epidemics produce unusually high incidence and case-fatality, particularly in children - Delay in initiating doxycycline (beyond day 5 of illness) is the single strongest modifiable risk factor for severe or fatal outcome

Genetic risk factor — G6PD deficiency: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked enzymopathy affecting ~10% of Black males in the U.S., is a documented genetic risk factor for fulminant RMSF (death by day 5 of illness). Walker et al. (PMID: 6687526) reported that "all three patients were male individuals of African descent with glucose-6-phosphate dehydrogenase (G6PD) deficiency," presenting with extensive thrombosis, fibrin thrombi at infection sites, absent/preterminal rash, severe pulmonary lesions, and shock-related organ damage including hepatic necrosis, despite minimal mononuclear inflammatory response on microscopy — an atypical, hyperacute pathological picture distinct from the classic vasculitic course.

Protective factors: No specific host genetic protective variant has been established. Prompt tick removal (reducing attachment time below the transmission threshold) and antimicrobial chemoprophylaxis are not recommended as primary prevention (post-exposure prophylactic antibiotics are explicitly discouraged by CDC because they may only delay, not prevent, illness).

Gene–environment interaction: The G6PD–RMSF interaction is the clearest documented gene-environment interaction: the underlying enzymatic deficiency does not cause disease alone but interacts with rickettsial infection (likely via unknown secondary effects of oxidative/hemolytic stress) to produce an accelerated, fulminant, thrombotic phenotype rather than the more typical subacute vasculitic course.

Suggested ontology terms: NCBITaxon:783 (Rickettsia rickettsii, per NCBI Taxonomy — verify directly), CHEBI/HGNC: G6PD (hgnc:4057).

3. Phenotypes

RMSF phenotypes are best organized as: (a) classic triad/early symptoms, (b) rash evolution, (c) gastrointestinal, (d) laboratory abnormalities, (e) neurological, (f) multi-organ/severe complications.

Classic triad

The classic triad of fever, headache, and rash is present in <5% of patients in the first 3 days of illness, rising to 60–70% by the second week CDC; emedicine. This low early sensitivity is the central diagnostic challenge in RMSF — treatment must not await the full triad.

Fever — HP:0001945 (Fever); nearly universal, acute onset
Severe headache (typically frontal) — HP:0002315 (Headache); majority of patients
Malaise/fatigue — HP:0033834 or HP:0012378 (Fatigue)
Myalgia — HP:0003326 (Myalgia)

Cutaneous

Rash — HP:0000988 (Skin rash). Occurs in ~90% of cases eventually, but only in 1–4 days after symptom onset and in <50% during the first 3 days of illness. Classic evolution: begins on ankles/wrists as small, discrete, macular, blanching, rose-colored lesions; spreads centripetally to trunk and head over hours to days; becomes papular, then petechial/purpuric by day 2–3 of rash CDC signs & symptoms.
Petechiae/purpura — HP:0000965 (Petechiae) / HP:0000978 (Bruising); a late, severity-associated sign
Histopathology (skin biopsy): lymphohistiocytic capillaritis and venulitis with perivascular/interstitial infiltrate and erythrocyte extravasation; leukocytoclastic vasculitis with neutrophilic infiltrate and nuclear dust seen in 73% of biopsies; fibrin thrombi and capillary-wall necrosis in a minority; immunohistochemical staining for R. rickettsii is positive in affected endothelium in nearly all confirmed cases but only ~70% sensitive overall (Kao et al., J Cutan Pathol 1997; PMC workup ref).

Gastrointestinal

Gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal pain) occur in up to 80% of patients; diarrhea in up to 45% — commonly leading to misdiagnosis as gastroenteritis, especially in children PMC8159303. - HP:0002018 (Nausea), HP:0002013 (Vomiting), HP:0002014 (Diarrhea), HP:0002027 (Abdominal pain), HP:0002039 (Anorexia)

Laboratory abnormalities

Thrombocytopenia — HP:0001873; ~60% of patients; mechanistically attributed to intravascular platelet consumption from vasculitic endothelial injury
Hyponatremia — HP:0002902; found in ~50–60% of cases, more common with CNS involvement, mechanistically linked to SIADH secondary to CNS vasculitis/inflammation
Elevated liver enzymes — HP:0002910 (Elevated hepatic transaminase); >70% of patients with enzyme testing show at least one abnormality
Elevated CSF protein/pleocytosis — CSF WBC >5/µL (pleocytosis) in 87.5% of meningoencephalitis cases; median CSF WBC 41 cells/µL; elevated protein (>50 mg/dL) in 87.5%; hypoglycorrhachia in 18.8% PMC5781900

Neurological (severe disease)

Meningoencephalitis — HP:0002480 or HP:0002383 (Encephalitis); altered mental status, focal neurologic deficits, increased tone, reflex abnormalities
Cerebral edema, cerebral infarction/stroke, cerebral vasospasm — HP:0002119 (Cerebral vasculitis-related); "starry sky" appearance on neuroimaging (perivascular/deep white-matter microinfarcts), especially in children
Autopsy in fatal RMSF encephalitis shows gliosis, demyelination, and necrosis in affected brain regions

Multi-organ complications (severe/fatal disease)

Hepatic injury, renal failure, lobar pneumonia (non-cardiogenic pulmonary edema), meningoencephalitis, cardiac or respiratory failure, and disseminated intravascular coagulation (DIC) — typically emerging 8–15 days after onset in untreated/undertreated patients.

Phenotype characteristics

Onset: Acute, 3–12 days post-tick-attachment (average ~7 days)
Severity: Highly variable — from self-limited febrile illness to fulminant multi-organ failure within 5 days (G6PD-deficient patients)
Progression: Rapidly progressive if untreated; can be halted/reversed with early doxycycline
Quality of life impact: Long-term sequelae in survivors of severe (especially pediatric encephalitic) disease include behavioral disturbances and learning disabilities as the most commonly reported long-term problems MedLink Neurology; limb amputation has been reported after severe peripheral vasculitis/gangrene in fulminant cases.

4. Genetic/Molecular Information

RMSF is not a Mendelian/monogenic disease — there is no causal human gene. The relevant "genetic/molecular information" for this KB entry is twofold: (a) the human host modifier gene (G6PD) affecting severity, and (b) the pathogen's molecular virulence determinants.

Host modifier gene: - G6PD (glucose-6-phosphate dehydrogenase; HGNC:4057; X-linked) — deficiency is a documented severity modifier associated with fulminant, rapidly fatal RMSF (PMID: 6687526). This is not a "pathogenic variant causing RMSF" in the classic sense but a modifier/susceptibility relationship (relationship_type: MODIFIER or SUSCEPTIBILITY in dismech schema terms) — no specific G6PD allele/variant was singled out in the literature beyond "G6PD deficiency" broadly (common variants: G6PD A- in African-descent populations).

Pathogen (R. rickettsii) virulence factors — molecular mechanism: - rOmpA (outer membrane protein A, gene ompA) — surface autotransporter protein conserved throughout the spotted fever group; implicated in adhesion to host cells. Notably, targeted knockout of ompA in R. rickettsii did not diminish virulence in a mammalian (guinea pig) model, indicating redundancy among adhesins (Noriea et al., mBio 2015; PMC4453529). - rOmpB (outer membrane protein B, gene sca5) — conserved across both spotted-fever and typhus groups; implicated in both adhesion and invasion via interaction with the host receptor Ku70. - Sca1, Sca2, Sca4 ("gene D") — additional surface-cell-antigen (sca) family autotransporter proteins; Sca1 is the only sca gene present in all sequenced Rickettsia genomes. - Host receptor Ku70 — a subunit of DNA-dependent protein kinase (DNA-PKcs), identified as a mammalian receptor mediating rickettsial (initially characterized for R. conorii, homologous mechanism proposed for R. rickettsii) internalization via OmpB–Ku70 interaction, requiring cholesterol-rich membrane microdomain ubiquitination (mediated by c-Cbl ubiquitin ligase) and engaging clathrin/caveolin-2-dependent endocytosis (Martinez et al., Cell 2005, PMID: 16360032). - Additional endothelial receptors implicated with partial (~40% each) contribution when silenced individually: α2β1 integrin, FGFR1, Epac1 — indicating multiple redundant invasion pathways. - Post-invasion, R. rickettsii rapidly escapes the transient phagocytic vacuole (via phospholipase activity) to replicate freely in the host cytoplasm by binary fission, and spreads cell-to-cell by hijacking host actin polymerization machinery (actin-based motility), analogous to Listeria/Shigella.

Functional consequence: Loss-of-function of individual adhesins does not abrogate virulence (redundancy), but disruption of the invasion/intracytoplasmic-survival machinery broadly is essential to intracellular parasitism and endothelial tropism.

Epigenetics / chromosomal abnormalities: Not applicable — RMSF has no described epigenetic disease mechanism or chromosomal abnormality; it is an acute bacterial infection.

Suggested ontology terms: hgnc:4057 (G6PD); GO:0044409 (entry into host), GO:0075512 (clathrin-dependent endocytosis of virus by host cell — analogous GO term set exists for bacteria under GO:0035821 modulation of process of another organism); CHEBI not directly applicable to pathogen proteins.

5. Environmental Information

Environmental/vector factors: - Primary tick vectors (United States): - Dermacentor variabilis (American dog tick) — most frequently associated with transmission; found in eastern, central, and Pacific coastal U.S. - Dermacentor andersoni (Rocky Mountain wood tick) — western U.S. vector - Rhipicephalus sanguineus (brown dog tick) — increasingly important vector in Arizona and along the U.S.–Mexico border, associated with unusually high incidence and case-fatality (especially pediatric) in that region - Free-roaming dog populations and peridomestic tick infestations are key amplifying factors in the brown-dog-tick-driven Arizona/Sonora epidemic - Tick attachment duration is a critical transmission determinant: unfed nymphs/adults require >10 hours of attachment for transmission, whereas ticks that have already partially fed can transmit in as little as ~10 minutes (reflecting rickettsial "reactivation"/increased virulence after a blood meal) — earlier literature commonly cites a 4–6 hour minimum attachment threshold. - Seasonality: Peak May–August (tick questing season), though cases occur year-round, especially in warmer southern latitudes.

Lifestyle factors: Occupational/recreational outdoor activity (agriculture, forestry, hiking, camping), dog ownership (dogs both serve as sentinel hosts and can carry ticks into the home/peridomestic environment).

Infectious agent: Rickettsia rickettsii — obligate intracellular, aerobic, Gram-negative coccobacillus; taxonomically placed in order Rickettsiales, family Rickettsiaceae, genus Rickettsia, spotted fever group. (NCBI Taxonomy ID for R. rickettsii should be independently confirmed at ncbi.nlm.nih.gov/taxonomy — not definitively retrieved in this search pass.)

Sources: CDC clinical overview, MMWR RR6502a1

6. Mechanism / Pathophysiology

Causal chain overview: Tick bite → dermal/subcutaneous rickettsial inoculation → hematogenous/lymphatic dissemination → endothelial cell invasion (via OmpA/OmpB-mediated adhesion, Ku70/integrin/FGFR1/Epac1-mediated receptor engagement, and cholesterol-microdomain-dependent, ubiquitin/clathrin/caveolin-2-facilitated endocytosis) → rapid escape from the phagosome into free cytoplasmic residence → intracellular replication and cell-to-cell spread via actin-based motility → direct and immune-mediated endothelial injury → disseminated small-vessel vasculitis → increased microvascular permeability, coagulation activation, and multi-organ dysfunction.

Endothelial injury and vascular permeability (central pathophysiologic event): "Fatal rickettsioses are fundamentally a vasculitis" — R. rickettsii directly infects microvascular endothelial cells throughout the body, and the dominant pathophysiological effect is markedly increased vascular permeability, producing vasogenic cerebral edema and non-cardiogenic pulmonary edema (Walker/Olano/UTMB review; ScienceDirect overview). A key molecular mechanism: rickettsial infection induces phosphorylation of VE-cadherin, directly attenuating homophilic adherens-junction protein–protein interactions, causing endothelial paracellular barrier dysfunction and microvascular hyperpermeability (Woods & Olano, PMC3373609). Rickettsial infection also disrupts and reduces the tight-junction protein zonula occludens-1 (ZO-1), associated with inflammasome activation (PMC11784141). Oxidative injury via generation of oxygen free radicals by infected endothelial cells further compounds membrane injury (PMID 9720025-class studies).

Coagulopathy/thrombocytopenia: Endothelial injury exposes subendothelial collagen/tissue factor, triggering platelet adhesion/activation and consumption (intravascular platelet destruction), together with mild activation of the coagulation cascade (increased fibrinogen, mildly prolonged aPTT) — producing the characteristic thrombocytopenia and, in severe/fulminant cases, disseminated intravascular coagulation with fibrin thrombi (PMID: 2105679, canine model). Retinal vasculitic foci correlate temporally (24–48h post-fever onset) with areas of altered vascular permeability, providing a directly visualizable model of the systemic process.

Immune response: Clearance of rickettsiae is critically dependent on cytotoxic CD8+ T lymphocytes and interferon-gamma (IFN-γ) — in murine models, MHC class I-knockout mice were >50,000-fold more susceptible to lethal rickettsial infection than wild-type, indicating CTL activity is more critical than IFN-γ effects alone for recovery (Walker, Olano, Feng; PMID: 11179362). CD4+ T cells also contribute via macrophage activation (iNOS/NO-mediated bactericidal activity), and macrophages/infiltrating T-lymphocytes produce cytokines that both control infection and, paradoxically, worsen vascular permeability/injury as part of the host inflammatory response to endothelial infection (PMC3691998, "Host Defenses to R. rickettsii Infection Contribute to Increased Microvascular Permeability").

Cellular processes and cell types involved: - Endothelial cells (primary target; CL:0000115 endothelial cell) — direct infection, junctional disruption, apoptosis-resistance subversion to prolong the intracellular replicative niche - Platelets (CL:0000233) — consumption/aggregation at sites of endothelial injury - Macrophages/monocytes (CL:0000235) and CD8+/CD4+ T lymphocytes (CL:0000625, CL:0000624) — immune clearance and inflammatory amplification - Perivascular dermal and CNS vasculature — site of clinically visible vasculitis (skin) and of encephalitis-associated microinfarction (brain)

Tissue damage mechanisms: Vasculitis-driven ischemia/microinfarction, vasogenic edema, oxidative stress, and (in fulminant G6PD-deficient cases) thrombotic microangiopathy with fibrin thrombi and organ necrosis (notably hepatic necrosis) in the near-absence of the typical mononuclear inflammatory infiltrate — suggesting a distinct, more hyperacute/thrombotic pathological subtype in this genetically susceptible group.

Suggested GO terms: - GO:0007566 / more precisely bacterial entry processes — GO:0044409 (entry into host), GO:0035821 (modulation of process of another organism) - GO:0016477 (cell migration) / actin-based motility analogous to GO:0030044 (in intracellular pathogen movement literature, often annotated under host actin cytoskeleton reorganization, GO:0030036) - GO:0034332 (adherens junction organization) — for VE-cadherin disruption - GO:0002532 (production of molecular mediator involved in inflammatory response), GO:0050818 (regulation of coagulation) - GO:0001525 (angiogenesis) not directly relevant; better: GO:0061028 (establishment of endothelial barrier), GO:0061028 disruption

Suggested CL terms: CL:0000115 (endothelial cell), CL:0000235 (macrophage), CL:0000624 (CD4-positive T cell), CL:0000625 (CD8-positive T cell), CL:0000233 (platelet)

7. Anatomical Structures Affected

Organ level: - Primary: Skin/cutaneous microvasculature (rash), systemic small blood vessels (arterioles, capillaries, venules) throughout the body — RMSF is fundamentally a systemic small-vessel vasculitis, not confined to one organ. - Secondary/complication organs: Brain (meningoencephalitis, cerebral edema, infarction — UBERON:0000955), lungs (non-cardiogenic pulmonary edema/ARDS — UBERON:0002048), liver (hepatocellular injury/necrosis — UBERON:0002107), kidneys (acute kidney injury — UBERON:0002113), heart (myocarditis/cardiac dysfunction — UBERON:0000948), gastrointestinal tract (UBERON:0001555, prominent early symptoms), retina (vasculitis visible on fundoscopy — UBERON:0000966), adrenal glands (case reports of adrenal hemorrhage/adrenalectomy) - Body systems involved: Integumentary, cardiovascular, nervous, respiratory, digestive, renal, hematologic/coagulation

Tissue/cell level: - Vascular endothelium (UBERON:0002316 blood vessel endothelium) is the principal cellular target — infection is fundamentally endotheliotropic - Dermal capillaries/venules (histopathology: lymphohistiocytic capillaritis/venulitis) - CNS white matter (perivascular microinfarcts, demyelination in fatal encephalitis)

Subcellular level: - Host cytoplasm (site of rickettsial replication after phagosomal escape) — GO:0005737 - Cholesterol-enriched plasma membrane microdomains (site of Ku70-mediated invasion) — GO:0005886 / lipid raft GO:0045121 - Adherens junctions (VE-cadherin) — GO:0005912; tight junctions (ZO-1) — GO:0005923

Localization: Systemic/disseminated — not focal or lateralized; skin rash is bilateral, acral-onset with centripetal spread.

8. Temporal Development

Onset: Acute; incubation period 3–12 days post-tick-attachment, average ~7 days (shorter incubation correlates with higher inoculum/exposure magnitude)
Onset pattern: Abrupt febrile illness
Progression: Classic disease course over the first 1–2 weeks: nonspecific febrile prodrome (days 1–3, often without rash) → rash onset (days 3–5) → petechial/purpuric evolution (days 5–7) → in untreated or delayed-treatment cases, multi-organ complications (days 8–15) → death (median around day 8–9 in fatal untreated cases; as early as day 5 in "fulminant" G6PD-deficient cases)
Disease course pattern: Monophasic acute illness (not relapsing-remitting); resolves fully with prompt treatment; can progress to fulminant multisystem failure without treatment
Duration: Self-limited with appropriate antibiotic therapy (clinical improvement typically within 24–72 hours of starting doxycycline); potentially fatal (days) without treatment
Remission: Treatment-induced; no spontaneous remission mechanism reported once vasculitic phase is established — untreated case-fatality is 20–30%
Critical period for intervention: Treatment initiated within the first 5 days of symptom onset is strongly associated with reduced morbidity/mortality — this is the single most important "critical window" in RMSF management

9. Inheritance and Population

RMSF is an acquired infectious disease with no Mendelian inheritance pattern. Population/epidemiological data:

Epidemiology: - 2023 U.S. surveillance: 1,205 cases of spotted fever rickettsioses (including RMSF) reported to CDC CDC Data & Statistics - Geographic concentration: >60% of cases in North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri - Distinct high-incidence/high-case-fatality foci: Arizona and northern Mexico border regions (brown-dog-tick-transmitted, disproportionately affecting children) - Seasonality: year-round with a strong May–August peak

"Inheritance"-analog (host modifier): G6PD deficiency is X-linked recessive (as a modifier, not disease-causing) — hemizygous males (and rarely homozygous females) are at higher risk for fulminant disease.

Population demographics: - Age: Highest reported incidence in adults >40 years old, but case-fatality is disproportionately high in young children (especially in the Arizona/brown-dog-tick epidemic) - Sex: Male sex is associated with increased risk of severe/fatal complications - Ethnicity/genetic background: African-descent males with G6PD deficiency are at particular risk for fulminant, rapidly fatal disease - Mortality: Case-fatality rate <0.5% with modern treatment nationally (varies significantly by region — much higher, historically 20-30%, in the pre-antibiotic/untreated era, and elevated in the Arizona tribal-community outbreaks)

Sources: CDC facts & stats, MMWR RR6502a1, PMC12928218 — pediatric mortality predictors, Sonora Mexico

10. Diagnostics

Clinical/laboratory tests: - PCR — detects R. rickettsii DNA from blood, plasma, or skin biopsy tissue; limited sensitivity early because the organism is endotheliotropic and does not circulate in large numbers in blood until disease is advanced; a negative PCR does not rule out RMSF and should never delay treatment CDC diagnosis/testing - Serology (IFA) — the standard serologic test is the indirect immunofluorescence assay (IFA) for IgG against R. rickettsii antigen; requires paired acute and convalescent sera 2–10 weeks apart demonstrating a ≥4-fold rise in titer; antibody titers are frequently negative in the first week of illness (a major diagnostic limitation — serology confirms retrospectively, it does not guide acute treatment decisions) - Skin biopsy with immunohistochemistry (IHC)/direct immunofluorescence — detects rickettsial antigen in endothelial cells of biopsied rash lesions; most sensitive in early disease before antibiotics are started, but available only at specialized reference laboratories (CDC); ~70% sensitivity even under optimal conditions - Laboratory abnormalities supportive of diagnosis (non-specific but pattern-suggestive): thrombocytopenia, hyponatremia, elevated hepatic transaminases, elevated CSF protein/pleocytosis in CNS disease - Imaging: Brain MRI in encephalitic cases may show the "starry sky" pattern of scattered perivascular/deep white-matter microinfarcts, meningeal enhancement, or cerebral edema

Genetic testing: Not applicable to the infection itself; G6PD enzyme activity testing (or genetic testing for G6PD variants) may be clinically relevant in patients (especially Black males) presenting with unusually fulminant/hyperacute RMSF, to explain severity and anticipate hemolysis risk, though this is not a diagnostic test for RMSF itself.

Clinical criteria: RMSF is a clinical diagnosis requiring empiric treatment — CDC/AAP explicitly recommend starting doxycycline based on clinical suspicion (fever + history of tick exposure in an endemic area/season ± rash) without waiting for laboratory confirmation, given the narrow therapeutic window. Case is classified as "probable" or "confirmed" retrospectively per CDC/CSTE surveillance case definitions (using the 4-fold IFA titer rise, PCR, IHC, or culture isolation as confirmatory criteria).

Differential diagnosis: Other spotted fever group rickettsioses, ehrlichiosis, anaplasmosis, meningococcemia, measles, enteroviral illness, viral exanthems, gastroenteritis (particularly in children, given the high frequency of GI symptoms), Kawasaki disease, drug reaction/Stevens-Johnson-type eruptions, leptospirosis, and dengue (in travel-relevant settings).

Screening: No population screening program exists; case-finding relies on clinical suspicion in tick-exposed patients during peak season in endemic regions.

Suggested NCIT terms: NCIT:C15473 (Polymerase Chain Reaction), NCIT:C15188 (Serology), skin biopsy → NCIT:C15230 (Biopsy Procedure)/immunohistochemistry NCIT:C16336.

11. Outcome/Prognosis

Mortality: - Untreated/inadequately treated: case-fatality historically 20–30% - Treated (modern era): case-fatality <1% overall; U.S. national surveillance estimates <0.5%, though this varies substantially by region, with much higher rates in specific high-burden pediatric/Indigenous-community outbreaks in Arizona/Sonora - Risk factors for fatal outcome: advanced age, male sex, delayed diagnosis/treatment (particularly beyond day 5), G6PD deficiency (fulminant subtype), possibly alcohol use disorder

Morbidity/complications: Hepatic injury, renal failure, pneumonia/ARDS, meningoencephalitis, cardiac/respiratory failure, DIC, digit/limb gangrene requiring amputation in severe vasculitic/thrombotic cases, and — in survivors of severe pediatric encephalitis — long-term behavioral disturbances and learning disabilities as the most commonly reported sequelae.

Recovery potential: Excellent with treatment initiated early (within 5 days) — most patients recover fully without sequelae. Recovery potential drops sharply once multi-organ vasculitic complications (renal failure, ARDS, DIC, encephalitis) have developed.

Prognostic factors: Time to treatment initiation (dominant factor), presence/severity of neurologic involvement, G6PD status, age extremes, and degree of thrombocytopenia/coagulopathy at presentation.

12. Treatment

Pharmacotherapy (first-line): - Doxycycline is the first-line treatment for all patients regardless of age, including children <8 years old and pregnant women — this is an explicit, evidence-based departure from the older tetracycline-class contraindication in young children. Multiple studies have shown that short courses (5–10 days) of doxycycline used for RMSF, even across up to five treatment courses before age 8, do not cause permanent tooth staining or enamel hypoplasia CDC — doxycycline & tooth staining research. Treatment should begin empirically based on clinical suspicion, ideally within the first 5 days of symptom onset, without waiting for laboratory confirmation. - NCIT term: NCIT:C820 (Doxycycline) under NCIT:C15986 (Pharmacotherapy) - Chloramphenicol — the only alternative agent with historical use, reserved for patients with life-threatening doxycycline allergy or in mild disease in pregnant patients; associated with increased mortality risk compared to doxycycline and carries risks of aplastic anemia and gray baby syndrome; oral formulation is not available in the U.S. - Explicit safety point: "Use of antibiotics other than doxycycline increases the risk of patient death" emedicine treatment

Pregnancy: Doxycycline is recommended as first-line even in pregnancy given the severity of untreated RMSF; available data suggest low risk of substantial teratogenicity at RMSF treatment dosing/duration.

Supportive care: Fluid/electrolyte management (for hyponatremia), transfusion support for severe thrombocytopenia/coagulopathy, ICU-level supportive care (mechanical ventilation, vasopressors, renal replacement therapy) for fulminant multi-organ disease. NCIT:C15747 (Supportive Care).

No vaccine currently exists for RMSF; prevention is entirely non-pharmacologic (see Section 13).

No targeted/gene/cell/immunotherapies are applicable — RMSF treatment is standard antimicrobial pharmacotherapy plus supportive care; there are no RMSF-specific clinical trials of novel therapeutics identified in this search (research is ongoing into recombinant rickettsial antigen vaccines, still preclinical/veterinary stage — see canine whole-cell antigen vaccine studies).

13. Prevention

Primary prevention (no vaccine available for humans): - Repellents: EPA-registered repellents containing DEET, picaridin, IR3535, oil of lemon eucalyptus (OLE), PMD, or 2-undecanone applied to skin - Acaricide/permethrin: 0.5% permethrin applied to clothing/gear (not skin) — effective at killing/repelling ticks - Protective clothing: long sleeves/pants, tucking pants into socks - Behavioral: avoiding tall grass, leaf litter, brushy trails, especially May–August in endemic regions - Post-exposure: full-body tick checks, checking pets/gear, showering promptly after outdoor exposure to remove unattached ticks (reducing the critical attachment-time window needed for transmission)

Secondary prevention: Prompt tick removal reduces transmission risk given the attachment-time dependence of transmission (though CDC does not recommend prophylactic antibiotics after a tick bite, as data do not support this practice preventing RMSF).

Public health/vector control: Environmental/peridomestic acaricide treatment and stray-dog population control have been used as public health interventions in the Arizona/Sonora brown-dog-tick epidemic (modeling studies on Rhipicephalus sanguineus control, PMC8951036).

Veterinary/One Health prevention: Tick control on dogs (topical/oral acaricides) reduces both canine disease and human exposure risk from peridomestic ticks, especially relevant to the brown dog tick transmission cycle.

Vaccine status: No licensed human vaccine; experimental whole-cell inactivated R. rickettsii vaccines have shown protective efficacy in the canine model (PMC12707144, PMC6346123) but are not available for human use.

14. Other Species / Natural Disease

Taxonomy: R. rickettsii naturally infects a broad range of vertebrate hosts and tick vectors across the Americas (North, Central, and South America — the same organism causing "febre maculosa brasileira" in Brazil).

Natural disease in companion animals — dogs (primary veterinary relevance): Dogs are naturally, highly susceptible to R. rickettsii infection and serve as important sentinel hosts due to high tick exposure. Clinical signs in dogs closely parallel human disease: high fever (up to 105°F/40.6°C), anorexia, lymphadenopathy, polyarthropathy, cough/dyspnea, abdominal pain, vomiting, diarrhea, and facial/limb edema Merck Veterinary Manual. A detailed natural-history study of experimentally tick-bite-infected dogs characterized clinical, hematological, molecular, and serological dynamics from exposure through convalescence and relapse (PMC4277292).

Comparative biology: The canine disease recapitulates the vasculitic/coagulopathic pathophysiology of human RMSF closely enough that experimental canine infection (via tick bite, the natural route) has been used as a translational model for vaccine development (whole-cell antigen vaccines protective in dogs, PMC6346123, PMC12707144) and for characterizing vascular permeability/coagulation pathophysiology (PMID: 2105679, foundational canine coagulation study).

Zoonotic/transmission considerations: RMSF is a zoonosis maintained in nature by tick–small-mammal (and, regionally, tick–dog) cycles; it is not communicable person-to-person (with rare, unconfirmed exceptions for blood transfusion; no documented transplant transmission). Dogs act as both amplifying/sentinel hosts and as tick-carriers into human peridomestic environments, making canine surveillance and tick control a key "One Health" intervention point, especially in the brown-dog-tick-driven Arizona epidemic.

15. Model Organisms

Mouse models: - C3H/HeN mice — described as providing "the best model to date for examining rickettsial disease with endothelial infection and injury." While much of the detailed published characterization uses the closely related R. conorii (Mediterranean spotted fever agent) in C3H/HeN mice — establishing disseminated endothelial infection by day 1, progressive rickettsemia, and death from vascular-injury-based meningoencephalitis and interstitial pneumonia by day 5–6 — this endothelial-target model system has also been used directly for R. rickettsii vaccine/pathogenesis studies. It recapitulates the core human pathophysiology: endotheliotropism, vasculitis-driven CNS and pulmonary injury. - MHC class I-knockout mice (C57BL/6 background) — used to demonstrate the essential role of CD8+ cytotoxic T lymphocytes in rickettsial clearance (>50,000-fold increased susceptibility to lethal outcome vs. wild-type) — a genetic immunodeficiency model rather than a disease-replicating model per se, but critical for defining protective immune mechanisms (PMID: 11179362). - Guinea pig model — used in virulence studies of R. rickettsii mutants (e.g., ompA knockout, which did not attenuate virulence), providing a classic rickettsiosis animal model with fever and scrotal/testicular necrosis as a virulence readout (Noriea et al., mBio 2015).

Canine model (natural/experimental): As above — the dog is both a natural disease host and a valuable experimental model (tick-bite-route infection) because it reproduces the vasculitic, coagulopathic, and clinical syndrome of human RMSF with high fidelity, and has been used for both pathophysiology studies (vascular permeability/coagulation, PMID 2105679) and vaccine efficacy testing.

Model limitations: Mouse models (especially with R. conorii rather than R. rickettsii itself) may not fully capture R. rickettsii-specific virulence factor biology (e.g., the ompA knockout virulence result may not generalize across species); the canine model, while pathophysiologically faithful, does not model human-specific risk factors such as G6PD deficiency-associated fulminant disease. No model has been reported that specifically recapitulates the G6PD-deficiency-associated fulminant/thrombotic human phenotype.

Applications: Endothelial infection/injury mechanisms, vascular permeability biology (VE-cadherin phosphorylation, ZO-1 disruption), immune clearance mechanisms (CD8+ T cell/IFN-γ dependence), and vaccine antigen efficacy testing (recombinant/whole-cell antigen protection studies in both mice and dogs).

Ontology Term Summary Table

Category	Suggested Term	ID
Disease	Rocky Mountain spotted fever	MONDO:0019359
Disease (Orphanet)	Rocky Mountain spotted fever	ORPHA:83311
Pathogen	Rickettsia rickettsii	NCBITaxon:783 (verify)
Gene (modifier)	G6PD	hgnc:4057
Phenotype	Fever	HP:0001945
Phenotype	Skin rash	HP:0000988
Phenotype	Petechiae	HP:0000965
Phenotype	Headache	HP:0002315
Phenotype	Thrombocytopenia	HP:0001873
Phenotype	Hyponatremia	HP:0002902
Phenotype	Elevated hepatic transaminase	HP:0002910
Phenotype	Encephalitis/Meningoencephalitis	HP:0002383
Phenotype	Vomiting	HP:0002013
Phenotype	Diarrhea	HP:0002014
Cell type	Endothelial cell	CL:0000115
Cell type	CD8-positive T cell	CL:0000625
Cell type	Macrophage	CL:0000235
Cell type	Platelet	CL:0000233
Anatomy	Blood vessel endothelium	UBERON:0002316
Anatomy	Brain	UBERON:0000955
Anatomy	Liver	UBERON:0002107
Treatment	Doxycycline	NCIT:C820 / CHEBI:50845
Treatment	Chloramphenicol	NCIT:C532 / CHEBI:17698

(Ontology mappings above are research suggestions and should be independently verified with OAK/runoak against the local sqlite adapters before use in a KB entry, per dismech curation SOP.)

Key Primary Sources Cited

Walker DH et al. Fulminant Rocky Mountain spotted fever and G6PD deficiency. Arch Pathol Lab Med 1983;107(3):121-5. PMID: 6687526
Martinez JJ et al. Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii. Cell 2005. PMID: 16360032
Feng HM, Whitworth T, Popov V, Walker DH. Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection. Infect Immun 2001;69:1841-6. PMID: 11179362
Noriea NF et al. Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence. mBio 2015. PMC4453529
Woods ME, Olano JP. Host defenses to Rickettsia rickettsii infection contribute to increased microvascular permeability. PMC3691998
Canine coagulation/vascular permeability study. PMID: 2105679
CDC. Diagnosis and Management of Tickborne Rickettsial Diseases, MMWR RR6502a1: link
CDC. Signs & Symptoms, Diagnosis/Testing, Clinical Care, Facts & Stats pages: cdc.gov/rocky-mountain-spotted-fever
Orphanet: ORPHA:83311; GARD: rarediseases.info.nih.gov

Note on gaps: No dedicated OMIM phenotype entry exists (expected, as RMSF is acquired/infectious). Precise NCBI Taxonomy IDs for Dermacentor variabilis/andersoni/Rhipicephalus sanguineus and confirmed R. rickettsii NCBITaxon ID were not definitively retrieved in this pass and should be looked up directly at ncbi.nlm.nih.gov/taxonomy before KB entry. No published RMSF-specific GWAS or additional host susceptibility loci beyond G6PD were identified.

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Deep Research

Rocky Mountain Spotted Fever (RMSF): Comprehensive Disease Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Classic triad

Cutaneous

Gastrointestinal

Laboratory abnormalities

Neurological (severe disease)

Multi-organ complications (severe/fatal disease)

Phenotype characteristics

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Ontology Term Summary Table

Key Primary Sources Cited