PEDIATRIC PUZZLER

GEORGE K. SIBERRY, MD, MPH, SECTION EDITOR

Frustration over unremitting fever in a 3-year-old girl:
Why, oh why?

By Lori Taylor, MD

It has been a busy afternoon in your office. At first glance, the chart of the next patient looks like more of the same: a previously healthy, 3-year-old girl who has a fever. You enter the examining room, and her mother relates the symptoms of the past few days. Fever as high as 104° F developed three days before this visit; other symptoms include an episode of vomiting on the first day of the fever and a complaint of mild abdominal pain today. No respiratory symptoms.

The girl's medical history is remarkable only for a positive tuberculosis skin test one month earlier, part of a routine 3-year-old physical. The 10 mm x 12 mm wheal that resulted was considered positive, given her close contact with family members from Southeast Asia. She was treated with isoniazid after a chest radiograph was read as normal.

The patient is the second child of Vietnamese immigrant parents; she and an older brother were born in the United States. The family has not traveled outside the United States in the past three years. Interestingly, her mother developed a fever and vomiting the day before the patient's symptoms began, but she reports that she is feeling "much better."

Your nurse records the patient's rectal temperature as 105.4° F! Sitting in her mother's lap, the girl looks miserable. She also eyes you suspiciously. The exam proceeds with difficulty, yet is mostly unrevealing. Eyes and ears are normal; the throat is mildly erythematous, without exudate. There is no rash, and you do not detect hepatosplenomegaly.

The high fever raises your concern about serious bacterial infection, so you decide to order preliminary laboratory tests. Urinalysis shows only an elevated specific gravity and a small amount of protein, both likely a consequence of the fever itself and poor fluid intake. The complete blood count reassures you: The white blood cell count is 6.3 x 10³/µL, with a differential of segmented neutrophils, 61%; lymphocytes, 24%; and monocytes, 15%. The hemoglobin level and platelet count are within normal limits.

An elevated monocyte count can be seen in Kawasaki disease, but no other findings at this time support that diagnosis. Could the recent positive skin test for tuberculosis be important? Unlikely, given the abrupt onset of symptoms, but you decide to keep that possibility in mind. Then there's the mother's report of symptoms similar to those of her daughter—something that needs to be considered. You conclude that the illness is most likely viral and prescribe symptomatic care.

Enter frustration

Over the next few days, you make plans to review the blood and urine cultures and stay in contact with the family. Two days later, there is no growth on cultures, but the patient is back in to see you, this time with her father, who reports that her fever has persisted—as high as 104° F. She hasn't vomited again, but has had episodes of watery, nonbloody diarrhea in the past two days. Still there are no respiratory symptoms. According to her father, the girl is listless and cranky while febrile but playful and active when the fever is down.

Now, in your examining room, her rectal temperature is 101.8° F. She is fearful of you and vigorously resists your exam. You persist. Faced with a child with five days of fever, you carefully examine her for signs of Kawasaki disease. Conjunctivae are not injected; lips are a bit cracked and dry but not red; and you do not detect significant lymph node enlargement. Rash or extremity changes? None to be found. Given the diarrhea, you examine the abdomen closely; there is no organomegaly or other abnormality to be found. Once again, your examination yields few clues. This is frustrating. Are you missing something?

Unquestionably, five days of high fever in a 3-year-old merits further attention. Given that the only other symptoms are related to the gastrointestinal tract, could this be a protracted fever with rotavirus or or adenovirus infection? Perhaps a bacterial etiology needs pursuing. While you have the patient in the office, you obtain a rectal swab for culture and instruct her father to collect a stool specimen at home. You repeat the CBC: Nothing new—still a normal WBC count (9.2 x 10³/µL) with a differential of segmented neutrophils, 52%; lymphocytes, 25%; and monocytes, 20%. Hemoglobin and platelets remain normal.

Could this be Epstein-Barr virus (EBV) infection? A Monospot (rapid heterophile antibody) test is negative, but the test can be unreliable in young children. The chemistry panel you ordered to look for the elevation of liver enzymes that can accompany EBV (and, for that matter, Kawasaki disease) is normal. You opt to wait for results of viral culture and rapid viral antigen testing from a nasopharyngeal swab and to reexamine the girl in several days. But wait! The laboratory pages you to report that the sedimentation rate is a whopping 99! No question: You had better get to the bottom of this child's problem.

Over the next few days, the fever continues to spike to 104° F several times a day. Diarrhea ceases, but the child complains of intermittent abdominal pain. Rapid viral antigen testing is negative for respiratory syncytial virus, adenovirus, parainfluenza, and influenza. The rectal swab and stool culture are negative for enteric pathogens. Stool contains neither red blood cells nor leukocytes. Further testing serves only to frustrate you (and her parents) as it fails to reveal the cause of illness: EBV IgG and IgM antibodies are negative; the serum amylase level is normal; abdominal and chest radiographs are negative; and an abdominal sonogram reveals only an enlarged spleen with normal echogenicity.

Entertaining the possibilities

On the tenth day of fever, you arrange for admission and further work-up. Many earlier laboratory tests are repeated, including blood, urine, and stool cultures. On the patient's first hospital night, she vomits and develops abdominal distention. Abdominal computed tomography (CT) reveals marked thickening of the wall of the terminal ileum, possibly with involvement of mesenteric lymph nodes (see Figure 1)! Quickly, you run through the differential diagnosis of terminal ileitis: inflammatory bowel disease, lymphoma, infectious enterocolitis (caused by Yersinia enterocolitica or Campylobacter jejuni), and tuberculosis. Perhaps that positive skin test is relevant after all! You decide to consult your colleagues in gastroenterology for help with a diagnosis.

The patient is being prepped for colonoscopy with terminal ileal biopsy when the laboratory calls. It's news about the repeat stool culture: They've grown Y enterocolitica. Cancel that colonoscopy!

The girl is started on trimethoprim-sulfamethoxazole (TMP-SMX), with rapid improvement. At follow-up several weeks later, her symptoms have resolved completely, and she is "back to her normal self," her parents report.

Why good questions beget good answers

How is it that the Y enterocolitica failed to grow on the previous two stool cultures? After all, the three specimens were cultured in the same hospital laboratory. It turns out that this lab—like many others—does not routinely culture for the fastidious Yersinia bacterium. Fortunately—for you and your patient—the resident who admitted the girl knew that, and specified "Yersinia" when ordering the culture.

Y enterocolitica is a gram-negative bacillus (see Figure 2) that belongs to the family Enterobacteriaceae, which includes Escherichia coli and Salmonella and Shigella species.¹ Y enterocolitica may be transmitted by ingesting undercooked pork, unpasteurized milk, or contaminated water. Person-to-person transmission via the fecal-oral route is believed to be much less common.² Outbreaks often occur during the holiday season among families that prepare and eat "chitterlings," an ethnic delicacy made of pork intestines.³ Infection is more common in cooler climates and in winter months. Incubation is usually four to six days but can range from one to 14 days.²

Y enterocolitica causes several defined syndromes, but also produces a variety of uncommon presentations. In infants and young children, the syndrome of enterocolitis, with fever and diarrhea, is most common.^2,4 Stool may contain leukocytes and RBCs, but tests of these blood components are often negative.⁵ In older children and adults, a so-called pseudo-appendicitis syndrome is more common; usually, it presents with fever, abdominal pain, and right-lower-quadrant tenderness; diarrhea is mild or absent.² The terminal ileitis and mesenteric adenitis found in children with this syndrome can mimic a variety of other disease states, including appendicitis, Crohn disease, tuberculosis, and lymphoma.³ Other rarer manifestations of Y enterocolitica infection are pharyngitis, meningitis, osteomyelitis, pyomyositis, conjunctivitis, pneumonia, glomerulonephritis, peritonitis, and primary cutaneous infection.^2,4 Invasive infection, such as bacteremia, occurs most often in young infants and patients in an iron overload state.⁶

Imaging findings associated with Y enterocolitica infection can help differentiate it from other diseases that it is known to mimic. Ultrasonography or a CT scan reveals such changes as thickening of the wall of the ileum and, sometimes, the cecum, with enlarged mesenteric lymph nodes. Ileal wall thickening in Y enterocolitica infection is mucosal or submucosal only, whereas that found in Crohn disease is usually transmural.⁷ If the bowel wall is not visualized, enlarged mesenteric lymph nodes may suggest Yersinia infection. This finding is not specific, however, and may occur in all the aforementioned diseases. Visualization of a normal appendix is obviously helpful in excluding appendicitis.

Diagnosis of Yersinia infection is usually established by stool culture. Recovery of the microorganism from stool requires specific techniques, such as selective agar, alkali treatment, and cold enrichment.¹ Because the incidence of Yersinia infection is relatively low, most clinical microbiology laboratories do not employ the selective techniques mentioned above unless they are specified on the order. Physicians must therefore maintain heightened suspicion of Yersinia infection whenever they are faced with a child who expresses significant abdominal complaints—whether diarrhea is present or absent. As this child's case illustrates, fever can be the presenting symptom, with only mild abdominal complaints (initially, at least).

Whether antibiotic therapy benefits patients who are infected with Yersinia is unclear. Patients in whom sites of infection are found outside the gastrointestinal tract, or who are immunocompromised, should receive an antibiotic. Such treatment is not believed to benefit patients with enterocolitis, the pseudo-appendicitis syndrome, or mesenteric adenitis, however.² Indeed, the improvement noted in our patient once antibiotic therapy was instituted may have been coincidental. If antibiotic therapy is deemed necessary, the microorganism is generally sensitive to TMP-SMX, aminoglycosides, and third-generation cephalosporins.²

A child in whom fever persists will always puzzle pediatricians. Other symptoms, no matter how subtle, may provide the keys to diagnosis. And when testing leads nowhere, it may help to step back and consider: If you aren't getting the answers you want, maybe you haven't asked the right questions. Physician, know thy laboratory!

REFERENCES

1. Cover TL, Aber RC: Yersinia enterocolitica. N Engl J Med 1989;321:16

2. Yersinia enterocolitica and Yersinia pseudotuberculosis infections, in Pickering L (ed): 2000 Red Book: Report of the Committee on Infectious Diseases, ed. 25. Elk Grove Village, Ill., American Academy of Pediatrics, 1997, pp 589–591

3. Tuohy AM, O'Gorman M, Byington C, et al: Yersinia enterocolitis mimicking Crohn's disease in a toddler. Pediatrics 1999;104:e36

4. Hoogkamp-Korstanje JA, Stolk-Engelaar VM: Yersinia enterocolitica infections in children. Pediatr Infect Dis J 1995;14:771

5. Abdel-Haq NM, Asmar BI, Abuhammour WM, et al: Yersinia enterocolitica infection in children. Pediatr Infect Dis J 2000;19:954

6. Kelly DA, Price E, Jani B, et al: Yersinia enterocolitis in iron overload. J Pediatr Gastroenterol Nutr 1987; 6:643

7. Puylaert JB, Van der Zant FM, Mutsaers JA: Infectious ileocecitis caused by Yersinia, Campylobacter, and Salmonella: Clinical, radiological and US findings. Eur Radiol 1997;7:3

DR. TAYLOR is assistant clinical professor of primary care pediatrics and adolescent medicine at the University of California, San Diego, and is in practice with UCSD Medical Group, La Jolla, Calif.

DR. SIBERRY is a fellow in pediatric infectious disease at The Johns Hopkins Hospital, Baltimore, Md.

Some of our most satisfying moments in pediatrics—and some of our best clinical pearls—result from solving perplexing cases. If you have a favorite, send it to

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George Siberry, ed. Lori Taylor. Pediatric Puzzler: Unremitting fever. Contemporary Pediatrics 2003;1:25.