A previously healthy 15-month-old male patient presented to an outside hospital with a 6-day duration of fever, rash, and nonbloody diarrhea with a sulfurous odor. There was no history of drinking water from a well. A physical examination revealed erythema of the lips and plantar aspect of the feet and a polymorphous light eruption on the trunk but no conjunctivitis or cervical lymphadenopathy. Laboratory data showed a white blood cell (WBC) count of 17 × 103 cells/μL (63% segmented neutrophils, 18% lymphocytes, 17% monocytes, 2% atypical lymphocytes), hemoglobin of 11.9 g/dL, platelet count of 281 × 103/μL, sodium of 131 mEq/L, albumin of 3.3 g/dL, aspartate aminotransferase (AST) of 64 U/L, alanine aminotransferase (ALT) of 48 U/L, and C-reactive protein (CRP) of 12.69 mg/dL. Urinalysis was normal except for positive urine ketones. Echocardiography did not reveal coronary arterial abnormalities. Based on the laboratory abnormalities and the presence of 4 of 6 clinical criteria, incomplete Kawasaki disease (KD) was diagnosed. However, despite treatment with high-dose intravenous immunoglobulin (IVIG, 2 g/kg/dose) and aspirin, followed by prednisolone 2 mg/kg/d, 2 additional courses of IVIG, and 3 days of intravenous methylprednisolone pulse (30 mg/kg/dose), his fevers and diarrhea persisted. He was transferred to our hospital for further evaluation and treatment.
On admission, his vital signs showed a temperature of 37.5°C, heart rate of 121/min, and blood pressure of 107/60 mm Hg. Erythema was observed on the lips and plantar aspect of the feet and at the Bacille Calmette-Guerin (BCG) inoculation site. Laboratory data showed WBC of 18 × 103 cells/μL (74% segmented neutrophils, 3% band neutrophils, 16% lymphocytes, 6% monocytes, 1% atypical lymphocytes), hemoglobin of 10.1 g/dL, platelet count of 382 × 103/μL, sodium 131 of mEq/L, albumin of 2.1 g/dL, AST of 40 U/L, ALT of 20 U/L, and CRP of 6.12 mg/dL. IVIG- and corticosteroid-refractory KD was diagnosed, and infliximab treatment was begun on hospital day 2, but his fevers continued unabated.
Cytokine analysis using serum obtained before the start of any treatment revealed significantly elevated interleukin (IL)-6 and soluble tumor necrosis factor receptor type II (sTNF-RII) and only slightly elevated neopterin, sTNF-RI, and IL-18, all compatible with KD.1 On hospital day 8, an additional study led to the patient’s diagnosis.
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On hospital day 8, Y. enterocolitica (serotype O:8) was identified from the stool culture. Blood cultures done on hospital days 3 and 8 returned negative. With suspicion of Y. enterocolitica being the causative pathogen, intravenous cefotaxime was started on hospital day 8. Thereafter, the fever and diarrhea, which had lasted for 20 days, rapidly resolved. Cefotaxime was continued for 5 days, and the patient was discharged on hospital day 14. At 1 month after discharge, echocardiography did not reveal any dilation of the coronary arteries.
Y. enterocolitica is a common causative pathogen in gastroenteritis in the pediatric population2 and is usually transmitted via ingestion of contaminated food or drink.3 Common symptoms of Y. enterocolitica infection are fever, abdominal pain, and watery diarrhea.4 Previous reports have suggested that Y. enterocolitica infection can cause KD-like symptoms, including fever, conjunctivitis, and rash,5–8 but their number is eclipsed by the numerous studies that have described the association between Y. pseudotuberculosis infection and KD.9–11 Six previously confirmed cases of Y. enterocolitica manifesting with KD-like symptoms all presented with prolonged fever and nonbloody diarrhea, although diarrhea is only observed in approximately one-third of KD patients with intestinal involvement.12 Laboratory tests showed significantly elevated WBC count and CRP level in all patients. All 6 patients were also unresponsive to initial IVIG treatment, and most had received additional treatment for IVIG-refractory KD before receiving the diagnosis of Y. enterocolitica infection. These findings underscore the difficulty of distinguishing Yersinia infection from KD. In the present case, the initial manifestation of KD-like symptoms accompanied by nonbloody diarrhea and the laboratory findings showing elevated inflammatory markers was in line with the findings of these previous studies. Among patients with KD-like symptoms, evaluation for Y. enterocolitica should be considered for those with persistent diarrhea, history of consumption of contaminated food or water, and lack of response to IVIG. Early detection of Y. enterocolotica may lead to earlier initiation of appropriate antibiotic treatment and may avoid additional treatments for KD.
Among Yersinia species, Y. pseudotuberculosis has been found to be strongly associated with KD-like illness. Y. pseudotuberculosis is known to produce a superantigen, Y. pseudotuberculosis-derived mitogen (YPM),13,14 which triggers the release of cytokines, including interferon (IFN)-γ, IL-2, IL-6, and tumor necrosis factor (TNF)-α via overstimulation of T cells15 and is thought to be responsible for the manifestation of KD-like symptoms.16 Similarly, Y. enterocolitica produces a superantigen that acts on T cells,17,18 causing a rapid surge of cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and TNF-α.19 The elevated IL-6 and sTNF-RII found in our case were consistent with this fact since the serum sTNF-RII level correlates with the serum TNF-α level 20.
Although the etiology of KD is still unknown, studies have suggested that a superantigen might be involved in some cases. Secretion of proinflammatory cytokines, such as TNF-α, IL-6, and IFN-γ, increases during the acute phase of KD.21–23 The similarity of the cytokine profile in the present case with that seen in KD gives rise to the hypothesis that Y. enterocolitica infection may manifest with KD-like symptoms via superantigen-mediated overstimulation of T cells and the release of proinflammatory cytokines. In the present case, CRP level showed moderate decrease after administration of steroids and infliximab, suggesting antiinflammatory treatments intended for KD might have alleviated the inflammatory response caused by Y. enterocolitica to some degree, although complete improvement was achieved only through antibiotic treatment.
In conclusion, we described a case of Y. enterocolitica infection, which mimicked the clinical features and cytokine profile of KD. Together with Y. pseudotuberculosis infections, Y. enterocolitica infections can present KD-like symptoms and should be always considered in the differential diagnosis of KD.
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