Title: Kawasaki disease shock syndrome: Case report and cytokine profiling
Abstract: Kawasaki disease (KD) is an acute common vasculitis prevalent in children. Severe forms of KD presenting with hemodynamic instability and shock have been recognized recently and are called KD shock syndrome (KDSS). This severe presentation has been associated with more severe markers of inflammation.1, 2 Here, we report the case of a 10-year-old girl who developed KDSS with multiple organ dysfunction. A previously healthy 10-year-old Japanese girl developed fever, vomiting, diarrhea, and bilateral cervical lymphadenitis. She was referred to hospital on the fourth day of fever. At this point, she had prolonged fever, jaundice, bilateral bulbar conjunctival injection, mild lip erythema, bilateral cervical lymphadenitis, and decreased turgor pressure. Blood test indicated hyperbilirubinemia (total bilirubin, 6.0 mg/dL; direct bilirubin, 5.2 mg/dL), elevated liver enzymes (aspartate transaminase, 68 IU/L; alanine aminotransferase, 116 IU/L; lactate dehydrogenase, 395 IU/L; γ-glutamyltransferase, 238 IU/L), dehydration and acute kidney injury (AKI; blood urea nitrogen, 60.8 mg/dL; creatinine, 2.76 mg/dL; uric acid, 9.3 mg/dL), elevated pancreatic enzymes (amylase, 307 IU/L), hyponatremia (natrium, 128 mmol/L), elevated inflammatory molecules (white blood cells, 17 700/μL; C-reactive protein, 15.8 mg/L; erythrocyte sedimentation rate, 98 mm/h; ferritin, 385 ng/mL), and coagulopathy (prothrombin time, 15.8 s; activated partial thromboplastin time, 32.3 s; fibrinogen, 1,228 mg/dL; D-dimer, 10.0 μg/mL). Laboratory data for other patients with KD (n = 63) are listed in Table S1. Immunoglobulin (Ig)G and IgM antibodies for hepatitis viruses, cytomegalovirus, and the Epstein–Barr virus were negative. Whole trunk contrast computed tomography showed hydrops of the gallbladder, mild ascites, and paralytic ileus. Although the blood pressure was slightly low (systolic blood pressure [SBP], 84 mmHg), normal cardiac function without coronary artery aneurisms and/or dilatation was confirmed on echocardiography. Use of i.v. immunoglobulin (IVIG) was postponed because the symptoms of KD were not prominent on admission. Therefore she was initially given i.v. extracellular fluid and antibiotics for AKI and possible sepsis. Although kidney function recovered quickly, high fever and other symptoms persisted. On the sixth day of fever, she had hypoxemia, and therefore required oxygen. Chest X-ray showed bilateral pleural effusion and cardiac dilatation. On echocardiography the ejection fraction had reduced to 57.0%; and SBP was found to have dropped to 70 mmHg. On the seventh day of fever, she developed polymorphous exanthema and edema of hands and feet, therefore, fulfilling the diagnostic criteria for KD. Because she was regarded as a high-risk KD patient based on Kobayashi score, she was treated with IVIG, aspirin, and i.v. prednisolone, according to the RAISE study.3 Although she was hypotensive, we did not use vasoactive agents in order to avoid coronary changes. On the eighth day of disease, she became afebrile. Hyperbilirubinemia, hyponatremia, hypoxemia, and hypotension recovered within the next few days. She developed desquamation of the fingers on the 14th day of fever. Systemic corticosteroids were reduced gradually according to the RAISE protocol and stopped on the 26th day of the disease. During the disease course, fever did not recur. She did not develop coronary dilation or aneurysms over the 6 month follow-up period. To investigate the pathophysiology of KDSS, cytokine profiling was performed using the plasma that was taken prior to IVIG treatment after informed consent was obtained from the parents. This study was approved by the Institutional Review Board at St Luke's International hospital and Kanazawa University. Compared with healthy donor or KD patients without shock,4 the present patient had markedly elevated levels of multiple cytokines (Fig. 1). In addition to elevated plasma interleukin-6, which is often observed in KD, elevated neopterin and soluble tumor necrosis factor (TNF) receptors were also found, suggesting the hyperactivation of the interferon-γ and TNF-α signaling pathways, respectively. Since the first case of KDSS was reported, there appears to be an increased incidence of IVIG resistance and coronary abnormalities in patients with KDSS.5 Compared with KD patients without shock, KDSS tends to occur in older children, and is associated with pulmonary complications, AKI, pancreatitis, neurological disorders, coagulopathy, and hemophagocytosis. Some of these complications can be induced by hypercytokinemia. Distinct cytokine signaling might be a key feature of KDSS. To increase our understanding of this disease, additional case reports and detailed studies are required. We would like to thank Professor Akihiro Yachie, Department of Pediatrics at Kanazawa university, for his help with cytokine profiling and intellectual advice. The authors declare no conflict of interest. R.O. and A.M. wrote the manuscript; R.O., K.Y., N.U., and A.M. treated the patient; M.S. performed cytokine profiling and gave conceptual advice. All authors read and approved the final manuscript. 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