Streptobacillary Rat-Bite Fever

1. Disease Information

Overview. Streptobacillary rat-bite fever is a systemic febrile zoonosis caused by Streptobacillus moniliformis, "a systemic illness classically characterized by fever, rigors, and polyarthralgias" (PMID: 17223620). It is one of two classic forms of rat-bite fever; the other, more common in Asia, is caused by Spirillum minus (spirillary RBF / sodoku). This report concerns the streptobacillary form.

Key identifiers.

Synonyms and alternative names. Streptobacillary fever; streptobacillosis; Haverhill fever and erythema arthriticum epidemicum (the food/water-borne, ingestion-acquired form); epidemic arthritic erythema. "Rat-bite fever" is the umbrella clinical term shared with the spirillary form.

Source of information. The knowledge base entry is derived from aggregated disease-level resources — case reports, case series, and narrative reviews — rather than large structured EHR cohorts. The disease is rare and, in most jurisdictions, not nationally reportable, so "it may be more prevalent than currently recognized" (PMID: 42623631).

2. Etiology

Primary cause — infectious. The disease is caused by infection with Streptobacillus moniliformis, a fastidious, pleomorphic, Gram-negative bacillus that is a commensal of the rat naso-/oropharynx. A second species, S. notomytis, is now recognized as "a distinct species from Streptobacillus moniliformis — the primary causative agent of rat-bite fever" and "has been implicated in rare human infections" (PMID: 40472936).

Risk factors (environmental / behavioral). - Rodent exposure — bites, scratches, handling, or contact with rodent excreta. "Rat-bite fever follows exposure to contaminated bodily fluids of infected rodents" (PMID: 34323361). - Occupational exposure — pet-shop employees, laboratory-animal workers, and others in contact with rodents. A fatal case occurred in a 24-year-old pet-shop employee who "contracted the disease through a minor superficial finger wound on a contaminated rat cage" (PMID: 15029568). - Age and social factors — young children and people of low socioeconomic status are overrepresented; RBF has "potentially lethal course in a vulnerable population (children and low socioeconomic class)" (PMID: 34672901). - Pet-rodent ownership — an increasing driver as pet rats become more common.

Genetic risk / protective factors. Not applicable. No causal genes, susceptibility loci, modifier genes, protective alleles, or gene–environment interactions are described for this acquired infection.

3. Phenotypes

The hallmark is the clinical triad: physicians should consider RBF "when fever, rash, and exposure to rats are part of the patient's history" (PMID: 11724672); it presents as a "clinical triad of symptoms, fever, rash and arthritis" (PMID: 39267964).

RBF presents with "unspecific symptoms, including fever, arthralgia, and polymorphous skin lesions" (PMID: 34323361). Onset is adult or pediatric (any age), severity ranges from mild self-limited illness to fatal sepsis (variable), and progression is acute and may be episodic/relapsing if untreated. Quality-of-life impact during acute illness is substantial (fever, disabling polyarthritis) but, with prompt treatment, is typically fully reversible; formal EQ-5D/SF-36 data are not available for this rare disease.

4. Genetic / Molecular Information

Not applicable. Streptobacillary RBF is an acquired bacterial infection with no human causal genes, no inheritance pattern, no pathogenic germline or somatic variants, no disease-defining epigenetic mechanism, and no chromosomal abnormality. Sections on causal genes, pathogenic variants (classification, allele frequency, somatic vs germline), modifier genes, and host epigenetics are Not Applicable. The relevant "molecular" entity is the pathogen genome itself (NCBI:txid34105), not a host locus. The clinical characterization emphasizes an acute systemic infectious course rather than a genetic disease (PMID: 17223620).

5. Environmental Information

• Infectious agents. Streptobacillus moniliformis (primary) and S. notomytis (PMID: 40472936). Spirillum minus causes the separate spirillary form.
• Environmental / occupational factors. Contaminated rodent cages, bedding, feces, and urine; the disease can be acquired occupationally without a bite via a contaminated cage (PMID: 15029568).
• Transmission routes. (1) Rodent bite or scratch; (2) direct handling / contact with excreta — "Rat-bite fever follows exposure to contaminated bodily fluids of infected rodents" (PMID: 34323361); (3) ingestion of contaminated food/water = Haverhill fever. Reviews confirm cases "result from rodent bites or exposure to contaminated food or water" (PMID: 42732473).
• Lifestyle factors. Keeping pet rodents; occupations with rodent contact.

6. Mechanism / Pathophysiology

Ordered causal chain

1. Rodent reservoir colonization — S. moniliformis resides as a commensal of the rat naso-/oropharynx → the rat becomes an asymptomatic carrier and source.
2. Inoculation — a bite, scratch, mucosal/skin contact with excreta, or ingestion of contaminated food/water → introduces bacteria into host tissue (or gut, for Haverhill fever).
3. Local establishment and lymphatic spread — bacteria seed regional tissue → drain to regional lymph nodes (sinusoidal mononuclear infiltrates observed at autopsy).
4. Hematogenous dissemination (bacteremia) — organisms enter the bloodstream → systemic spread and constitutional symptoms (fever, rigors, myalgia). Documented: autopsy shows "sinusoidal mononuclear cell infiltrates in regional lymph nodes and the liver" (PMID: 2718962).
5. Branch A — direct septic seeding → the bacteremia deposits organisms in joints, cardiac valves, and bone → septic arthritis, infective endocarditis, osteomyelitis (PMID: 40472936, PMID: 15029568).
6. Branch B — immune-mediated injury → bacteremia/antigenemia triggers host immune responses → leukocytoclastic (small-vessel) vasculitis and reactive arthritis, with induced ANCA and anti-endothelial antibodies. Documented: "general weakness, intermittent fever, leukocytoclastic vasculitis, and arthritis are reported," and this was "the first reported case of ANCA positivity associated with RBF" (PMID: 37450033).
7. Convergence — tissue damage → both branches produce mononuclear/neutrophilic infiltration and fibrinous exudate → the acral rash, migratory polyarthritis, and, in severe disease, valvular destruction and multi-organ failure.
8. Terminal outcome (if untreated) → progressive sepsis, endocarditis, and multi-organ failure → death in ~10–13% of untreated cases.

Rat oropharyngeal commensal
│ inoculation (bite/scratch/contact/ingestion)
▼
   Local tissue seeding ── regional lymph nodes
│
▼
   BACTEREMIA (fever, rigors, myalgia)
│
   ┌────┴──────────────────────────┐
   ▼                               ▼
Branch A: septic seeding       Branch B: immune-mediated
(joints, valves, bone)         (LCV vasculitis, reactive
= septic arthritis,            arthritis, ANCA/anti-endothelial Ab)
endocarditis, osteomyelitis
   └───────────────┬───────────────┘
           ▼
Tissue injury: rash, polyarthritis,
valvular destruction, multi-organ failure
           ▼
Death (~10–13% untreated)

Cellular processes and immune involvement. Inflammation dominates, with mononuclear and neutrophilic infiltration, fibrinous endocarditis, mononuclear meningitis, hepatosplenomegaly, lymphadenopathy, and erythrophagocytosis on autopsy (PMID: 2718962). The immune-mediated branch can generate autoantibodies that mimic ANCA-associated vasculitis (PMID: 37450033).

Suggested ontology terms. GO:0006954 (inflammatory response); GO:0006935 (chemotaxis); GO:0002250 (adaptive immune response); GO:0006909 (phagocytosis, for erythrophagocytosis). Cell types: CL:0000775 (neutrophil), CL:0000235 (macrophage), CL:0000738 (leukocyte), CL:0000115 (endothelial cell, vasculitis target).

Molecular pathways / omics. No host signaling-pathway (Wnt/MAPK/mTOR/PI3K-AKT), transcriptomic, proteomic, metabolomic, or lipidomic disease signature is defined — as expected for an acute bacterial infection rather than a chronic host-driven disease. Molecular work centers on pathogen detection (16S rRNA, qPCR, mNGS), not host profiling.

7. Anatomical Structures Affected

Organ level (primary). Skin (rash), joints (arthritis), and blood (bacteremia). Secondary/complication organs. Heart valves (endocarditis; UBERON:0002134 tricuspid, UBERON:0002137 aortic, UBERON:0002135 mitral), bone (osteomyelitis; UBERON:0001474 bone tissue), meninges (UBERON:0002360), lungs (interstitial pneumonia), liver and spleen (hepatosplenomegaly), and kidneys (acute renal failure in severe sepsis).

Body systems. Integumentary, musculoskeletal, cardiovascular, hematologic/lymphatic, and — in disseminated disease — respiratory, hepatobiliary, renal, and central nervous systems.

Localization / lateralization. The rash is characteristically acral and often bilateral (hands and feet, including palms and soles); the arthritis is migratory and typically asymmetric/polyarticular.

Suggested UBERON terms. UBERON:0002097 (skin of body), UBERON:0002360 (meninges), UBERON:0001474 (bone tissue), UBERON:0000948 (heart), UBERON:0002405 (immune system), UBERON:0001456 (joint / articular structures).

8. Temporal Development

• Incubation. Typically 3–10 days after exposure for the streptobacillary form (Haverhill fever similar).
• Onset pattern. Acute/abrupt — fever, chills, myalgia, followed within days by rash and migratory polyarthritis.
• Disease course. If untreated, a relapsing/episodic fever pattern can occur, or progression over days-to-weeks to endocarditis and sepsis. A fatal pet-shop case progressed to death 59 days after the initiating injury (PMID: 15029568).
• With treatment. Resolution in days to a few weeks; the acute systemic illness is otherwise self-limited in some but unpredictably severe in others.
• Critical period for intervention. Early empiric antibiotic therapy (before endovascular seeding) is the decisive window; it "can prevent serious complications" (PMID: 41480582).

9. Inheritance and Population

• Inheritance / genetics. Not applicable — acquired infection with no heritable component, penetrance, expressivity, anticipation, founder effect, or carrier frequency.
• Epidemiology. Rare and underreported; not nationally reportable in most settings (PMID: 42623631). No reliable population prevalence/incidence figures exist.
• Age distribution. Skewed toward children — in a California reference-laboratory series, "50% of the isolates [were] from patients 9 years old or younger" (PMID: 11724672).
• Sex ratio. Approximately equal in the same series (roughly balanced sex distribution).
• Vulnerable groups. Children and people of low socioeconomic status (PMID: 34672901); occupationally exposed workers.
• Geographic distribution. Worldwide where rats and humans coexist; streptobacillary form predominates in the Americas and Europe, spirillary form (Spirillum minus) more common in Asia. The largest Canadian series reported 11 cases on Vancouver Island (2010–2016) (PMID: 31015812).

10. Diagnostics

Approach. Diagnosis requires a high index of suspicion anchored on the exposure history, because "Rat bite fever is a diagnosis that can be easily missed from both a clinical and a microbiological point of view" (PMID: 34672901) and "its nonspecific initial presentation combined with difficulties in culturing its causative organism produces a significant risk of delay or failure in diagnosis" (PMID: 17223620).

Microbiological detection.

Laboratory abnormalities. Nonspecific: leukocytosis/neutrophilia (or normal WBC), thrombocytopenia, elevated CRP (PMID: 41480582).

Diagnostic traps / serologic cross-reactivity. RBF has produced false-positive dengue IgM serology (PMID: 41245666) and induced ANCA/anti-endothelial antibodies mimicking ANCA-associated vasculitis (PMID: 37450033).

Differential diagnosis. Meningococcemia, disseminated gonococcal infection/gonococcal arthritis, Rocky Mountain spotted fever, secondary syphilis, infective endocarditis of other causes, reactive/viral arthritis, and systemic vasculitides (PMID: 34323361).

Genetic testing / omics diagnostics. Not applicable for host diagnosis; molecular tools target the pathogen.

11. Outcome / Prognosis

• Untreated mortality. RBF "carries a mortality rate of 10%" if untreated (PMID: 17223620); severe complications carry "a mortality rate as high as 13% without proper treatment" (PMID: 16858964, PMID: 42732473).
• Complications. Infective endocarditis (native and prosthetic valves; can require valve replacement), aortic root abscess, septic arthritis, osteomyelitis, meningitis, interstitial pneumonia, and refractory cardiogenic shock. A fatal case progressed to endocarditis "involving first the aortic valve and then the mitral valve and septum" (PMID: 15029568); another required VA-ECMO and died of refractory cardiogenic shock (PMID: 42732473).
• Recovery with treatment. Excellent — most patients recover fully with prompt, appropriate antibiotics.
• Prognostic factors. The dominant modifiable determinant is time-to-diagnosis/treatment; endovascular involvement (endocarditis) markedly worsens prognosis. Host genetic prognostic biomarkers do not exist.

12. Treatment

First-line pharmacotherapy. Penicillin is the standard therapy; RBF has an "almost omnisensitive susceptibility pattern" and responds to "a commonly available standard therapy (penicillin)" (PMID: 34672901). Penicillin G / amoxicillin are curative in uncomplicated disease.

Surgical / interventional. Valve repair/replacement for endocarditis; incision-and-drainage/debridement for abscesses and septic joints; mechanical circulatory support (ECMO) in refractory shock (often a marker of late presentation).

Advanced/experimental therapeutics, pharmacogenomics, immunotherapy, gene/cell/RNA therapy. Not applicable — this is a bacterial infection managed with standard antibiotics.

Suggested NCIT terms. NCIT:C1145 (Penicillin), NCIT:C299 (Amoxicillin), NCIT:C560 (Ceftriaxone), NCIT:C561 (Doxycycline), NCIT:C1728 (Ampicillin).

13. Prevention

• Primary prevention (behavioral/occupational). Avoidance of rodent exposure, personal protective equipment, and rodent control. "Keeping rats as pets cannot be recommended" (PMID: 34672901); "Education on hazards of animal contact and other preventive measures are needed in small places of business like pet shops" (PMID: 15029568).
• Wound care / post-exposure prophylaxis. Immediate cleansing of rodent bites/scratches and consideration of post-exposure antibiotic prophylaxis (penicillin/amoxicillin) after high-risk exposures.
• Secondary prevention. Early empiric therapy in exposed febrile patients prevents complications (PMID: 41480582).
• Immunization. No licensed human vaccine exists.
• Public-health measures. Rodent control, education, and improved clinical awareness; because the disease is not reportable, surveillance is limited.

14. Other Species / Natural Disease

• Reservoir. Rats (Rattus norvegicus, NCBI:txid10116) carry S. moniliformis as a nasopharyngeal commensal. The organism "is also a pathogen in certain laboratory and domestic animals" (PMID: 7707673).
• Natural / veterinary disease. Causes epizootics in mice (Mus musculus, NCBI:txid10090), disease in guinea pigs and other species, and recurs in barrier-maintained rodent colonies; it is an occupational hazard for laboratory-animal personnel (PMID: 7707673). Reported in a dog phlegmon.
• Zoonotic potential. High — pet and feeder murid rodents are documented sources of zoonotic Streptobacillus transmission in a global systematic review (PMID: 37643287).
• Taxonomy. Causative agents: S. moniliformis (NCBI:txid34105), S. notomytis (distinct species; PMID: 40472936).

15. Model Organisms

Because this is a naturally occurring zoonosis, "model organisms" are the natural rodent hosts rather than engineered genetic disease models. Laboratory mice and rats serve as infection/carriage models and are relevant to colony health and occupational exposure (PMID: 7707673). Guinea pigs and other laboratory species are naturally susceptible. No knockout/knock-in/transgenic host-genetic models are relevant, since there is no host genetic etiology. Research applications center on pathogen biology, transmission, diagnostics development (e.g., qPCR/mNGS validation using clinical and animal matrices; PMID: 35738493), and colony surveillance.

Mechanistic Model / Interpretation

The disease can be understood as a two-branch dissemination model downstream of a single initiating event (rodent-to-human inoculation of a rat commensal). The septic branch explains the most lethal manifestations (endocarditis, osteomyelitis, septic arthritis) via direct hematogenous seeding, while the immune-mediated branch explains vasculitic rash, reactive arthritis, and autoantibody phenomena. Both branches converge on inflammatory tissue injury that manifests as the classic triad and, when unchecked, multi-organ failure.

The overarching interpretation, synthesizing all 15 findings, is that danger in RBF is a function of recognition, not host susceptibility. The organism is nearly omnisensitive to antibiotics, so nearly all mortality is attributable to delayed diagnosis driven by nonspecific symptoms and difficult microbiology.

Evidence Base

Limitations and Knowledge Gaps

• Evidence quality. The literature is almost entirely case reports and small case series; there are no randomized trials or large prospective cohorts. Reported mortality (10–13%) derives from historical/aggregate reviews, not modern population data.
• Underreporting. RBF is not nationally reportable in most jurisdictions, so true incidence/prevalence are unknown and likely underestimated.
• Pathophysiology. The immune-mediated branch (vasculitis, ANCA induction) is documented in isolated cases; the mechanistic link (molecular mimicry vs. bystander activation) is inferred, not experimentally demonstrated.
• Species attribution. The clinical significance and relative frequency of S. notomytis vs S. moniliformis are only beginning to be resolved as sequencing supplants MALDI-TOF.
• No host-omics. As a non-genetic infection, there are no host transcriptomic/proteomic/metabolomic signatures, biomarkers, or genetic model organisms of the disease per se.
• Diagnostics. Molecular assays (qPCR, mNGS) are validated largely on mock/animal matrices; broad clinical validation and availability remain limited.

Proposed Follow-up Experiments / Actions

1. Prospective surveillance / registry. Establish a multicenter RBF registry (given non-reportable status) to quantify incidence, exposure patterns, species distribution (S. moniliformis vs S. notomytis), and outcomes.
2. Molecular diagnostic deployment. Validate and disseminate 16S rRNA PCR, triplex/multiplex qPCR (PMID: 35738493, PMID: 33618204) and mNGS in routine clinical labs, and standardize SPS-aware blood-culture protocols (PMID: 33693831).
3. Clinical decision support. Build an exposure-triggered alert ("febrile + rodent contact") to shorten time-to-empiric-therapy, the key outcome determinant.
4. Mechanistic studies. Investigate the immune-mediated branch — whether S. moniliformis antigens drive ANCA/anti-endothelial antibodies via molecular mimicry (PMID: 37450033).
5. Occupational/public-health intervention. Evaluate education and PPE programs for pet-shop and laboratory-animal workers, and formalize post-exposure prophylaxis guidance after rodent bites.
6. Species epidemiology. Systematically re-identify archived isolates by sequencing to define the burden of S. notomytis human disease.

Report compiled from 15 confirmed findings across 28 reviewed papers. Evidence source types: predominantly human clinical case reports/series and narrative reviews, with supporting in vitro/analytical diagnostic-development studies. This is an infectious, non-genetic disease; all host-genetic template sections are marked Not Applicable.

Artifacts

• OpenScientist final report
• OpenScientist final report

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Quotes not found in the cited source

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

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

• PMID:42732473 (abstract only): "a mortality rate as high as 13% without proper treatment"
• closest text in source: "BACKGROUND: Rat bite fever is a rare infection that can cause severe complications such as infective endocarditis with a mortality rate of 13% if left untreated"

Term Validation

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

Terms the report names something else

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

• MONDO:0020533 (2 mentions) - the report calls it "Mondo"; MONDO calls it streptobacillary rat-bite fever
• DOID:0050144 (1 mention) - the report calls it "Disease Ontology"; DOID calls it Kartagener syndrome
• UBERON:0001456 (1 mention) - the report calls it "joint / articular structures"; UBERON calls it face
• NCIT:C1145 (1 mention) - the report calls it "Penicillin"; NCIT calls it Lignan
• NCIT:C299 (1 mention) - the report calls it "Amoxicillin"; NCIT calls it Beclomethasone Dipropionate
• NCIT:C560 (1 mention) - the report calls it "Ceftriaxone"; NCIT calls it Hydroxyurea
• NCIT:C561 (1 mention) - the report calls it "Doxycycline"; NCIT calls it Ibuprofen
• NCIT:C1728 (1 mention) - the report calls it "Ampicillin"; NCIT calls it Celecoxib

Terms whose name is worth a second look

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

• HP:0001974 (1 mention) - the report calls it "Leukocytosis"; HP calls it Increased total leukocyte count, and lists "Leukocytosis" among its other names
• HP:0011227 (1 mention) - the report calls it "Elevated C-reactive protein"; HP calls it Elevated circulating C-reactive protein concentration, and lists "Elevated C-reactive protein level" among its other names
• GO:0006909 (1 mention) - the report calls it "phagocytosis, for erythrophagocytosis"; GO calls it phagocytosis
• CL:0000115 (1 mention) - the report calls it "endothelial cell, vasculitis target"; CL calls it endothelial cell
• UBERON:0001474 (2 mentions) - the report calls it "bone tissue"; UBERON calls it bone element, and lists "bones" among its other names
• UBERON:0002360 (2 mentions) - the report calls it "meninges"; UBERON calls it meninx