Fever, headache, arthralgias, and rash

June 1, 2018

A 15-year-old Caucasian male with a past medical history of attention-deficit/hyperactivity disorder presents to the hospital emergency department with a 1-week history of fever, headache, arthralgias, vomiting, and rash.

The case

A 15-year-old Caucasian male with a past medical history of attention-deficit/hyperactivity disorder (ADHD) presents to the hospital emergency department (ED) with a 1-week history of fever, headache, arthralgias, vomiting, and rash.

History

The patient states that initial symptoms all began around the same time 1 week prior to hospital presentation when he developed severe back pain throughout his entire upper and lower midline spine, followed by generalized headache and nonbloody, nonbilious vomiting. Four days prior to presentation, he began to have bilateral wrist pain that migrated to his bilateral shoulders, knees, and ankles. The pain worsened with movement and palpation, and the only alleviating factor was taking ibuprofen, which gave mild and brief pain relief. The pain was constant and described as sharp. This was followed by a flat, dark-purple rash on bilateral arms, hands, and legs that spared his chest and abdomen.

The constellation of his symptoms as well as a new onset of limping and difficulty bearing weight led to the patient’s ED visit. He did not experience neck pain, nor redness or warmth of his joints. He did not have any confusion, weakness in any of his extremities, or visual changes. He denied any chest pain, shortness of breath, or abdominal pain.

The teenager lives at home with 7 dogs and 2 cats. He had been visiting his father in Iowa who owns 1 dog and a pet rat. He recalls feeding the rat 3 weeks ago, when he was bitten on his fourth left finger. He had minimal bleeding that resolved after a few minutes. There was neither pus nor other drainage from the lesion. A small purple blister formed and resolved without intervention after 3 days. He did not have any other symptoms for the 2 weeks following the rat bite, until the back pain began.

Physical exam

The patient’s vital signs were normal and stable for his age, with blood pressure of 116/64 mm/Hg, pulse of 68 beats per minute, and respiratory rate of 18 breaths per minute. He was afebrile at 98.2°F 1 hour after given ibuprofen. A review of his growth chart revealed normal and symmetric growth with no recent weight changes. He was well appearing and well hydrated.  He was alert and oriented to person, place, and time and had no focal neurologic deficits. Mucous membranes were moist, and his posterior oropharynx was benign. His neck was supple with no pain on range of motion and no lymphadenopathy. He had regular rate and rhythm, no murmurs, and good distal pulses. His lungs were clear with no wheezing.

The patient’s abdomen was soft, nondistended, and nontender to palpation. He had positive bowel sounds and no hepatosplenomegaly. He had 5/5 strength in all extremities. He had a 0.5-cm to 1-cm purple closed blister without drainage on his left fourth digit (Figure 1) with a nonblanching macular petechial rash on bilateral hands, forearms, anterior lower legs, and feet. No rash was present on his chest, abdomen, palms, or soles. There was no erythema nor edema surrounding the blister on his left hand.

Laboratory tests

Initial laboratory evaluation revealed a normal complete blood count with differential, electrolytes, renal function, transaminases, creatine kinase, lactic acid, and coagulation factors. The patient did have an elevated erythrocyte sedimentation rate of 89 mm/hr (normal range [NR], 0-15 mm/hr); C-reactive protein of 20.8 mg/dL (NR, <0.5 mg/dL); and procalcitonin of 0.89 ng/mL (NR, <0.15 ng/mL).

Wound culture was obtained via puncturing the blister to express fluid, and blood culture was obtained on sodium polyanethole sulfonate (SPS)-free blood culture medium. Serum Streptobacillus moniliformis polymerase chain reaction (PCR) and serum Francisella fluorescent antibodies also were collected.

Differential diagnosis

The differential diagnosis for a teenager with fever, headache, arthralgias, and rash in the setting of a known animal bite is wide. This includes rabies, Rocky Mountain Spotted Fever (RMSF), ehrlichiosis, tularemia, and rat bite fever caused by either S moniliformis or Spirillum minus (Table 1).

Rabies includes initial symptoms such as fever, headache, and vomiting that make it difficult to distinguish among other illnesses. However, as rabies progresses and affects the brain and meninges, symptoms include agitation and confusion. Rabies is unique in that it causes muscle spasms in the throat when trying to swallow, which cause dysphagia, excess salivation, and hydrophobia. In animals, rabies is diagnosed with the presence of rabies virus antigen in brain tissue using the direct fluorescent antibody (DFA) test.1

In humans, diagnosis can be made by DFA test on skin biopsy from the neck; isolation of the virus from saliva; by detection of antibody in serum in unvaccinated people and cerebrospinal fluid (CSF) in all people; and by detection of viral nucleotide sequences in saliva or skin. Treatment for a patient once bitten by an animal suspected of being rabid includes rabies immunization and human rabies immune globulin (HRIG), but after symptoms have developed, neither the vaccine nor immune globulin improves prognosis.1

Rocky Mounted Spotted Fever is caused by the bacterium Rickettsia rickettsii and typically presents with fever, headache, myalgias, and a distinctive rash in the presence of a tick bite. The characteristic rash is a red petechial rash initially involving the wrists and ankles, and within hours spreading to the palms and soles and then inward to the trunk. Hyponatremia and thrombocytopenia typically accompany the illness. The gold standard for diagnosis is the indirect fluorescent antibody (IFA) serology test. Treatment is 7 to 10 days of oral doxycycline.1

Ehrlichiosis is a tick-borne infection that usually consists of headache, myalgias, and fatigue. Rash may be present but is uncommon. Diagnosis is made by serologic testing, but the organism also can be isolated in blood or CSF culture as well as via PCR assay. Treatment is oral doxycycline for 5 to 10 days.1

Tularemia is caused by the bacterium Francisella tularensis and causes fever, headache, fatigue, and a skin ulcer at point of contact with the bite site along with swollen lymph nodes near the ulcer. Diagnosis is generally via serologic testing, but PCR assay or DFA assay also may be used. Treatment is usually 7 to 10 days of intravenous (IV) gentamicin.1

Rat bite fever is caused by S moniliformis or S minus. The main presenting symptoms of rat bite fever caused by S moniliformis include fever, chills, headache, migratory polyarthralgia, rash, and absence of lymphadenopathy. In addition, S minus causes the same symptoms as S moniliformis but does include lymphadenopathy. The bacterium S moniliformis accounts for most cases of rat bite fever in the United States with S minus infections occurring primarily in Asia.1

Hospital course and diagnosis

Because of concern for possible rabies infection, the patient was given rabies vaccine and rabies immune globulin, then admitted. Infectious Disease was consulted, and the patient was started on IV penicillin G 3,000,000 units every 4 hours for 4 days. Endocarditis can be a rare complication of rat bite fever, so echocardiography was performed and was normal.

After starting antibiotic therapy, the patient remained afebrile for 4 days. His polyarthralgias in his shoulders, knees, ankles, and back gradually improved over his hospital stay. The blood culture on SPS-free culture media obtained on admission resulted to grow S moniliformis. Thus, it was determined that the patient’s rat bite fever was caused by S moniliformis.

Discussion

The bacterium S moniliformis is a highly pleomorphic, filamentous, gram-negative, nonmotile, and non–acid-fast rod. More than 2 million animal bites occur each year in the United States with rats contributing to about 1% of these cases. Infection from S moniliformis can be transmitted by rats, mice, gerbils, squirrels, or weasels via bites or scratches, handling of these rodents, or consuming food contaminated by these bacteria. It cannot be spread from one person to another (Figure 2).2

The incubation period ranges from 3 days to more than 3 weeks. There is generally little-to-no inflammation and no lymphadenopathy around the bite site. A maculopapular, purpuric, or petechial rash develops in about 75% of the patients and is generally on the peripheral extremities within a few days of fever onset. Over 50% of patients eventually develop migratory polyarthralgias. The mortality rate of untreated rat bite fever is approximately 10%.3,4

A fatal case of rat bite fever occurred to a healthy 10-year-old male who owned pet rats.5 He initially began to experience fevers to 102.6°F, vomiting, headache, and leg pain. He was seen by his primary care physician and discharged with a diagnosis of viral gastroenteritis. In the next 24 hours, he developed confusion and weakness and then collapsed at home. Paramedics found him unresponsive with dilated pupils, and 1 hour of resuscitation efforts were unsuccessful. During resuscitation, labs were obtained revealing that the patient had anemia, thrombocytopenia, and leukocytosis with bandemia. He also had evidence of disseminated intravascular coagulation, and lung, liver, and epiglottis tissue collected postmortem was positive for S moniliformis DNA by PCR.

Complications of rat bite fever include endocarditis; vasculitis; soft tissue and solid organ abscesses; osteomyelitis, and septic arthritis (Table 2). Endocarditis is the most common complication of rat bite fever with mortality at about 53%, although the majority of these deaths occur without appropriate antibiotic therapy.3,6 Endocarditis is suspected after rat bite fever has been confirmed in a patient with a new heart murmur.

In another case report, a 26-month-old male presented with 5 days of fever to 103°F improved with antipyretics, rash, malaise, and bilateral lower extremity arthralgias.7 He was initially diagnosed with a viral exanthema and subsequently discharged. Three days later, he developed bilateral edema of the feet and ankles that caused him to refuse to ambulate. He was found to have a grade II/VI systolic murmur. Expanded workup including preliminary blood and wound cultures were negative. The toddler’s fever and edema both improved on antipyretics after 3 days, and he was discharged. Two days later, his bacterial wound culture grew S moniliformis and the family admitted he had been exposed to pet rats at home. He was readmitted and received 7 days of IV/intramuscular (IM) penicillin G. Repeat blood and wound cultures were negative and due to the presence of the heart murmur, an echocardiogram was obtained, which was normal. The child’s fevers and swelling improved and he was discharged.7

If the patient had been found to have endocarditis, the treatment regimen typically would be 4 weeks of IV penicillin G plus 2 weeks of IV gentamicin. In those persons with penicillin sensitivity, vancomycin with gentamicin may be used.8

Rat bite fever has been seen to cause a spinal epidural abscess as well.9 A patient had been complaining of diffuse abdominal pain that was later discovered via ultrasound to be due to a bulging bladder. Neurological exam revealed paresthesias and hypesthesia distal to dermatome T-10 along with enhanced reflexes of his lower extremities. Magnetic resonance imaging (MRI) revealed an epidural space-occupying lesion compressing the spinal cord. The abscess was drained via laminectomy and the patient received IV penicillin G for 2 weeks, then oral penicillin V for 4 weeks after the abscess fluid was shown positive for S moniliformis.

In another case, a patient exhibited classic rat bite fever symptoms in addition to lower back tenderness.10 An MRI revealed vertebral osteomyelitis that required surgical debridement. Blood culture revealed S moniliformis. The patient received 6 weeks of ceftriaxone.

In yet another case, a patient diagnosed with rat bite fever began to have right hip pain on range of motion.11 Ultrasound showed right hip joint effusion, and right hip joint aspiration was collected, which proceeded to grow S moniliformis. A subsequent MRI revealed bone marrow edema in proximal femoral epiphysis with concern for osteomyelitis. The patient was treated with 4 weeks of IV penicillin G and then 4 weeks of oral amoxicillin.

Diagnosis and treatment recommendations

The American Academy of Pediatrics (AAP) states that S moniliformis can be isolated from blood, synovial fluids, abscess aspiration, or the site of the bite lesion. Because SPS is inhibitory to S moniliformis growth, SPS-free media should be used when culturing. Culture should be held for up to 3 weeks if S moniliformis is suspected. The bacterium also can be detected using a nucleic acid amplification-based assay.1

The Centers for Disease Control and Prevention (CDC) notes that in the absence of a positive culture, identification of pleomorphic gram-negative bacilli in appropriate specimens supports a preliminary diagnosis of S moniliformis.2

Treatment recommendations from the AAP include IV penicillin G for 7 to 10 days or IV penicillin G for 5 to 7 days followed by oral penicillin V for 7 days. There is limited evidence for use of ampicillin, cefuroxime, and cefotaxime. Doxycycline or streptomycin may be used if severe penicillin allergy exists. In cases complicated by endocarditis, antibiotic therapy requires dual therapy via high-dose penicillin G for 4 weeks in combination with streptomycin or gentamicin.1

Treatment for the 50% of patients with rat bite fever presenting with migratory polyarthralgias is achieved through symptomatic care and nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control.12

Patient outcome

 

The patient was transitioned to amoxicillin on day 5 of his hospitalization, and he was discharged on oral amoxicillin 500 mg 3 times a day for 5 days. He had follow-up with the Infectious Disease clinic 1 week after discharge that revealed he had finished his antibiotic course and that his pain and oral intake continued to improve.

References:

1. Kimberlin DW, Brady MT, Jackson MA, Long SS. Red Book2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.

2. Centers for Disease Control and Prevention. Rat-bite fever (RBF): Transmission. Available at: https://www.cdc.gov/rat-bite-fever/transmission/index.html. Updated May 23, 2011. Accessed May 4, 2018.

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

4. Gaastra W, Boot R, Ho HT, Lipman LJ. Rat bite fever. Vet Microbiol. 2009;133(3):211-228.

5. Adam JK, Varan AK, Pong AL, McDonald EC; Centers for Disease Control and Prevention. Notes from the field: fatal rat-bite fever in a Child-San Diego County, California, 2013. MMWR Morb Mortal Wkly Rep. 2014;63(50):1210-1211.

6. Wang TK, Wong SS. Streptobacillus moniliformis septic arthritis: a clinical entity distinct from rat-bite fever? BMC Infect Dis. 2007;7:56.

7. Theodoro MF, Morrison J, Hill B, Berman D. Arthralgia and vesicular rash in a toddler. Clin Pediatr (Phila). 2017;56(14):1365-1367.

8. Madhubashini M, George S, Chandrasekaran S. Streptobacillus moniliformis endocarditis: case report and review of literature. Indian Heart J. 2013;65(4):442-446.

9. Hammer A, Wolff D, Geissdörfer W, et al. A spinal epidural abscess due to Streptobacillus moniliformis infection following a rat bite: case report. J Neurosurg Spine. 2017;27(1):92-96.

10. Sato R, Kuriyama A, Nasu M. Rat-bite fever complicated by vertebral osteomyelitis: a case report. J Infect Chemother, 2016;22(8):574-576.

11. Flannery DD, Akinboyo I, Ty JM, Averill LW, Freedman A. Septic arthritis and concern for osteomyelitis in a child with rat bite fever. J Clin Microbiol. 2013;51(6):1987-1989.

12. Akter R, Boland P, Daley P, Rahman P, Al Ghanim N. Rat bite fever resembling rheumatoid arthritis. Can J Infect Dis Med Microbiol. 2016;2016:7270413.

 

 

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