# Rat Bite Fever Resembling Rheumatoid Arthritis

Authors: Ripa Akter; Paul Boland; Peter Daley; Proton Rahman; Nayef Al Ghanim
Journal: Canadian Journal of Infectious Diseases and Medical Microbiology
 (2016)

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## Abstract

Rat bite fever is rare in Western countries. It can be very difficult to diagnose as blood cultures are typically negative and a history of rodent exposure is often missed. Unless a high index of suspicion is maintained, the associated polyarthritis can be mistaken for rheumatoid arthritis. We report a case of culture-positive rat bite fever in a 46-year-old female presenting with fever and polyarthritis. The clinical presentation mimicked rheumatoid arthritis. Infection was complicated by discitis, a rare manifestation. We discuss the diagnosis and management of this rare zoonotic infection. We also review nine reported cases of rat bite fever, all of which had an initial presumptive diagnosis of a rheumatological disorder. Rat bite fever is a potentially curable infection but can have a lethal course if left untreated.


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## Body

## 1. Introduction

Rat bite fever (RBF) is a systemic febrile illness caused by eitherStreptobacillus moniliformis, common in Western countries, orSpirillum minus, which is the most prevalent pathogen in Asia [1, 2]. It is transmitted to humans by bites or scratches from infected rats. Classic clinical features include fever, rash, and polyarthritis [1]. When RBF presents with symmetrical polyarticular synovitis, rheumatoid arthritis may initially be diagnosed incorrectly, leading to delay in appropriate therapy [3–7]. Complications of RBF include septic arthritis, endocarditis, and rarely discitis, as in our patient. The mortality rate of untreated cases ranges from 7% to 13% and for cases complicated by endocarditis it can be up to 53% [1, 2].


## 2. Case Report

A 46-year-old female was admitted with a one-week history of fever and symmetric polyarthritis of the distal upper and lower extremities, with thirty minutes of morning stiffness. A few days prior to her admission, she had a one-day history of nausea, vomiting, and diarrhea. She denied recent travel or illicit drug use. Her previous medical history was significant for a seizure disorder, irritable bowel syndrome, chronic mechanical back pain, and iron deficiency anemia. Her family history was unremarkable for any rheumatological illness.On examination, she was febrile (38°C), tachycardic (130 beats per minute), and hypotensive (96/64 mmHg). The most prominent physical finding was effusions in her wrists, ankles, and selected metatarsophalangeal joints. Her cardiopulmonary, abdominal, and dermatological examinations were otherwise unremarkable. Erythrocyte sedimentation rate was 76 mm/hr (normal: 0–12 mm/hr) and C-reactive protein was 149 mg/L (normal: 0–8 mg/L). There was a mild leukocytosis of 11.1 × 109/L (normal: 4.8–10.8 × 109/L). Initial blood culture and serological tests including hepatitis B and hepatitis C, parvovirus B19, HIV, Lyme disease,Chlamydia trachomatis, andNeisseria gonorrhea were negative. Rheumatological workup including rheumatoid factor, anti-nuclear antibody, anti-cyclic citrullinated peptide antibody, anti-neutrophil cytoplasmic antibodies, anti-dsDNA antibody, and complement levels was all within normal limits. Chikungunya virus serology was not ordered as this diagnosis was unlikely given she had not travelled. A presumptive diagnosis of seronegative rheumatoid arthritis was made, based on the clinical presentation of symmetrical inflammatory polyarthritis and negative infectious workup. She was started on a trial of oral prednisone. She experienced mild improvement in her synovitis. She was discharged home on triple therapy for rheumatoid arthritis which included methotrexate, sulfasalazine, and hydroxychloroquine.The patient returned to the hospital next day with worsening synovitis, fever (39°C), and new onset of back pain localized to the lumbar spine. Sulfasalazine and methotrexate were discontinued because of a new transaminitis (aspartate aminotransferase 105 U/L (normal: 0–37 U/L); alanine aminotransferase 114 U/L (normal: 0–55 U/L)). The ESR was elevated at 124 MM/HR and C-reactive protein at 170 mg/L. Right ankle aspiration was performed followed by methylprednisolone injection due to ongoing severe pain. The synovial fluid sample was inadequate for gram stain; however, the culture was negative. She then received intravenous methylprednisolone, 250 mg every 24 hours for 2 days without improvement. Repeated blood culture grewStreptobacillus moniliformis in the anaerobic flask. MRI revealed L5-S1 discitis (Figure 1) and transthoracic echocardiogram showed no evidence of endocarditis. On further questioning, the patient admitted to having a pet rat and a pet cat, both of which had died of an unknown illness in the week prior to the initial presentation to hospital. The patient was told by a local veterinarian that the rat was “in kidney failure” though further details are unavailable. The patient spent the night prior to the death of the rat comforting the ailing animal in her arms. During this time, she received a scratch to her chest.Figure 1
Sagittal MRI pulse sequences of lumbosacral spine at presentation. (a) (T1-weighted) shows markedly reduced signal at the L5-S1 level while (b) (T2-weighted) shows increased T2 signal both in keeping with edema. (c) shows enhancement of the vertebral end plates. All findings are in keeping with discitis.
(a)
(b)
(c)A diagnosis of RBF was made. The patient then was treated with intravenous ceftriaxone with discontinuation of steroids and hydroxychloroquine with symptomatic improvement. She was discharged home with a 3-month course of intravenous ceftriaxone on the advice of infectious disease and neurosurgery specialists to ensure resolution of her discitis. Three months after discharge, the patient was well with complete resolution of her arthritis, marked improvement in the lower back pain, and normal inflammatory markers. A repeat MRI showed resolution of the discitis.


## 3. Discussion

Streptobacillus moniliformis is not routinely reported to public health authorities in most jurisdictions, and hence the true incidence rate is unknown. We report a challenging case of RBF with discitis involving L5-S1, which was initially presumed to be rheumatoid arthritis. RBF with discitis is extremely rare. To our knowledge, this is the third reported case of discitis associated with rat bite fever. Dubois et al. reported a case of RBF with spondylodiscitis involving T5-T6 and L2-L3 [12]. Nei et al. described another case of discitis involving L3-L4 [13].Apart from direct rat bite or scratch, infection can also spread to humans by bites or scratches from animals that prey on rodents, such as cats, dogs, and pigs [8].Streptobacillus moniliformis is part of the normal nasopharyngeal flora of rats. Other rodents such as mice, guinea pigs, ferrets, squirrels, and gerbils also colonize this bacteria [7]. Ingesting contaminated food products can also cause RBF, as described in Haverhill, Massachusetts, in 1926 [8]. RBF in farmers due to ingestion of unpasteurized milk has been reported [8]. Pet owners, children, and those working in pet shops and animal research laboratories are at an elevated risk of contracting this infection [14]. Ninety percent of patients develop fever within 3–10 days of exposure, which can follow a relapsing pattern [2]. Typically a maculopapular, petechial, or purpuric rash is seen in the extremities and biopsy is consistent with a leukocytoclastic vasculitis [2, 15, 16]. Other symptoms include vomiting and headache [14]. A migratory polyarthritis is seen commonly affecting the hands, wrists, elbows, knees, and, rarely, the sternoclavicular and sacroiliac joints [2, 3, 17, 18].Streptobacillus moniliformis septic monoarthritis is described, in some cases requiring surgical debridement [19, 20]. Additional complications include osteomyelitis, pericardial effusion, endocarditis, pneumonia, meningitis, and multiorgan failure [1, 2, 14, 20].The pathogenesis of arthritis in RBF is multifactorial. Systemic symptoms, such as fever and rash, may occur with a sterile synovial fluid culture, suggesting a reactive phenomenon due to an immune mediated process. In other cases, synovial fluid cultures are positive with or without bacteremia suggesting a direct infectious process [4, 21, 22]. Features that suggest an immune mediated phenomenon may include vasculitic rash, hypocomplementemia, and cryoglobulinemia [23]. Wang and Wong suggest that septic arthritis caused byStreptobacillus moniliformis detected in synovial fluid without bacteremia is a separate entity with distinct clinical features in which fever and rash are uncommon [21].The diagnosis of RBF can be challenging as blood cultures are usually negative [14].Streptobacillus moniliformis is a facultatively anaerobic, highly pleomorphic gram negative bacillus [21]. Bacteria can vary in length from two to fifteen μm. Its growth can be inhibited by sodium polyanethol sulfonate, an anticoagulant found on most aerobic culture bottles [21]. Therefore, this organism is more likely to grow in anaerobic cultures [3]. Positive blood, synovial fluid, or rarely skin lesion culture followed by identification using gas chromatography or sequencing of 16 s rRNA genes can confirm the diagnosis [3–6, 16]. Up to 25% of affected patients may have a false positive serology test for syphilis [23].Although this infection is difficult to diagnose, its prognosis is favorable. The standard treatment of RBF is penicillin or, in the case of penicillin allergy, tetracycline [21].Streptobacillus moniliformis is also susceptible to cephalosporins, carbapenems, erythromycin, and clindamycin [21].Table1 summarizes nine cases of RBF mimicking a rheumatological disorder. Six out of the nine cases received steroid therapy (Table 1). In a case described by Tattersall and Bourne, a patient received cyclophosphamide when inflammatory vasculitis was suspected (Table 1). These cases highlight the importance of maintaining a broad differential that includes RBF when assessing potential cases of rheumatoid arthritis. The positive blood culture was the main clue to the diagnosis in our case. This case report also highlights the potential hazard of misdiagnosis and treatment with immunosuppressive agents. Infectious etiology is always on the differential, such that a zoonotic exposure history and blood cultures should be obtained when assessing a patient with fever and arthritis. Also occupational, travel, and recreational history should be sought for potential rodent exposure in suspected cases.Table 1
Reported Cases of Rat bite fever with initial presumed diagnosis of rheumatological disorders.
Study/year/[reference]
Age/sex
Rat bite/scratch
Occupation
Family history of rheumatological disorders
Clinical features
Affected joints
Joint aspirate analysis
Joint aspirate culture
Identification method ofStreptobacillus moniliformis
Blood culture
Rheumatological workup
Joint erosion
Initial presumed diagnosis
Treatment
Outcome
Legout et al./2005[3]
60/female
Rat bite
Pet  shop employee
Father- seropositive rheumatoid arthritis
Fever and polyarthritis
Symmetrical affecting small joints of both hands and ankles and right knee
Right knee synovial fluid: leukocytosis (40 × 109/L) with 90% neutrophils
GNB
PCR amplification of part of 16S RNA gene
Negative
RF, ANA, ANCAs, specific anti-filaggrin antibody, and cryoglobulin were negative
No erosion
Rheumatoid arthritis
Initial: NSAIDs and IV  methylprednisolone 500 mg/day for 3 days, no improvement Postculture: arthrotomy of right knee and 4 weeks of antibiotics which included IV penicillin followed by oral rifampin and clindamycin
Successfully treated
Dendle et al./2006[4]
49/female
Rat bite
Not reported
Not reported
Polyarthritis, fever, rash, pneumonia, and hepatitis
MCP, wrists, knees, right elbow, and right ankle
Right elbow: numerous PMNNo formal analysis-sample clotted
Pleomorphic GNB
16S rRNA gene sequencing
Negative
ANA and RF compliment levels were normal
No erosion
Rheumatoid arthritis or Still’s disease
Initial: oral prednisone 25 mg daily with worsening synovitis Postculture: doxycycline 100 mg twice daily for 6 weeks
Successfully treated
Stehle et al./2003[5]
72/male
Rat bite
Not reported
Not reported
Polyarthritis
Both knees, elbows, and left 3rd MCP
Right Knee: leukocytosis(around 50 × 109/L) with 83% neutrophils Rearthrocentesis of both knees, right elbow, and left 3rd MCP: analysis not reported
Streptobacillus moniliformis grew on repeat synovial fluid culture
16S rRNA gene sequencing
Negative
Not reported
No erosion
Atypical rheumatoid arthritis
Outpatient:  NSAID and deflazacort for almost 1 month, no improvement Postadmission: bolus of IV steroids, minimal improvement Postculture: broad spectrum antibiotics
Successfully treated
Holroyd et al./1988[6]
59/male
No
Not reported
Not reported
Fever and polyarthritis
PIP, MCP, wrist and knees, ankles, elbows, and shoulders bilaterally
Left knee: leukocyte 3,700/mm3 with 80% PMN Left wrist: 57,000/mm3 and 90% PMN
Left wrist:pleomorphic GNB with bullous swelling
Gas chromatography of the cellular fatty acid of organism
Streptobacillus moniliformis
Negative RF and weakly positive ANA 1 : 40
Not reported
Rheumatoid arthritis
Outpatient: patient took NSAIDs for 1 day prior to admission Postculture:  ticarcillin and gentamicin; penicillin G for total 10 days
Successfully treated
Kanechorn and Niumpradit/2005 [7]
61/female
Rodent bite
Retired nurse
Not reported
Fever, petechial rash, myalgia, and symmetrical polyarthritis
Fingers, wrists, knees, and ankles
Site of joint aspiration not reported.Analysis: leukocyte counts of over 64,000 cells/mm3 and all neutrophils
Negative
Not reported
Negative
ANA and RF  negative
Not reported
Septic arthritis and rheumatoid arthritis
Initial: erythromycin, Ibuprofen as well as rabies vaccination and tetanus toxoid prior to admission Postadmission:  dexamethasone 4 mg every 6 hours,  amoxicillin/clavulanic acid plus doxycycline, no improvement After joint analysis: ceftriaxone and penicillin G for 4 weeks, arthrotomy and debridement of joints, unreported sites of joints
Successfully treated
Abdulaziz et al./2006[8]
68/male
Rat exposure, no bite
Dairy farmer
Not reported
Symmetrical polyarthritis, rash, fever, myalgias, and headache
PIP’s, MCP’s, wrists, ankles, and knees
Left knee: white blood cell count of 19,250/mm3, 84% PMN leukocytes, and CPPD crystals
Negative
Not reported
Pleomorphic gram negative bacilli
Not reported
No erosion
Acute polyarticular pseudo gout
Initial:  ibuprofen and NSAIDs Postculture:  penicillin G for 14 days successfully treated
Successfully treated
Tattersall and Bourne/2003[9]
56/male
Rat bite
Not reported
Not reported
Fever, rash, asymmetric polyarthritis, hand ischemia, sore throat, and loose stools
Right elbow, wrist, shoulder, left thumb MCP joint, both midtarsal joints, and right ankle
Left thumb MCP: analysis not reportedLeft ankle: urate crystals
Gram negative pleomorphic coccobacillusStreptobacillus moniliformis
DNA sequencing
Negative
Autoantibodies and ANCAs were negative
Not reported
Vasculitis or  reactive arthritis
Initial: IV methylprednisolone and cyclophosphamide for few days with minimal improvement Postculture: oral doxycycline for 6 weeks
Successfully treated
Dworkin et al./2010[10]
59/male
Rat exposure,  no bite
Not reported
Not reported
Polyarthritis, diarrhea, malaise, and presumed endocarditis
knees, ankles, wrists, right elbow
Left knee: analysis not reported
Pleomorphic GNB
16S rRNA gene sequencing
Negative
ANA elevated 1 : 160 and normal compliment, RF and, ANCA levels
Not reported
Polyarthritis of infectious or collagen vascular disease etiology
Initial: NSAIDs and steroids Postculture: penicillin, doxycycline, and gentamycin for 6 weeks
Successfully treated
Budair et al./2014[11]
29/male
Rat exposure
Manual laborer in a warehouse
Not reported
Malaise, fever, sore throat, rash, and polyarthralgia
Right second MCP, right elbow, right knee and both ankles
Right ankle aspiration: yellow cloudy fluidAnalysis not reported
Culture negative
16S rRNA PCR identified organism
Negative
ANA, double stranded DNA antibody, glomerular basement membrane antibody, myeloperoxidase antibody and proteinase-3 antibodies, RF, and immunoglobulins were all normal
Not reported
Vasculitis
Postorganism identification: intravenous benzylpenicillin and 3 weeks of oral amoxicillin
Successfully treated
GNB: gram negative bacilli; PIP: Proximal Interphalangeal; MCP: metacarpophalangeal; RF: rheumatoid factor, ANA: anti-nuclear antibody, ANCA: anti-neutrophil cytoplasmic antibody; NSAID: nonsteroidal anti-inflammatory drug; IV: Intravenous; PCR: polymerase chain reaction; PMN: Polymorphonuclear; CPPD: calcium pyrophosphate dihydrate.



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