Research Article | Open Access
Chih-Jen Chen, Fu-Chen Huang, Mao-Meng Tiao, Ying-Hsien Huang, Li-Yan Lin, Hong-Ren Yu, Kuender D. Yang, Yi-Chuan Huang, Chih-Cheng Chen, Wei-Chiao Chang, Ho-Chang Kuo, "Sonographic Gallbladder Abnormality Is Associated with Intravenous Immunoglobulin Resistance in Kawasaki Disease", The Scientific World Journal, vol. 2012, Article ID 485758, 5 pages, 2012. https://doi.org/10.1100/2012/485758
Sonographic Gallbladder Abnormality Is Associated with Intravenous Immunoglobulin Resistance in Kawasaki Disease
Objective. Kawasaki disease (KD) is an acute systematic vasculitis in children which causes coronary arterial lesions and hydrops of gallbladder. Our objective is to correlate the clinical significance and influence on disease outcome of patients with gallbladder abnormalities in Kawasaki dissease. Methods. Children who met KD diagnosis criteria and were admitted for IVIG treatment were retrospectively enrolled for analysis. Patients with abdominal sonography were divided into 2 groups based on the absence (Group A, ) or presence (Group B, ) of gallbladder abnormalities (GBA), defined as hydrops or acalculous cholecystitis. Between the two groups, clinical features, demographic data (including admission days, coronary artery lesions, IVIG resistance), and laboratory data before/after IVIG treatment were collected for analysis. Results. The presence of sonographic gallbladder abnormalities is correlated with higher levels of serum CRP, GPT, and neutrophils. It also points to an increased number of IVIG resistance rates in group B. There was no significant statistical difference among clinical features, age, gender, admission days, or coronary artery lesions between the two groups. Conclusion. Sonographic gallbladder abnormalities are associated with higher CRP, GPT, neutrophil and IVIG resistance in KD. It can be used as a predictor of IVIG resistance in patients with KD.
Kawasaki disease (KD) is an acute multisystemic vasculitis syndrome of unknown etiology first described by Tomisaku Kawasaki et al. more than 40 years ago in Japan . Since then, it has surpassed rheumatic fever to become the leading cause of acquired heart disease in children living in developed countries [2–4]. Typical diagnostic criteria for KD include an illness unexplained by another disease, fever (at least five days), and four of the five following conditions: bilateral nonpurulent conjunctival injection, oral mucosal changes (erythema or dryness or fissuring of the lips, strawberry tongue, and erythema of the oropharynx), peripheral extremity changes (edema or erythema of palms or soles, desquamation of tips of fingers and toes), rash (polymorphic and nonvesicular, commonly truncal), and cervical lymphadenopathy (over 1.5 cm) [1, 5, 6]. However, a wide range of other atypical clinical features which are not included in the diagnostic criteria such as uveitis, aseptic meningitis, urethritis, arthralgia, arthritis, abdominal pain, liver function impairment, heart failure, and gallbladder hydrops have been widely recognized as well [7–9]. The most severe complication of KD is coronary artery lesion (CAL)  (such as coronary artery aneurysm, coronary artery fistula …) and is the leading cause of acquired heart disease of children [3, 4, 10]. High-dose intravenous immunoglobulin (IVIG) therapy (2 g/kg) with high-dose aspirin (80~100 mg/kg/day) is the standard treatment for KD, and it decreased the incidence of the coronary artery aneurysm from 20% to 3–5% [8, 11–13].
Previous research has pointed out the relatively self-limited nature and laboratory features of acute hydrops of the gallbladder (AHGB) in KD [14, 15]. Reported with less frequency but of equal importance is the clinical finding of acute acalculous cholecystitis (ACC) in KD patients [16–19]. Whether the presence of sonographic gallbladder abnormalities (AHGB and ACC) that are seen in KD patients has an influence on disease outcome is an area of interest that has rarely been explored. Thus, this study was conducted to investigate the correlation between the clinical significance of gallbladder abnormalities and its influence on disease outcome of Kawasaki disease.
2.1. Study Design and Participants
From 2005 to 2007, the medical charts of children who fulfilled the criteria for KD  and were treated with IVIG at Kaohsiung Chang Gung Memorial Hospital were analyzed retrospectively. This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital. Patients whose symptoms did not fit the KD criteria, did not perform abdominal ultrasonography, or did not have complete clinical or laboratory data were excluded. Patients were initially treated with a single dose of IVIG (2 g/kg) during a 12-h our period. Aspirin was also given at an anti-inflammatory dose until the fever subsided and then switched to 3–5 mg/kg/day as a single daily dose. Low-dose aspirin was continued until all signs of inflammation subsided and the CAL (coronary arterial lesion) regressed as detected by two-dimensional (2D) echocardiography as our previous reports [22, 23]. CAL formation was defined as the internal diameter of the coronary artery measuring at least 3 mm or the internal diameter of a segment at least 1.5 times that of an adjacent segment, as observed in the echocardiogram [11, 24].
Demographic data and the principal clinical features of KD  that occur in the acute stage were recorded. Laboratory data, including complete blood count (CBC), differential count (DC), hemoglobin (Hb), platelet (Plt), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and C-reactive protein (CRP), were included for analysis. Laboratory data was obtained before IVIG administration (before IVIG) and 3 days after completing the initial IVIG treatment (after IVIG). IVIG resistance is defined as a return of fever associated with one or more of the initial symptoms that led to the diagnosis of KD within 2–7 days after the initial IVIG treatment and included patients who needed a second dose of IVIG (1-2 g/kg) due to initial IVIG treatment failure [8, 25].
2.2. Sonographic Examination and Diagnostic Criteria for Gallbladder Abnormality
Patients with abdominal sonography were divided into 2 groups based on the absence (group A) or presence (group B) of gallbladder abnormalities (hydrops or acalculous cholecystitis). Hydrops is defined as an enlargement (longitudinal and horizontal diameter greater than that for age-matched average values) without changes in normal anatomical characteristics (i.e., without sludge, stone, increased wall thickness, or pericholecystic fluid) of the gallbladder [26–28]. Whereby ultrasonographic criteria for acute acalculous cholecystitis consisted of two out of the following four characteristics: (1) distention of the gallbladder, (2) gallbladder wall thickness greater than 3.5 mm, (3) presence of sludge, and (4) pericholecystic fluid collection [29–31]. Between the two groups, demographic data (including admission days, CAL, and initial IVIG resistance), clinical features, and laboratory data before/after IVIG treatment were collected for analysis.
2.3. Statistical Analysis
Comparison of continuous data (mean ± standard deviation) was calculated by Student’s t-tests. The median values of each parameter were used as cutoff values. Univariate analysis with chi-square test and multivariate analysis with logistic regression were used to assess the parameters between the two groups. A value <0.05 was accepted as statistically significant. All statistical tests were performed using spss 13.0 for Windows (SPSS Inc., Chicago, IL, USA).
A total of 93 children were diagnosed with KD during the study period. Out of these, 77 [53 boys (69%) and 24 girls (31%)] had performed abdominal sonography and were enrolled for further analysis. Sixteen (21%) of the 77 children had abnormal gallbladder findings, 11 (69%) were acute hydrops of gallbladder (AHGB), and 5 (31%) were acute acalculous cholecystitis (ACC). 75% (12/16) of those with positive findings were boys. None had sonographic evidence of pancreatic pathology or intra/extrahepatic biliary tree dilatations. Demographic characteristics, clinical manifestations, and laboratory findings before and after IVIG treatments are shown in Table 1 through 4. There were no significant differences between the two groups in terms of age, total admission days, coronary artery lesion involvement, or clinical features (Tables 1 and 2). We found that the presence of sonographic gallbladder abnormalities (GBAs) is correlated with initial IVIG resistance (7/61 versus 6/16, ), higher levels of serum CRP ( versus mg/L, ), GPT ( versus U/L, ), neutrophils ( versus %, ), and lower levels of lymphocytes ( versus %, ) (Tables 3 and 4). Lymphocyte and platelet counts tended to increase in both groups after IVIG treatment, albeit without statistical significance ( versus , ) for lymphocyte, but with significance for platelet count ( versus /mm3, ).
|CAL: coronary artery lesion; IVIG: intravenous immunoglobulin. *.|
A multivariate analysis using significant parameters namely gallbladder abnormality, pre IVIG neutrophil, lymphocyte, CRP, GPT and post IVIG platelet, neutrophil, CRP, GPT was performed to see it’s correlation with IVIG resistance. Only 2 independent variables, GBA and post IVIG platelet count, and (both with confidence interval of 95%, range 1.382 to 29.630 for GBA and 1.016 to 1.14 for platelet count respectively) were identified to be significantly associated with IVIG resistance.
Lastly, the group with GBA was subdivided into two groups, acute hydrops of gallbladder () group and acalculous cholecystitis () group. There were no significant differences among patient characteristics, admission days, CAL involvement, IVIG resistance, clinical features, or laboratory findings between these two groups (Table 5 and other data not shown).
|AHGB = acute hydrops of gallbladder; ACC = acute acalculous cholecystitis; CAL: coronary artery lesion; IVIG: intravenous immunoglobulin.|
The association between KD and hydrops of the gallbladder has been reported as early as the late 1970s and early 1980s in the form of isolated case reports [15, 21, 26, 32–34]. Due to the advent of the gray-scale ultrasound, more and more cases of hydrops of the gallbladder were being diagnosed and recognized as an occasional clinical entity of KD with an incidence rate of 5–14% [14, 15]. In our study, 21% (16/77) of KD patients who performed abdominal sonography had hydrops or acalculous cholecystitis, with 31% (5/16) being that of acute acalculous cholecystitis. Only a few handful of reports have correlated the finding of acalculous cholecystitis with KD [16–19], nevertheless, as is evident in our study and those presented in the literature, it is still a relevant finding.
One of the most dreaded complication of KD is the involvement of the coronary arteries, with sequelae such as myocardial infarction, coronary artery fistula formation, coronary artery dilatation, and coronary artery aneurysms [6, 10]. Fortunately, a highly effective treatment with IVIG and aspirin could lower the incidence of coronary aneurysm formation from 20–25% in those who are untreated to just 3–5% in treated cases [12, 35]. Though the treatment with IVIG is effective, 10–20% (with some reporting up to 38% ) of cases will be resistant to initial IVIG therapy, and these are at increased risk for coronary artery lesions and morbidity/mortality [12, 20, 25, 37, 38].
In our study, there were no significant differences between the gallbladder abnormality and nongallbladder abnormality groups in terms of age, sex, coronary artery involvement, or total admission days. However, the group of GBA is associated with a higher level of neutrophils, GPT, and CRP. This finding is comparable with those reported previously in the literature [26, 33, 34]. Of special interest and novel finding is the association between the presence of sonographic GBA with that of initial IVIG resistance. Previous research on the risks of IVIG resistance in KD [39, 40] also reported increased levels of neutrophils, CRP, GPT, and lower platelet counts, the same laboratory parameters that were found in our study. This makes perfect sense since this group is associated with increased risk of IVIG resistance.
Although the pathophysiology behind these gallbladder abnormalities may be different, they may share a common root in KD. Currently, the etiology behind both AHGB and ACC in KD is unknown, however; common to both is the proposed mechanism of (1) adenopathy around the cystic duct causing obstruction, (2) vasculitis or perivasculitis of the gallbladder wall, and (3) inflammatory infiltrates with polymorphs, lymphocytes, and eosinophils [15, 30, 34, 41]. Previously unaware of the relatively benign and self-limited nature of gallbladder hydrops and acute acalculous cholecystitis in KD, these changes were observed in the pathological specimens of gallbladders resected from KD patients in the late 1980s [15, 28].
To the best of our knowledge, the association between the presence of sonographic GBA and that of initial IVIG resistance in KD has never been reported. In addition to the previously known laboratory values that have been associated with IVIG resistance , we provide an additional “Visual” parameter that can be used as a supplement to the risk-scoring system . This finding can alert the physician, providing care for a group of KD patients which are at an increased risk for developing coronary artery lesions, to plan ahead and make the necessary adjustments to treatment.
Conflict of Interests
The authors have declared that no conflict of interests exists.
C.-J. Chen and F.-C. Huang contributed equally to this paper.
This study was in part supported by funding from Grants (NSC 100-2314-B-182-061-MY3) from the National Science Council of Taiwan, Grant CMRPG8A0481 from the Chang Gung Memorial Hospital, Taiwan. The institutes had no influence on the collection, analysis, and interpretation of the data, or on the preparation of the papers.
- T. Kawasaki, F. Kosaki, S. Okawa, I. Shigematsu, and H. Yanagawa, “A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan,” Pediatrics, vol. 54, no. 3, pp. 271–276, 1974.
- J. C. Burns, H. I. Kushner, J. F. Bastian et al., “Kawasaki disease: a brief history,” Pediatrics, vol. 106, no. 2, article E27, 2000.
- H. C. Kuo and W. C. Chang, “Genetic polymorphisms in Kawasaki disease,” Acta Pharmacologica Sinica, vol. 32, no. 10, pp. 1193–1198, 2011.
- J. C. Burns and M. P. Glodé, “Kawasaki syndrome,” The Lancet, vol. 364, no. 9433, pp. 533–544, 2004.
- T. Kawasaki, “Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children,” Japanese Journal of Allergology, vol. 16, no. 3, pp. 178–222, 1967.
- J. W. Newburger, M. Takahashi, M. A. Gerber et al., “Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association,” Circulation, vol. 110, no. 17, pp. 2747–2771, 2004.
- J. W. Newburger, M. Takahashi, M. A. Gerber et al., “Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association,” Pediatrics, vol. 114, no. 6, pp. 1708–1733, 2004.
- H. C. Kuo, K. D. Yang, C. D. Liang et al., “The relationship of eosinophilia to intravenous immunoglobulin treatment failure in Kawasaki disease,” Pediatric Allergy and Immunology, vol. 18, no. 4, pp. 354–359, 2007.
- H. C. Kuo, K. D. Yang, S. H. H. Juo et al., “Itpkc single nucleotide polymorphism associated with the kawasaki disease in a taiwanese population,” PLoS ONE, vol. 6, no. 4, Article ID e17370, 2011.
- C. D. Liang, H. C. Kuo, K. D. Yang, C. L. Wang, and S. F. Ko, “Coronary artery fistula associated with Kawasaki disease,” American Heart Journal, vol. 157, no. 3, pp. 584–588, 2009.
- H. C. Kuo, C. D. Liang, C. L. Wang, H. R. Yu, K. P. Hwang, and K. D. Yang, “Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease,” Acta Paediatrica, vol. 99, no. 10, pp. 1578–1583, 2010.
- J. W. Newburger, M. Takahashi, A. S. Beiser et al., “A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome,” The New England Journal of Medicine, vol. 324, no. 23, pp. 1633–1639, 1991.
- H. C. Kuo, K. D. Yang, W. C Chang, L. P. Ger, and K. S. Hsieh, “Kawasaki disease: an update on diagnosis and treatment,” Pediatrics & Neonatology, vol. 53, no. 1, pp. 4–11, 2012.
- M. E. Melish, R. V. Hicks, and V. Reddy, “Kawasaki syndrome: an update,” Hospital Practice, vol. 17, no. 3, pp. 99–106, 1982.
- E. A. Suddleson, B. Reid, M. M. Woolley, and M. Takahashi, “Hydrops of the gallbladder associated with kawasaki syndrome,” Journal of Pediatric Surgery, vol. 22, no. 10, pp. 956–959, 1987.
- J. W. Hou, M. H. Chang, M. H. Wu, and C. Y. Lee, “Kawasaki disease complicated by gallbladder hydrops mimicking acute abdomen: a report of three cases,” Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi, vol. 30, no. 1, pp. 52–60, 1989.
- D. S. Babcock, “Sonography of the acute abdomen in the pediatric patient,” Journal of Ultrasound in Medicine, vol. 21, no. 8, pp. 887–899, 2002, quiz 900-901.
- J. L. Ternberg and J. P. Keating, “Acute acalculous cholecystitis. Complication of other illnesses in childhood,” Archives of Surgery, vol. 110, no. 5, pp. 543–547, 1975.
- S. C. Huang and Y. J. Yang, “Septic shock and hypofibrinogenemia predict a fatal outcome in childhood acute acalculous cholecystitis,” Journal of Pediatric Gastroenterology and Nutrition, vol. 53, no. 5, pp. 548–552, 2011.
- H. Kato, T. Sugimura, T. Akagi et al., “Long-term consequences of Kawasaki disease: a 10- to 21-year follow-up study of 594 patients,” Circulation, vol. 94, no. 6, pp. 1379–1385, 1996.
- R. W. Goldsmith, D. Gribetz, and L. Strauss, “Mucocutaneous lymph node syndrome (MLNS) in the continental United States,” Pediatrics, vol. 57, no. 3, pp. 431–435, 1976.
- H. C. Kuo, C. D. Liang, H. R. Yu et al., “CTLA-4, position 49 A/G polymorphism associated with coronary artery lesions in Kawasaki disease,” Journal of Clinical Immunology, vol. 31, no. 2, pp. 240–244, 2011.
- H. C. Kuo, Y. J. Lin, S. H. H. Juo et al., “Lack of association between ORAI1/CRACM1 gene polymorphisms and kawasaki disease in the Taiwanese children,” Journal of Clinical Immunology, vol. 31, no. 4, pp. 650–655, 2011.
- S. T. Shulman, J. De Inocencio, and R. Hirsch, “Kawasaki disease,” Pediatric Clinics of North America, vol. 42, no. 5, pp. 1205–1222, 1995.
- R. P. Sundel, J. C. Burns, A. Baker, A. S. Beiser, and J. W. Newburger, “Gamma globulin re-treatment in Kawasaki disease,” Journal of Pediatrics, vol. 123, no. 4, pp. 657–659, 1993.
- T. L. Slovis, D. W. Hight, A. I. Philippart, and R. S. Dubois, “Sonography in the diagnosis and management of hydrops of the gallbladder in children with mucocutaneous lymph node syndrome,” Pediatrics, vol. 65, no. 4, pp. 789–794, 1980.
- J. P. McGahan, H. E. Phillips, and K. L. Cox, “Sonography of the normal pediatric gallbladder and biliary tract,” Radiology, vol. 144, no. 4, pp. 873–875, 1982.
- Y. S. Choi and B. Sharma, “Gallbladder hydrops in mucocutaneous lymph node syndrome,” Southern Medical Journal, vol. 82, no. 3, pp. 397–398, 1989.
- D. E. Tsakayannis, H. P. W. Kozakewich, and C. W. Lillehei, “Acalculous cholecystitis in children,” Journal of Pediatric Surgery, vol. 31, no. 1, pp. 127–131, 1996, discussion 30-31.
- M. Imamoǧlu, H. Sarihan, A. Sari, and A. Ahmetoǧlu, “Acute acalculous cholecystitis in children: diagnosis and treatment,” Journal of Pediatric Surgery, vol. 37, no. 1, pp. 36–39, 2002.
- S. E. Mirvis, J. R. Vainright, and A. W. Nelson, “The diagnosis of acute acalculous cholecystitis: a comparison of sonography, scintigraphy, and CT,” American Journal of Roentgenology, vol. 147, no. 6, pp. 1171–1175, 1986.
- D. B. Magilavy, D. P. Speert, T. M. Silver, and D. B. Sullivan, “Mucocutaneous lymph node syndrome: report of two cases complicated by gallbladder hydrops and diagnosed by ultrasound,” Pediatrics, vol. 61, no. 5, pp. 699–702, 1978.
- E. Grisoni, R. Fisher, and R. Izant, “Kawasaki syndrome: report of four cases with acute gallbladder hydrops,” Journal of Pediatric Surgery, vol. 19, no. 1, pp. 9–11, 1984.
- B. F. Bradford, B. S. Reid, B. J. Weinstein, K. S. Oh, and B. R. Girdany, “Ultrasonographic evaluation of the gallbladder in mucocutaneous lymph node syndrome,” Radiology, vol. 142, no. 2, pp. 381–384, 1982.
- J. W. Newburger, M. Takahashi, and J. C. Burns, “The treatment of Kawasaki syndrome with intravenous gamma globulin,” The New England Journal of Medicine, vol. 315, no. 6, pp. 341–347, 1986.
- A. H. Tremoulet, B. M. Best, S. Song et al., “Resistance to intravenous immunoglobulin in children with Kawasaki disease,” Journal of Pediatrics, vol. 153, no. 1, pp. 117–121, 2008.
- J. C. Burns, E. V. Capparelli, J. A. Brown, J. W. Newburger, and M. P. Glode, “Intravenous gamma-globulin treatment and retreatment in Kawasaki disease,” Pediatric Infectious Disease Journal, vol. 17, no. 12, pp. 1144–1148, 1998.
- J. W. Newburger, “Kawasaki disease: who is at risk?” Journal of Pediatrics, vol. 137, no. 2, pp. 149–152, 2000.
- R. Uehara, E. D. Belay, R. A. Maddox et al., “Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan,” Pediatric Infectious Disease Journal, vol. 27, no. 2, pp. 155–160, 2008.
- S. Cha, M. Yoon, Y. Ahn, M. Han, and K. L. Yoon, “Risk factors for failure of initial intravenous immunoglobulin treatment in Kawasaki disease,” Journal of Korean Medical Science, vol. 23, no. 4, pp. 718–722, 2008.
- S. Mercer and B. Carpenter, “Surgical complications of Kawasaki disease,” Journal of Pediatric Surgery, vol. 16, no. 4, pp. 444–448, 1981.
- K. Durongpisitkul, J. Soongswang, D. Laohaprasitiporn, A. Nana, C. Prachuabmoh, and C. Kangkagate, “Immunoglobulin failure and retreatment in Kawasaki disease,” Pediatric Cardiology, vol. 24, no. 2, pp. 145–148, 2003.
- L. A. Sleeper, L. L. Minich, B. M. McCrindle et al., “Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance,” Journal of Pediatrics, vol. 158, no. 5, pp. 831–835, 2011.
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