A Rodential Reckoning: A Case Report and Systematic Review of Streptobacillary Endocarditis

ABSTRACT Introduction Endocarditis is a rare, often fatal complication of rat bite fever caused by Streptobacillus moniliformis. Only 39 cases have been reported (including this case) as of 2022. We describe a case and aim to perform this entit’s first systematic literature review. Methods We performed a systematic review in CENTRAL, EMBASE, MEDLINE, SciELO, and LILACS. The terms used were terms used were (but not limited to) rat bite fever, Streptobacillus moniliformis, Spirillum minus, and endocarditis. We included all abstracts and articles with patients with echocardiographic or histologic-proven endocarditis. In case of discordance, a third reviewer was involved. Our protocol was submitted to PROSPERO (CRD42022334092). We also performed searches for studies on the reference list of included articles. Results We retrieved 108 and included 36 abstracts and articles. A total of 39 patients (including our report) were identified. The mean age was 41.27, and 61.5% were males. The most common findings were fever, murmur, arthralgias, fatigue, splenomegaly, and rash. Underlying heart disease was present in 33%. Exposure to rats was noted in 71.8% of patients, with 56.4% recalling a rat bite. Anemia was seen in 57%, leukocytosis in 52%, and elevated inflammatory markers in 58% that had lab work performed. The mitral valve was most affected, followed by the aortic, tricuspid, and pulmonary valves. Surgical intervention was required in 14 (36%) cases. Of those, 10 required valve replacement. Death was reported in 36% of cases. Unfortunately, the literature available is limited to case series and reports. Conclusion Our review allows clinicians to suspect better, diagnose, and manage Streptobacillary endocarditis.


INTRODUCTION
Rat bites have historically been associated with febrile disease, with rat bite fever (RBF) being an entity described in medical literature for about 2300 years, first reported in India. 1 Rodents carry microorganisms in their oral and nasopharyngeal membranes, which can inoculate humans through bites or transdermal contact with urine or feces. 2 These diseases were initially identified amongst rural communities and populations traditionally exposed to rodents.The advent of pet-keeping and the rise of occupations involving contact with rats, notably laboratory and pet shop workers, in the 21st century led to recent shifts in epidemiological trends in the western world. 3The disease has also been noted among snake-keepers, and some authors suggest that rat-consuming snakes could be temporary reservoirs for human infections. 4RBF has been attributed to two species of bacteria, Streptobacillus moniliformis, and Spirillum minus. 1 Spirillum minus has been documented in Asian countries, causing the Sodoku disease, which roughly translates to "rat-poison". 2 Streptobacillus moniliformis has been documented in North America 5 causing streptobacillary RBF if transmitted through bites.The disease transmitted via contaminated food or water has been described as Haverhill fever, a name derived from a town in Massachusetts wherein contamination of the raw milk at a local dairy farm gave rise to an epidemic among schoolchildren in 1926. 6Streptobacillus moniliformis is a non-motile, microaerophilic, Gram-negative rod-shaped bacterium that is a member of the family Leptotrichiaceae.It exhibits slow growth on anaerobic blood cultures, making laboratory identification challenging. 3,7F is a rare disease with a mortality rate of 13%. 1 The mortality rate is higher with complications like septic shock and endocarditis.The data on endocarditis is limited owing to the rarity of the disease, possible underdiagnosis, and underreporting.To our knowledge, only 38 cases have been reported between 1915 and 2022.We describe a patient who presented with an acute stroke weeks after she said being bitten by a rat and was later found to have infective endocarditis of her native mitral valve with cultures yielding Streptobacillus moniliformis.We also present a systematic review of all the cases of Streptobacillus moniliformis endocarditis reported to date.

CASE REPORT
A 75-year-old healthy, independent Caucasian female presented from home, endorsing worsening back pain for a week that limited her ability to walk around the house.She mentioned being bitten by a pet rat a few weeks prior, with subjective fevers and chills lasting for a few days after the bite without accompanying rashes or skin changes.She denied a personal history of intravenous drug use.She did not have previous valvular surgeries or any previous valvular lesions.Her medical history included osteoarthritis and hypertension.
At the emergency room, vitals were significant for a temperature of 37.6C, and pulse was measured at 86 beats per minute, respirations at 18 breaths per minute, blood pressure at 110/64 mm Hg with 97% oxygen saturation on room air.Her physical exam was significant for a systolic 2+ high-pitched murmur on the left fifth intercostal space on the midclavicular line.Her oral exam revealed poor dentition with caries, and the site of her reported rat bite on her right index finger showed a small well-healed wound.Labs on admission revealed a white blood cell count of 11.8x10 3 /mm 3 (reference range [RR]: 4-11.8x10 3 /mm 3 ), hemoglobin 10.1 g/dL (RR: 13-17.7g/dL),platelets 220x10 3 /mm 3 (RR: 150-450x10 3 /mm 3 ), sodium 138 mEq/L (RR: 136-145 mEq/L), potassium 3.5 mEq/L (RR: 3.4-5.3mEq/L), blood urea nitrogen 15 mg/dL (RR: 8-21mg/dL), creatinine 0.5 mg/dL (RR: 0.5-1.3mEq/L).High-sensitivity troponins were initially measured at 59.22 ng/L (RR: <14ng/L), with a repeat drawn a few hours later measured at 57.78 ng/L.An electrocardiogram on admission revealed sinus rhythm with no concerning ST-T wave changes with a few premature atrial contractions at a rate of 98 beats per minute.A chest X-ray revealed bibasilar opacities concerning atelectasis.
Cardiology was consulted for the troponin leak and recommended a transthoracic echocardiogram that revealed a preserved ejection fraction with no regional wall abnormalities.Valvular vegetations were initially not discerned.Given the absence of clinical features of the acute coronary syndrome, conservative management was pursued with plans for an outpatient ischemic evaluation.
On day three of hospitalization, she underwent a spine MRI that revealed a herniated disc at T11/T12.Following the scan, she experienced a new onset of verbal aphasia.CT imaging and angiography of the head and neck were unremarkable.She spiked a fever of 39.3C later that day.After repeat blood cultures, she was started on ceftriaxone and azithromycin for suspicion of lobar pneumonia based on new infiltrates on a repeat chest x-ray.Given persistent aphasia, she underwent a brain MRI that showed acute infarcts in the left parietal and frontal lobes and cerebellum (Figure 1), consistent with an embolic etiology.A transesophageal echocardiogram revealed marked thickening of the posterior mitral leaflet with a 12 mm complex echodensity adherent to the atrial surface (Figure 2).This was accompanied by moderate eccentric and posteriorly directed mitral regurgitation.
Blood cultures later revealed Gram-negative rods on the Gram stain in one of four bottles, speciated as Streptobacillus moniliformis.A peripherally inserted central line was subsequently placed, and she was prescribed a 6-week course of IV ceftriaxone at 1g/day.Her aphasia improved, and she was safely discharged with outpatient follow-up with Infectious disease.
The search was performed between April 28 th to 30 th , 2022.We included all abstracts and articles describing characteristics of patients with echocardiographic or histologic-proven (biopsy or autopsy) endocarditis due to Streptobacillus moniliformis or Spirillum minus.The pediatric and adult populations were included.Duplicated retrievals were excluded.In case of discordance, a third reviewer (CO) was involved in a final decision.We excluded articles, not in English,  Portuguese, French, or Spanish.We also searched for studies on the reference list of the included articles.
The information was extracted by AM and EMHP.It included sex, age, symptoms, laboratory findings, diagnosis of endocarditis, echocardiogram findings, involved valves, vegetation size, treatment and surgery performed, complications, and outcomes.Since this was a qualitative and systematic review, we did not perform a meta-analysis.Our protocol was submitted to PROSPERO (CRD42022334092).

RESULTS
We retrieved 108 results, and we included 36 abstracts and articles.Figure 3 shows the flow diagram according to PRISMA guidelines.There were a total of 39 cases reported  (including our case). We ecluded one duplicated case 42 .Table 1 presents the initial findings and work-up of rat bite endocarditis, while Table 2 presents the complications, treatment, and outcomes.

DISCUSSION
The clinical features of RBF encompass a variety of non-specific symptoms, challenging the diagnosis.Notable symptoms documented were fevers in 30% of patients, arthralgias and arthritis in 49%, lymphadenopathy in 25%, and morbilliform or petechial rash in 75%. 1,2The onset of symptoms is usually as early as 3 days and up to 2-3 weeks after exposure. 1,2ndocarditis is a rare complication of RBF, and only 39 cases have been reported.  Perur review, the mean age is 41 years, males are more affected, and children are affected in 50% of patients.As opposed to uncomplicated rat bite fever, streptobacillary endocarditis seems to have more specific symptoms.Rat bite fever usually manifests with fever, migratory polyarthralgia, and a rash, maculopapular or purpuric.Most patients with rat bite endocarditis present with a murmur, and almost one-fourth present with splenomegaly. 2Arthralgia, arthritis, and skin lesions are also common in rat bite endocarditis.The skin rash may also show findings typical of endocarditis, such as Osler nodes and splinter hemorrhages.As with any endocarditis, 43 underlying heart disease seems to be a risk factor.Interestingly there were 2 case reports of Streptobacillus moniliformis leading to endocarditis in patients with Tetralogy of Fallot, 30,37 and only one case in a patient with a mechanical valve. 29fortunately, concerning laboratory workup, almost one-third of the cases were reported in the first half of the 20th century [Cases Reported prior to1950], and many did not provide any laboratory workup.Anemia, leukocytosis, and elevated inflammatory markers are common findings.
The mitral valve is the most commonly affected valve accounting for 63.6% of the cases, followed by the aortic (31.8%), tricuspid (9%), and pulmonary (4.5%) valves.A similar pattern of valve involvement is seen in other infective endocarditis.Embolization does not seem to be a common phenomenon since there are only 4 cases, although the overall incidence of embolization in infective endocarditis, it is up to 44%. 44Organs affected in our series included the spleen, kidney, and brain.
Given the limited number of cases, there was variability in antibiotic choices for the treatment.The most commonly used antibiotic was penicillin.Ceftriaxone was the second most used antibiotic.Other antibiotics include chloramphenicol, streptomycin, gentamicin, amikacin, tetracycline, doxycycline, amoxicillin, piperacillin-tazobactam, cefuroxime, and meropenem.For our patient, we used ceftriaxone since it is considered one of the first-line antibiotics for rat bite fever with no endocarditis 1 and has been extensively and successfully studied for other etiologies of endocarditis. 43,45The role of surgical intervention is based on factors like abscess formation >1cm, poor response to antibiotics, large vegetations with embolic events, and heart failure or the development of cardiogenic shock. 43,45In our review, surgical intervention was required in 14 cases.Of those, 10 required valve replacement.
Death has been reported in 13 cases (36%); however, 6 of them occurred in the first half of the 20th century, and only 7 of the deaths were patients who failed antibiotic therapy.The mortality of rat bite endocarditis is much higher when compared to uncomplicated rat bite fever, which, when untreated, can cause death in up to 13% of patients. 1

CONCLUSION
This case comprises an interesting series of events that began with a rat bite and eventually culminated with the identification of vegetation on the valves of the heart and Streptobacillus moniliformis in the blood.Our systematic review aims to shed light on a rare complication of a disease with high morbidity and mortality.Understanding clinical profiles may help clinicians better suspect, diagnose, and manage Streptobacillary endocarditis.

Figure 1 .
Figure 1.FLAIR MRI section showing in A -strokes in the left cerebellar; and in B -left parietal (B) regions of the brain, concerning an embolic etiology.(FLAIR: Fluid Attenuated Inverse Recovery; MRI: Magnetic Resonance Imaging).

Figure 2 .
Figure 2. Trans-esophageal echocardiography showing a 12 mm-sized mobile atrial vegetation with marked thickening of the posterior mitral leaflet.

Table 3 summarizes
the most common presentations, laboratory work-up, complications, echocardiogram findings, and mortality.

Table 2 .
Complications, treatments offered and outcomes

Table 3 .
Summary of findings