Which Animal Bite Could Cause This Patient’s Fever and Shortness of Breath?

A 74-year-old Caucasian male with severe Alzheimer’s disease presented to the emergency department with fever, lethargy, and a rash. Four days prior to presentation, he sustained an animal bite on his right hand while alone in his home garden. His wife cleaned the wound with soap and water, but no further medical attention was sought. The patient was unable to describe the animal that had bitten him or the circumstances around the event. 

Over subsequent days, he developed swelling and erythema of the right hand that extended up to the elbow, with fever, rigors, shortness of breath, and progressive difficulty ambulating.

Physical Examination

The patient appeared comfortable but was febrile to 101.8°F. His conjunctiva were clear, with anicteric sclera and a clear oropharynx. He had no cranial nerve deficits and was able to follow simple commands and move all extremities. 

His neck was supple, not tender, and he did not have cervical, axillary, or inguinal lymphadenopathy. Respiratory, cardiac, and abdominal examinations were normal. 

A dry punctate wound on the right hand between the second and third metacarpals was evident, without surrounding erythema or discharge, and there was a diffuse macular rash on his bilateral upper and lower extremities with involvement of the palms (Figure). 

He had no joint effusions or limitations in range of motion. 

Laboratory Tests

Laboratory testing revealed a neutrophil predominant leukocytosis with a white blood cell count of 18,900/µL, 87% neutrophils (normal: 4000/µL-11,000/µL, 45% to 75% neutrophils), a mildly elevated asparate transaminase of 38 U/L (normal 7 U/L-37 U/L), and an elevated total bilirubin of 2.4 mg/dL (normal: 0.3-1.2 mg/dL). 

His urine analysis and creatinine levels were normal. A chest x-ray showed no acute cardiopulmonary abnormalities. 

The emergency department physician admitted the patient, obtained blood cultures, and started intravenous piperacillin-tazobactam. Public health officials were consulted.

(Answer and discussion on next page)

Answer: Rat Bite 

Laboratory Tests

Laboratory testing revealed a neutrophil predominant leukocytosis with a white blood cell count of 18,900/µL, 87% neutrophils (normal: 4000/µL-11,000/µL, 45% to 75% neutrophils), a mildly elevated asparate transaminase of 38 U/L (normal 7 U/L-37 U/L), and an elevated total bilirubin of 2.4 mg/dL (normal: 0.3-1.2 mg/dL).

His urine analysis and creatinine levels were normal. A chest x-ray showed no acute cardiopulmonary abnormalities.

The emergency department physician admitted the patient, obtained blood cultures, and started intravenous piperacillin-tazobactam.

Diagnosis

The inability of the patient to identify the biting animal allowed for a wide array of possible infections. The predominant pathogens in bite wounds include the normal oral flora of the biting animal in addition to human skin flora.¹

 Among other pathogens, dog and cat bites can transmit Capnocytophaga canimorsus or Pasteurella multocida respectively, each of which can result in rapidly progressive and severe skin and soft tissue infection or sepsis. Rodents such as rats, chipmunks, or squirrels can carry and transmit Streptobacillus moniliformis, or rat bite fever, while raccoons and other mammals can transmit rabies virus. Rabbits are a recognized reservoir of Francisella tularensis, although this pathogen more commonly causes a severe respiratory infection. Outdoor exposure allows the possibility of tick bites that can transmit Rickettsia, Lyme disease, Ehrlichia chaffeensis, and human granulocytic anaplasmosis, however these infections are generally geographically distributed so the location within the United States the exposure occurred is important. Bites and envenomation from spiders, namely the brown recluse spider, can cause a serious illness with necrosis at the bite site.

Follow-Up Testing

Following admission, the patient became progressively less cooperative, attempted to bite a nurse, and became somnolent with whole-body rigidity. An Infectious Diseases physician and the Monroe County Department of Public Health (MCDPH) were contacted regarding suspected rabies infection. MCDPH consulted with the New York State Department of Health (NYSDOH) and clinical rabies was ruled out, but the patient was eligible for rabies immunoglobulin and vaccine.

However, the combination of a fever with a macular rash following a bite from an unknown animal raised the concern for rat bite fever. Serum and cerebrospinal fluid analysis was negative by cultures, including testing for viral encephalitis, West Nile serum and cerebrospinal fluid IgM and serum IgG, Lyme disease antibody, and Treponema pallidum antibody.

An EEG showed mild to moderate encephalopathy and no seizure activity. Admission blood cultures at RGH were negative, and additional samples were sent to the NYSDOH for further testing.

Approximately 1 week following collection, the New York State Public Health Lab (PHL) received whole blood for culture and molecular analysis to identify Streptobacillus moniliformis. Efforts were made to culture the organism from the whole blood by inoculating trypticase soy agar (TSA) with 5 % sheep blood, brain heart infusion agar (BHIA) with horse blood, chocolate agar, phenylethyl alcohol agar (PEA), MacConkey agar, and trypticase soy broth (TSB). All media were incubated at 37°C in 5% CO2 and showed no growth after 7 days.

The organism was likely not viable because of the delay in transport, storage conditions prior to shipment, and administration of antibiotic treatment prior to specimen collection. The whole blood additionally underwent DNA extraction followed by 16S rRNA gene PCR with sequence analysis.

On hospital day 10, the sequence generated from the PCR product matched S. moniliformis DNA using both commercial and public databases of well-characterized bacterial strains. The patient finished a 2-week course of antibiotics with amoxicillin, and was discharged to a rehabilitation facility. 

Discussion

What made this case unique was the lack of information regarding the bite encounter due to the patient’s severe AD and the non-specific set of symptoms that acutely followed. Animal bites have the potential for transmission of a variety of organisms, both bacterial and viral. The animal species and the circumstances of the injury are important, as well as, the degree of trauma incurred. Severe or multiple bites increase the chance of infectious disease transmission through larger inoculum sizes and introduction of organisms directly into soft tissues.

When a rash is also present, the distribution, proximity to the bite, and involvement of the palms and soles are details that can aid diagnosis. This case illuminates the diagnostic challenges for rat bite fever, particularly when an accurate exposure history cannot be obtained. A high index of clinical suspicion was necessary in conjunction with coordination with the health department to make the diagnosis.

A closer epidemiological investigation corroborated a possible rat bite occurrence; the patient’s wife had observed recent rat activity in the yard where her husband was gardening.

Rat Bite Fever

S. moniliformis, the primary causative agent of RBF in the United States, is a rare zoonotic disease, both in New York State and nationally.^2-9 Nationally, over 200 cases have been documented; however, since RBF is not a nationally notifiable disease, this number is likely a great underestimate of the true case count.^2,4-6,9

Transmission of S. moniliformis occurs by direct contact through a bite or scratch from an infected rat or from exposure to their oral secretions or food/water contaminated with rat waste products. Less commonly, the disease can be transmitted by other rodents (eg, mice, gerbils, or squirrels) or rodent-eating animals (eg, weasels, cats, and dogs).

Symptoms. Symptom onset usually occurs within 3-10 days of exposure, but can take up to 3 weeks.^2-9 They include the sudden onset of chills, fever, headache, muscle pain, and vomiting. Typically, within a few days after fever onset, a maculopapular rash develops over the extremities.

Treatment. Penicillin is most commonly used to treat S. moniliformis infections, but the bacterium is also sensitive to cephalosporins, macrolides, and tetracycline.^2-9 If left untreated, severe sequelae, including endocarditis, myocarditis, meningitis, pneumonitis, septicemia, and hepatosplenomegaly can occur.^2-9 The case fatality rate for RBF ranges from 7% to 13%.^2-9

Discussion. Of the >2 million animal bites that are reported annually in the US, only 1% are attributed to rat bites.^2,6,9 Until recently, persons most at-risk primarily included young children (<5 years of age), and particularly those living in poverty. Today, however, keeping rats as personal pets or using them for laboratory purposes has broadened those persons at-risk to include rat owners, pet shop employees, and laboratory workers.

It is estimated that 10% to 100% of domestic rats and 50% to 100% of wild rats are colonized with S. moniliformis.^2-4,6,9 As such, occupational and recreational exposures to wild rats in particular are becoming a relevant risk factor for RBF—placing those persons who engage in outdoor activities like farming, hunting, and trapping at increased risk for disease.⁶

The RBF case described here supports the notion that risk factors for the disease are continually expanding, and even common outdoor recreational activities, such as backyard gardening, may place one at increased risk.

In the wake of severe weather activity, particularly flood events that have been occurring across New York State, the likelihood of rodent-human interactions could be expected to rise. As such, what are considered rare zoonotic diseases may become more prevalent in the general population. Increased precipitation in warm months can lead to an amplified rat population size, as a result of increased vegetation and food availability.

On the other hand, increased rainfall can lead to flooding which, in turn, can upset the natural habitat for rodent populations. Interestingly, while such events may diminish the size of rat populations those that survive may seek to re-establish themselves around or inside homes, where they can come into contact with humans.¹⁰ At present, it is estimated that 10% of all rat bites result in S. moniliformis infection.^2,3,6-9 An environmental site visit to the patient’s residence, conducted by MCDPH, did not yield any noticeable rodent activity around the outside property, which was well overgrown with vegetation.

Illnesses subsequent to known animal, mosquito, or tick bites may be easily diagnosed when the source of the bite is known and medical attention is promptly sought. When an unknown bite exposure occurs, prompt medical attention, combined with timely epidemiologic investigation is key to identification of disease and proper treatment. In such instances, medical providers should immediately report any bites of unknown origin to their local department of health for epidemiologic exposure and risk assessment.

Although rare, RBF should not be overlooked as a cause of disease when symptomology is compatible and the possibility of rat exposures exist. Ultimately, collaboration among the infectious disease physicians who treated the patient, the local and state health department epidemiologists who investigated disease exposures, and the state PHL laboratorians who identified S. moniliformis in the patient specimen is what solved this mystery.

Hear details from the case's author in the podcast below:

References:

1. Talan DA, Citron DM, Abrahamian FM, et al. Bacteriologic analysis of infected dog and cat bites. N Engl J Med. 1999;340(2):85-92.

2. Elliott SP. Rat bite fever and Streptobacillus moniliformis. Clin Microbiol Rev. 2007;20(1):13-22.

3. Glasman PJ, Thuraisingam A. Rat bite fever: a misnomer? BMJ Case Rep. 2009; 2009:2009.

4. Lewis BK, Vanderhooft S. Rat bite fever: fever, arthritis, and rash in a 4-year-old boy. Ped Dermatol. 2012;29(6):767-771.

5. CDC. Fatal rat-bite fever—Florida and Washington, 2003. MMWR Morb Mortal Wkly Rep. 2005;53:1198-1202.

6. Gaastra W, Boot R, Ho HTK, Lipman LJA. Rat bite fever. Vet Microbiol. 2009;133(3):211-228.

7. American Academy of Pediatrics. Rat bite fever. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red book: 2009 report of the committee on infectious diseases. 28th ed. 2009.

8. Heymann DL, ed. Control of communicable diseases manual. 19th ed. Washington, DC: American Public Health Association; 2008.

9. Freels LK, Elliott SP. Rat bite fever: three case reports and a literature review. Clin Ped. 2004;43(3):291-295.

10. AJ, Campbell-Lendrum CF, Corvalan KL, et al (eds). Climate change and human health—risks and responses. Geneva, Switzerland: World Health Organization. 2003; 103-132.