May 2005

Editorial note:
Our guest columnists this month are Victoria McMeen, MD, and Karen Bowlware, MD, from the University of Oklahoma College of Medicine. Dr. McMeen received her degree from the National Medical University in Ukraine. She is now in her third year of pediatric residency at the University of Oklahoma. Victoria looks forward to a fellowship in allergy and immunology through the University of Virginia.

Karen Bowlware received her degree from the University of Oklahoma College of Medicine in 1997. She then completed her pediatric residency through the University of Oklahoma Health Sciences Center Tulsa in 2000. Subsequently, she completed a fellowship in pediatric infectious diseases at the University of Texas Southwestern Medical Center at Dallas in 2003. Karen is a clinical assistant professor of pediatric infectious diseases at the University of Oklahoma Health Sciences Center.

Case

A 4½-year-old boy was admitted to the hospital for evaluation of a persistent fever, with elevations as high as 105° F. He also had severe headache, cervical lymphadenopathy with sore throat and neck pain. The history of the chief complaint began three weeks earlier with the onset of exudative pharyngitis. At that time, his rapid test for group A strep (GAS) was positive, and he was given a dose of benzathine penicillin. However, his fever and pain persisted intermittently, in spite of several additional ß-lactam antibiotics. A repeat rapid strep test at that time was negative.

The patient lives in rural Oklahoma with daily exposure to several cats and a family dog. There had been no known sick contacts, no tick bites or unusual dietary habits and his immunizations were up to date.

Examination on admission revealed a fever of 38.3° C and a HR of 120. His respiratory rate and blood pressure were normal. He was generally ill appearing, non-communicative and moderately dehydrated. His neck had a “bull neck” appearance from marked bilateral lymph node enlargement and his mouth and throat revealed an ulcer on the anterior aspect of his tongue (Figure 1) with enlarged, exudative tonsils. The only other positive finding was mild liver enlargement with the liver edge being 1.5 centimeters below the right costal margin.

Lab tests revealed an elevated white blood cell count at 24,500/mm, with 67% neutrophils, 2% bands, 19% lymphocytes and 12% monocytes. His C-reactive protein was 9 mg/dl (normal <0.9) and erythrocyte sedimentation rate (ESR) of 55 mm/hr (normal <20). A complete metabolic profile, including liver enzymes, was normal. A chest radiograph and computed tomography (CT) scan of the chest were normal. A CT scan of the neck (figure 2) revealed: A, Diffuse bilateral cervical chain lymphadenopathy. B, Lymphadenopathy with areas of low attenuation consistent with a component of necrosis. Treatment was initiated with ampicillin/sulbactam (Unasyn, Pfizer). The patient failed to improve until gentamycin was added on the second hospital day. After that, he rapidly defervesced and his symptoms began to resolve. Later it was learned that the patient had played with rabbit fur a few days prior to having been diagnosed with GAS tonsillitis.

What’s Your Diagnosis?

1. Cat scratch disease
2. Group A strep adenitis with abscess
3. Epstein-Barr Virus (EBV) mononucleosis
4. Oropharyngeal tularemia

Answer

The answer was proven serologically to be D, oropharyngeal tularemia. The amoxicillin-clavulanate was discontinued and the patient completed a 10-day course of IV gentamycin, mostly at home, with a good outcome. Tularemia will be discussed in some depth below.

Cat scratch disease (CSD) can certainly cause cervical lymphadenitis, abscess formation and persistent fever. However, it would be very unlikely to cause the lesion on the tongue or exudative tonsillitis. Sometimes it is difficult to clinically distinguish severe CSD and tularemia. In cases such as these, I have used gentamycin since it seems to be effective for both, with a subsequent serological confirmation of the diagnosis.

This was the procedure I followed in a case involving an adolescent who presented with oculoglandular syndrome of Parinaud. He was febrile, moderately sick with the eye findings as shown in figures 3 and 4. The granuloma under the upper lid was suggestive of CSD, but I could not be sure and treated him with gentamycin. He had a remarkably rapid recovery from what was shown serologically to be cat scratch disease. If one is considering doing cultures of a lesion for tularemia, the lab should be notified so that special precautions can be taken to ensure the lab is not accidentally contaminated with the dangerous organism.

Group A strep (GAS) tonsillitis would likely resolve with all the antibiotics he received along the way. Although GAS can cause an abscess in the cervical area, it is unlikely it would have been as prolonged as the case presented. The scenario of the case makes one wonder whether the manifestation of GAS played a role in the subsequent development of this fairly rare form of tularemia.

EBV would not likely cause a sore on the tongue nor improve with gentamicin therapy.

Francisella tularensis

Tularemia is an acute zoonotic disease caused by Francisella tularensis, a small gram-negative coccobacillus. It is a facultative, intracellular pathogen that primarily targets mononuclear phagocytes. Similar to tuberculosis, intracellular replication is followed by the development of a granulomatous host response. F. tularensis was first isolated in 1912 in Tulare County, California and subsequently named after Dr. Edward Francis who dedicated much of his life to investigating the organism.

F. tularensis causes epizootics in lagomorphs and rodents, which are believed to be the main sources of tularemia. Methods of transmission include direct contact with infected animals and bites from ticks, deer flies and fleas. Additional modes include drinking contaminated water, infected food, and the inhalation of contaminated particles. During a 10-year period between 1990 and 2000, four states accounted for 56% of tularemia cases seen in the U.S.: Arkansas, Missouri, South Dakota and Oklahoma. The incidence of tularemia is highest in children between the ages of 5 and 9, and adults over 75, with more cases occurring during the summer.

There are two predominate strains of F. tularensis that account for most human disease. Jellison type A (F. tularensis biovar tularensis), found predominately in North America, is highly virulent with a mortality rate as high as 10%. Jellison type B (F. tularensis biovar palaearctica), found predominately in Europe and Asia, is less virulent, with a mortality rate of less than 1%. There are several reports of disease associated with a type C in Europe; however, this type is a rare cause of tularemia in humans.

There are seven distinguishing forms of tularemia, depending on the site of inoculation: ulceroglandular, glandular, oculoglandular, pulmonary, oropharyngeal, intestinal and typhoidal. Ulceroglandular is the most common manifestation. The average incubation period ranges from three to seven days (range: 1-14 days). Tularemia has an acute onset with symptoms related to the mode of transmission and fever, chills, weakness, myalgias, arthralgias, vomiting and diarrhea.

The patient presented with the oropharyngeal form, but with the unusual manifestation of a large, deep primary glossal ulceration. It is not clear what the exact source and timing of exposure was prior to the onset of disease. Regardless, he played in an area where sources of tularemia exist. McGovern first reported oropharyngeal tularemia in 1963. In the past, the incidence rate of oropharyngeal tularemia has been reported between 2% and 5%. Forty-four cases of tularemia were reported in Oklahoma between 1999 and 2003. Two of the 44 were the oropharyngeal form, including our patient. (Oral communication with John Bos, MPH, Oklahoma State Department of Health, in July 2004). Patients with oropharyngeal tularemia may present with tonsillopharyngitis, cervical lymphadenitis and membranous stomatitis. There were several reports of oropharyngeal tularemia with ulcerations of oral and pharyngeal mucosa; however, we found only one other report in the literature of a glossal ulcerative lesion described with oropharyngeal tularemia. If untreated, this form of tularemia can progress to suppuration of the affected regional lymph nodes, retropharyngeal abscess and septicemia with involvement of other organs. A full recovery can take several months.

Tularemia is usually diagnosed by serological testing. A single serum titer of above 1:128 by microagglutination (MA) or a fourfold titer rise between sera obtained at least two weeks apart, with one of the specimens having a minimum titer above 1:128 by MA, is considered positive.

Presumptive diagnosis of tularemia can be made when a titer of >1:160 is determined by tube agglutination or >1:80 by slide agglutination. Isolating F. tularensis is difficult because of its special growth requirements and should be approached cautiously because of risk of transmission to laboratory personnel. Although not yet commercially available, the development of a polymerase chain reaction (PCR) method for rapid diagnosis is promising.

Clinical outcomes can be very favorable with early recognition and appropriate treatment. Even though pharyngitis with cervical lymphadenopathy is frequently caused by group A ß-hemolytic streptococcus or viruses, other conditions need to be considered in the differential diagnosis. Infectious mononucleosis, herpetic gingivostomatitis, herpangina, diphtheria, peritonsillar abscess, Vincent’s angina, tuberculosis, cat scratch disease, rickettsial and fungal infections, actinomycosis, lymphoma and leukemia may present with similar symptoms.

Tularemia can be successfully treated with aminoglycoside antibiotics; however, F. tularensis is resistant to ß-lactam antibiotics, including ceftriaxone. Appropriate therapy includes streptomycin sulfate, gentamicin or amikacin for a minimum of 10 days. Oral ciprofloxacin has been effective in treating mild cases of tularemia. Doxycycline also has efficacy, but has been associated with clinical relapses.

There has been renewed interest in tularemia due to its potential use in bioterrorism. Because of this, tularemia has been reinstated on the list of nationally notifiable diseases. A high level of suspicion should be maintained, since tularemia is considered to be a Category A bioterrorism agent by the CDC. We report this case of oropharyngeal tularemia associated with a primary glossal ulceration as a rare presentation of an infectious disease requiring a heightened level of awareness.

Acknowledgements

We thank Faridali G. Ramji, MD, FRCPC, pediatric radiologist, Children’s Hospital of Oklahoma, for his review of computed tomography images and John Bos, MPH, Oklahoma State Department of Health, for his assistance in reviewing cases of oropharyngeal tularemia in Oklahoma. We would also like to thank Terrence Stull, MD, for his review of this report.

Columnist comments:

An excellent review of tularemia can be found in the 5th edition (2004) of Feigin and Cherry’s Textbook of Pediatric Infectious Diseases in chapter 138, pages 1628-1635 by Feigin and Lau. However, the guest columnists put together a very nice list of references, and these references are available upon request along with a fully referenced version of this discussion. Just e-mail me at jhbrien@aol.com, and I will forward the referenced version to you.

I have enjoyed the participation of many of you functioning as guest columnists over the last few years. Again, I welcome anyone who has an interesting case with suitable images if they would like to share as a guest writer of this column. If you are interested, again just contact me.

I had mentioned in previous issues of this publication that the 29th Annual Uniformed Services Pediatric Seminar (USPS) was going to be held in San Antonio, Texas. Well, it was an outstanding success. It contained great CME as well as a good time for all. The Uniformed Services Section of the American Academy of Pediatrics (AAP) gives an Outstanding Service Award every year at this meeting. This award honors a uniformed, usually retired pediatrician who has demonstrated a long-term commitment to military pediatrics. This year the award went to George Kotchmar, MD, Col., Medical Corps, U.S. Air Force (Retired), who is currently a professor of Clinical Pediatrics and director of the Division of Pediatric Infectious Diseases at the University of South Carolina School of Medicine (figure 5). The world of military pediatrics, and especially infectious diseases, is a fairly small group of individuals. George and I were in different branches of the military, but knew each other through most of our careers, and we retired from the military in the same year (1997). George is a 1966 graduate of The Citadel and then went on to obtain his degree from the Medical University of South Carolina. His pediatric residency and infectious disease fellowship was at the Wilford Hall USAF Medical Center. His special areas of interest are HIV/AIDS, antimicrobial resistance and health care policy. Over the last several years, Dr. Kotchmar has also been responsible for putting on an excellent pediatric infectious diseases update meeting each year in mid-June, at the Sea Pines Resort at Hilton Head, S.C., which is very informative and fun to attend. You can find out more about it by going to the Sea Pines Resort CME Web site, www.seapinescme.com.

Also in attendance at the USPS this year was AAP President Carol D. Berkowitz, MD, (right) and the President-Elect, Eileen M. Ouellette, MD, JD, (left) shown in figure 6 with Joseph Lopreiato, MD, FAAP, Captain, Medical Corps, U.S. Navy. Joe is the chairman of the Uniformed Services Section of the AAP. Next year, the USPS will be held in Biloxi, Mississippi, sponsored by the Department of Pediatrics at Keesler Air Force Base. So, if you would like to rub shoulders with some of the AAP’s top leaders, come to the USPS. I have already made plans to attend, so perhaps I’ll see you there.

Lastly, I would like to thank Drs. McMeen and Bowlware for contributing this very interesting case and discussion of tularemia.