Background
Kawasaki disease, also called mucocutaneous lymph node disease, is an acute febrile multisystem vasculitis. The term Incomplete Kawasaki disease is used in the presence of a minimum of two diagnostic criteria of clinical Kawasaki disease accompanied by at least 5 days of fever, the absence of any other reasons characterising the disease, and the presence of severe systemic inflammation findings. Although the term incomplete Kawasaki disease and atypical Kawasaki disease are used interchangeably in the literature, the term “atypical Kawasaki disease” is proposed to be used in the presence of symptoms not typically seen in Kawasaki disease, such as renal failure and aseptic meningitis. Coronary involvement is seen in 20–25% of the untreated Kawasaki patients and constitutes the most important part of the disease. The disease particularly involves mid-size arteries, and exudative infiltration of lymphocyte and mononuclear cells into the blood vessel walls causes vasculitis. For this reason, clinicians encounter atypical involvements in different parts of the body according to the site of vessel involvement.Reference Newburger, Takahashi and Gerber 1
Gastrointestinal symptoms, notably diarrhoea, abdominal pain, and vomiting frequently occur, and elevated serum aminotransferases, gallbladder hydrops, and rarely other cases of gastrointestinal involvement such as ischaemic colitis, intussusception, hepatic necrosis, splenic infarct, intestinal pseudo-obstruction, colitis, and colon oedema are also reported.
In this paper, we present an intravenous-immunoglobulin-resistant incomplete and atypical Kawasaki case that does not meet typical Kawasaki criteria, specifically showing gastrointestinal involvement such as hepatosplenomegaly, severe abdominal pain, progressive bowel oedema accompanying abdominal distension, and hydrops of the gallbladder.
Case
A 3-year-old boy presented with fever and abdominal pain that began 5 days earlier. His body temperature was 38.8°C with a heart rate of 124/minute. He had a right-sided 2×1.5-cm cervical lymphadenopathy, strawberry tongue, and erythema in the oral mucosa. No other abnormal finding was present on physical examination.
Laboratory examinations revealed a white blood cell count of 6.7×109/L with a predominance of neutrophil of 82.1%, red blood cell count of 4.5×109/L, haemoglobin level of 103 g/L, haematocrit of 31.0%, platelet count of 190×109/L, aspartate aminotransferase of 85 IU/L, alanine aminotransferase of 121 IU/L, albumin of 25 g/L, total bilirubin level of 23 mg/L, and potassium level of 2.4 mmol/L. Levels of serum acute-phase reactants including erythrocyte sedimentation rate (67 mm/hour) and C-reactive protein (122 mg/L) were high. Pyuria was found in urinalysis; however, urine culture was negative. Echocardiography revealed normal coronary arteries.
The patient was admitted with incomplete Kawasaki diagnosis. Aspirin – at a dose of 80 mg/kg/day, divided into four doses/day – was started with a single dose of intravenous immunoglobulin (2 g/kg) on the 6th day of the disease. The patient had increased abdominal pain and abdominal distension and still had fever after intravenous immunoglobulin. The X-ray of the abdomen revealed dilatation in all segments of the intestine and an enlargement of the intestinal wall (Fig 1). The abdominal ultrasound showed hepatomegaly, splenomegaly, multiple lymphadenopathies particularly in the right lower quadrant, gallbladder hydrops, marked dilatation in the small intestine, and oedema on the intestinal wall. Abdominal ultrasound taken 6 hours later showed that bowel oedema had progressed. The patient continued to suffer from abdominal pain significantly. As the albumin level decreased to 20 g/L, the patient was given albumin infusion considering that it would contribute to intestinal pathology. Echocardiography performed on day 8 showed diffuse dilatation in the left mean coronary artery and the right coronary artery (Fig 2). The patient who had persistent fever at 36 hours after the completion of the initial intravenous immunoglobulin infusion and had high C-reactive protein levels was considered to be intravenous immunoglobulin resistant. A second dose of intravenous immunoglobulin treatment was administered. After the second dose of intravenous immunoglobulin treatment, it was observed that abdominal distension was markedly reduced, and abdominal ultrasound showed that hydrops of the gallbladder and oedema on the bowel walls regressed. In addition, the patient who did not have fever showed regression of transaminase and C-reactive protein levels. At the same time, the aspirin dose was decreased to the anti-thrombotic dose. The echocardiography examination on day 15, however, showed that the dilatation in the right coronary artery expanded to 7 mm with a fusiform aneurysm (Fig 3) and the left coronary artery was enlarged diffusely to 4.5 mm. During the 1st-month and 2nd-month examinations of the patient, it was observed that the aneurysm had significantly regressed. On the 6th month, examination revealed that right coronary artery internal diameter was back to normal size according to the body surface area. Aspirin therapy was discontinued.
Figure 1 Abdomen x-ray. Dilatation in all segments of the intestine, and an enlargement of the intestinal wall.
Figure 2 Day 8. (a) Dilatation in the right coronary artery (RCA). (b) Diffuse dilatation in the left mean coronary artery (LMCA).
Figure 3 Day 15. An aneurysm in the right coronary artery (RCA).
Discussion
Incomplete Kawasaki disease is considered when fewer symptoms of mucocutaneous inflammation are present. Although the term incomplete Kawasaki disease and atypical Kawasaki disease are used interchangeably in the literature, the term atypical Kawasaki disease is proposed to be used in the presence of symptoms not typically seen in Kawasaki disease, such as renal failure and aseptic meningitis.Reference Newburger, Takahashi and Gerber 1
The aetiology of Kawasaki disease remains unknown, although many studies about the introduction of one or more pathogens are available. In these studies, Staphylococcus aureus Streptococcus pyogenes, and numerous atypical pathogens were isolated. Although a small number of studies have suggested that the human coronavirus NL63 and the bocavirus play a role in the aetiology of the Kawasaki disease, no direct and definite connection has been established in the current literature of any agent of infection in the aetiology of the Kawasaki disease.Reference Principi, Rigante and Esposito 2 It is not clear why some patients with Kawasaki disease are confronted with gastrointestinal symptoms. Selective expansion of Vβ2 T cells has been shown in blood and jejunal mucosa. Therefore, it is being asserted that pathogenic bacteria that colonise the intestinal mucosa cause abdominal symptoms, producing exotoxins that act like superantigens.Reference Abe, Kotzin and Jujo 3
Although common, gastrointestinal symptoms are not considered part of the diagnostic criteria for Kawasaki disease. Abdominal pain, vomiting, and diarrhoea are commonly seen in many patients with Kawasaki disease. Baker et alReference Baker, Lu and Minich 4 examined the disease-related symptoms in 198 Kawasaki disease patients during the 10 days before diagnosis, and reported that one or more gastrointestinal symptoms – diarrhoea, vomiting, abdominal pain, and so on – were present in 61% of the patients. In addition, abdominal involvement may include jaundice, cholangitis, elevated liver enzymatic levels, gallbladder hydrops, and rarely intestinal obstruction, pseudo-obstruction, pancreatitis, splenic infarct, hepatic infarct, ischaemic colitis, and bowel oedema.
In terms of gastrointestinal involvement, our patient had hepatosplenomegaly, elevation of hepatic enzymes and hypoalbuminaemia, gallbladder hydrops, and bowel oedema, a quite rarely reported condition in Kawasaki disease.
In Kawasaki disease, hepatomegaly and elevated aminotransferase are indicative of hepatic dysfunction and is usually subclinical. Hypoalbuminaemia occurs owing to shifting of albumin from the intravascular compartment to the interstitial space as a result of increased capillary permeability and capillary leakage rather than hepatic dysfunction. Hepatic involvement ranges from a mild asymptomatic elevation in liver enzymes to severe cholestatic hepatitis. In one study, it was determined that 37.2% of 239 patients with Kawasaki disease have abnormal aminotransferase levels, and transaminase levels were elevated more than twice in 20% of the patients.Reference El-Adawy, Dominguez and Anderson 5 However, the findings of hepatic dysfunction in Kawasaki disease are self-limiting and do not represent a significant cause of morbidity and mortality. In autopsy series, findings supporting vasculitis as the cause of hepatic dysfunction in Kawasaki disease were revealed. In addition, polymorphonuclear leucocyte and eosinophil infiltration into sinusoids and particularly to the “bile ducts” in the portal, and proliferation in kupffer cells, fatty degeneration and severe congestion have been described.Reference Bader-Meunier, Hadchouel and Fabre 6
Hydrops of the gallbladder is defined as an increase in the longitudinal and horizontal diameter of the gallbladder compared with the mean value, which is calculated according to age and is a well-established entity for Kawasaki disease. It has been reported that hydrops of the gallbladder is seen at a rate of 14% in Kawasaki disease, and also its presence is a risk factor for intravenous immunoglobulin resistance. Although the mechanism of gallbladder hydrops, which has a self-limiting character, is not fully understood, findings of vasculitis on the gallbladder wall and inflammatory infiltration are considered to be responsible. Less frequently, biliary obstruction and acalculous cholecystitis occur.Reference Suddleson, Reid and Woolley 7
Surgical abdominal complications of Kawasaki disease have rarely been reported in the literature. These complications include gallbladder hydrops with cholestasis, small intestinal occlusion, paralytic ileus ischaemic colitis and massive liver necrosis, haemorrhagic duodenitis, and appendicular vasculitis.
The cardiac sequelae in patients with Kawasaki who have gastrointestinal involvement have rarely been investigated in the literature. In Italy, it was reported that 4.6% of 219 patients with Kawasaki disease presented with acute severe abdominal symptoms. Of these ten patients, 9 presented with incomplete Kawasaki disease, and it was reported that coronary artery aneurysms developed in 50% of these patients despite early intravenous immunoglobulin.Reference Zulian, Falcini and Zancan 8 El-Adawy et alReference El-Adawy, Dominguez and Anderson 5 reported that liver function tests were applied to 163 patients with Kawasaki disease and coronary artery aneurysm development was seen more frequently in patients who had abnormal liver function tests (33 versus 17%), but no statistically significant difference was found. In another study, of 77 patients with Kawasaki disease, those with gallbladder abnormalities were compared with those without, and no significant difference was found regarding the development of coronary artery lesions.Reference Chen, Huang and Tiao 9 Miyake et alReference Miyake, Kawamori and Yoshida 10 reported that intestinal pseudo-obstruction developed in seven of 310 patients with Kawasaki disease and that coronary artery disease was found in five of those patients. Similarly to the patient we presented, Maurer et alReference Maurer, Unsinn and Waltner-Romen 11 found that a patient with abdominal pain and an incomplete diagnosis of Kawasaki disease had a distinct thickening of the duodenal wall in an ultrasound; despite early administration of intravenous immunoglobulin, giant coronary aneurysms have been reported to have developed. Diagnosis can be delayed in incomplete cases in which abdominal complaints remain in the forefront and by extension treatment. For this reason, it could be considered that the development of cardiac sequelae increases in these cases.
Although gastrointestinal involvement is quite common, bowel oedema is a quite rarely reported complication. There are only a few reports about intestinal involvement in Kawasaki disease. In those articles, focal intestinal dilatation accompanied by thickening of the bowel wall were reported, and the condition was shown to result from inflammatory changes and vasculitis involving bowel vessels. In our case, we believe that bowel oedema is due to vascular damage and vasculitis, and hypoalbuminaemia contributes to this pathology. In a study reporting autopsy data from Kawasaki patients, the majority of the large and mid-sized mesenteric vessels and 20% of small vessels showed pathologic changes of vasculitis.Reference Amano, Hazama and Kubagawa 12 Nagata et alReference Nagata, Yamashiro and Maeda 13 showed that in the acute stage of Kawasaki disease active T cells and active helper T cells increased and T cytotoxic cells decreased upon examination of the jejunal mucosa.
In conclusion, it should not be forgotten that Kawasaki disease is a multisystemic disease that affects several organs and systems, and should not be overlooked, particularly in patients presenting with incomplete and atypical involvements.
Acknowledgements
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Financial Support
This research received no specific grant from any funding agency or from commercial or not-for-profit sectors.
Conflicts of Interest
None.
Ethical Standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation (Ethical guidelines for biomedical research on human participants 2006, India) and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committees.
