Kawasaki Disease With Combined Cholestatic Hepatitis and Mycoplasma pneumoniae Infection: A Case Report and Literature Review

Kawasaki disease (KD), also called mucocutaneous lymph node syndrome, is a febrile multisystem vasculitis mainly affecting children younger than 5 years. KD typically manifests as skin lesions and in the lymph nodes and oral and conjunctival mucosa. It may induce coronary artery abnormalities, such as aneurysms, but gastrointestinal and hepatobiliary involvement are not common. We reviewed 32 cases of patients with a diagnosis of KD with hepatobiliary involvement between 2000 and 2021 and present the case of a 4-year-old girl who received a diagnosis of KD with combined cholestatic hepatitis and Mycoplasma pneumoniae infection. In the 33 cases reviewed, in addition to the classical clinical findings of KD, the most common clinical presentations were jaundice and abdominal pain. Moreover, abnormal laboratory results indicating hyperbilirubinemia, cholestasis, and hepatitis, among other conditions, were noted. Abdominal ultrasonography revealed abnormal findings in more than half children with KD with hepatobiliary involvement. Furthermore, cardiac involvement was noted in a high proportion of the patients. In particular, we noted the case of a 4-year-old girl with a rare presentation of 3-day fever combined with abdominal pain and jaundice. Her levels of aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, alkaline phosphatase, and γ-glutamyl transpeptidase were 489 (15–50) U/L, 253 (5–45) U/L, 4.3 (<1.5) mg/dl, 2.4 (<0.2) mg/dl, 337 (134–315) U/L, and 145 (5–32) U/L, respectively. These results were indicative of cholestatic hepatitis. Furthermore, her serological test results for mycoplasma infection were positive. KD was diagnosed because the patient had high fever for more than 5 days and presented with lymphadenopathy on the left side of neck, a polymorphic skin rash, redness of oral mucosa with strawberry tongue, and nonpurulent conjunctival congestion. After intravenous immunoglobulin injection (IVIG) and acetylsalicylic acid administration, the fever subsided rapidly and clinical manifestations, such as jaundice and abdominal pain, were mitigated. The laboratory parameters gradually returned to within normal ranges. Echocardiography revealed no aneurysm. In conclusion, KD with cholestatic hepatitis should be considered when pediatric patients present with fever combined with abdominal pain and jaundice. Early treatment with IVIG and aspirin is recommended and can effectively relieve cholestatic hepatitis.


INTRODUCTION
Kawasaki disease (KD) is a multisystem inflammatory disease encompassing medium vessel vasculitis, potentially including the coronary arteries. The prevalence of KD among children in Japan between 1994 and 2002 and Taiwan between 1997 and 2010 was 119.6-151.2 and 48.5-82.8 per 100,000 person-years, respectively (1,2). The average male-female ratio of KD was 4:1, with onset before the age of 5 years in 80% of cases (1). The etiology of KD remains unclear; one study reported immunologic abnormalities, but further investigation is required (3). KD diagnosis is based on various clinical measures provided by the American Heart Association and Japanese Ministry of Health (4,5). Typically, KD symptoms include fever lasting at least 5 days combined with at least four of the following five manifestations: (i) conjunctival congestion in both eyes; (ii) changes in the lips and oral cavity, such as reddening of the lips, strawberry tongue, or diffuse injection of oral and pharyngeal mucosa; (iii) polymorphous exanthema; (iv) changes in the peripheral extremities; and (v) acute nonpurulent cervical lymphadenopathy and the exclusion of other diseases with similar findings (1). Alternatively, patients may present with three or fewer of these criteria along with coronary abnormalities or abnormal laboratory data, and this condition is classified as incomplete KD (4)(5)(6). Gastrointestinal and hepatobiliary involvement are rare clinical presentations in KD (7), and respiratory, neurological, genitourinary, and musculoskeletal involvement are also relatively uncommon clinical manifestations (1). The most common reason for sudden death in KD is cardiovascular involvement (1), but the administration of oral aspirin and intravenous immunoglobulin (IVIG) within 10 days of symptom onset can reduce the risk of coronary abnormalities (6).
Herein, we report the case of a girl presenting with an unusual initial onset of KD characterized by fever, acute abdominal pain, jaundice, and lymphadenopathy on the left side of the neck. This patient received early treatment with aspirin and IVIG. We also review 32 other cases of KD with hepatobiliary involvement reported between 2000 and 2021; thus, a total of 33 cases, including our case, were reviewed.

disease) AND (cholestatic), (Kawasaki disease) AND (hepatitis).
An article was excluded if no laboratory hepatobiliary data or intact image report were available or the patient was older than 18 years. Initially, we included 26 articles plus the article on the case reported herein, but three articles were then excluded. Finally, we reviewed 24 articles involving 33 cases (Table 1).

Case Description
The patient was a girl aged 4 years and 2 months who was otherwise healthy before presenting with KD symptoms; she had achieved normal developmental milestones and received regular vaccinations. She did not have any relevant medical, psychosocial, or family history. She was admitted to our hospital because she had persistent high fever (≤38.5 • C) for 3 days. Her parents stated that she had first developed diffuse abdominal pain and swelling on the left side of the neck and had initially been taken to a local general practitioner, who suspected acute gastroenterocolitis. Because of the persistent fever and subsequent development of jaundice, she was brought to our hospital for further evaluation. When admitted, she had poor appetite and vomiting and had developed symptoms of respiratory tract infection, such as rhinorrhea and coughing with sputum. Sore throat, dyspnea, diarrhea, constipation, dysuria, and reductions in urine output were not noted.
A physical examination revealed that the patient had a 39 • C fever, scleral icterus in both eyes, nonpurulent conjunctival congestion, oral mucosa redness, swelling on the left side of the neck, diffuse abdominal tenderness in the periumbilical area, and crackles in the lungs. Chest X-ray revealed an elevated level of pulmonary infiltrates in both lungs ( Figure 1A). Her laboratory data were as follows: hemoglobin = 10.2 (normal range = 11.0-14.5) g/dl, leukocytes = 24,700 (4,000-12,000) 10 6 /L, thrombocytes = 250,100 (130,000-400,000) 10 6  cytomegalovirus, and hepatitis A, B, and C. Furthermore, tests for antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, and antistreptolysin O were negative, as were the results of the influenza A/B and group A streptococcus antigen screening test and pneumococcal urinary antigen testing. Nasal swab and stool tests revealed negative results for adenovirus, and results for rotavirus were also negative. The stool microscopy results were normal. Samples were collected for culture, and the patient was treated with 80 mg/kg ceftriaxone for enteric fever and cholestatic hepatitis and with azithromycin for bronchopneumonia (induced by the M. pneumoniae infection). Treatment response was poor, and the fever persisted. Abdominal ultrasonography indicated acute gastroenterocolitis with ileus and pelvic ascites but without cystic duct or bile duct dilatation. Neck tissue ultrasonography revealed multiple lymphadenopathies on the left side of the neck (largest dimensions: 2.08 cm × 1.49 cm; Figure 1B).
The high fever persisted for 2 days after admission (>5 days total), and a polymorphic skin rash developed, accompanied by lymphadenopathy on the left side of the neck, oral mucosa redness with strawberry tongue, and nonpurulent conjunctival congestion. The patient received a diagnosis of KD, and a single dose of IVIG as a 12-h 2 g/kg intravenous infusion and acetylsalicylic acid (50 mg/kg/day, divided into four doses) was administered. Echocardiography revealed no coronary artery involvement. After the administration of IVIG and aspirin, the fever and abdominal pain subsided and the jaundice and skin rash gradually resolved. Acetylsalicylic acid was reduced to one dose of 3-5 mg/kg at 48 h after the fever had subsided, and liver function improved gradually. Further laboratory examination results are presented in Table 2. The patient was discharged and followed up at our outpatient department. Abnormal laboratory data gradually returned to normal, and the echocardiography results for the coronary arteries in the outpatient department follow-up were normal.

DISCUSSION
In KD, hepatobiliary involvement is an atypical presentation. Our patient was a girl aged 4 years and 2 months with KD. In addition to fever, a classical symptom of KD, our patient had lymphadenopathy on the left side of the neck, a polymorphic skin rash, redness of the oral mucosa with strawberry tongue, and nonpurulent conjunctival congestion. Echocardiography indicated no coronary artery involvement. Jaundice with abdominal pain was diagnosed early, and febrile cholestatic hepatitis was also noted. Studies have reported different rates of diarrhea, vomiting, abdominal pain, hepatic dysfunction, and bile duct hydrops as nonspecific symptoms of KD, although these symptoms are not among the diagnostic criteria (4,8,9). In the present case, we observed the development of cholestatic hepatitis. Our findings indicate that cholestatic hepatitis can be an atypical early sign of KD, and early treatment with IVIG can rapidly improve liver function, cholestasis, and other conditions and also prevent cardiac complications. In this study, in addition to the reported case, we reviewed another 32 cases of KD with hepatobiliary involvement reported between 2000 and 2021 in studies retrieved from PubMed, Google Scholar, Crossref, and Web of Science; the details of these studies are presented in Tables 3, 4 (7,. The mean age of the pediatric patients in the reports was 5.26 years. The age at the onset of KD with hepatobiliary involvement was later than the average age at KD onset, with 73 and 27% patients presenting with classical and incomplete KD, respectively. In addition to the classical clinical findings, the most common clinical presentations in these patients were jaundice and abdominal pain. In total, 76% of the patients presented with jaundice and 48% presented with abdominal pain. Laboratory data indicated hyperbilirubinemia, cholestasis, hepatitis, and other abnormalities. For five patients, direct bilirubin data were

References
This study Anjani et al.
Morita et al.
Menon et al.
Paglia et al.
Sarkar et al.
Bylund et al.  not available, and for two, total bilirubin data were not available; however, all the other patients exhibited an increase in direct bilirubin and total bilirubin. Furthermore, all the patients except three (for whom serum inflammatory marker data were not available) exhibited an increase in serum inflammatory markers.
In total, 91% of the patients had increased levels of liver enzymes. However, γ-glutamyl transpeptidase activity was examined in 24 patients, all of whom had high cholestatic indexes. The 33 patients were all prescribed IVIG and oral acetylsalicylic acid when KD was diagnosed. After treatment, fever subsidence was noted for all these patients, and rapid regression of jaundice was noted in 96% of these patients. Although jaundice was identified in most of the cases, not all had notable results for abdominal ultrasonography and echocardiography. Moreover, 33% of the patients had an enlarged liver, 18% had a thickened gallbladder wall, and one patient was revealed to have intrahepatic bile duct stasis through abdominal ultrasonography. Despite the diverse abdominal ultrasonography results, only one of the patients had autoimmune sclerosing cholangitis; the others all had negative abdominal ultrasonography results after follow-up.
In addition, 39% of the patients had dilated coronary arteries, resulting in aneurysms. Preventing coronary artery aneurysm is crucial because it may cause stenosis of the vessels, often resulting in coronary artery obstruction and myocardial ischemia (1). Furthermore, 30% of the patients had other comorbidities. Overall, abnormal abdominal ultrasonography findings were obtained for 61% of the patients, and echocardiography revealed cardiac involvement in 45% of the patients. A high proportion of children with KD with hepatobiliary involvement appear to have cardiac involvement, but the physiopathology of hyperbilirubinemia and cholestatic liver damage in KD remains undetermined. Vasculitis-associated inflammation and obstruction in the liver and gallbladder are considered the cause of increased transaminase levels and cholestasis (9). Increased serum γ-glutamyl transpeptidase activity is a marker of cholangiocyte injury and is indicative of bile duct damage. Acute hydrops of the gallbladder in some patients suggests that inflammatory cholangiocyte injury may extend from small to large bile ducts (17). However, hydrops of the gallbladder is an atypical sign of KD (1). Children with KD develop isolated gall bladder hydrops without bilirubin or liver transaminase elevation, which should also be considered.
Abdominal ultrasonography in 91% of the patients reviewed did not indicate hydrops of the gallbladder, and cholestasis in 96% of these patients was mitigated after IVIG treatment.
Regarding the pediatric diagnosis of KD, a differential diagnosis may be required given that KD is diagnosed on the basis of clinical criteria; no specific diagnostic test has been developed. Various organ systems are involved in atypical KD, including the central nervous system and ocular, renal, joint, and gastrointestinal systems. Abdominal manifestations are sometimes acute, and severe abdominal pain similar to that associated with appendicitis or pancreatitis may lead to a surgical intervention (28). Such atypical manifestations of KD may delay treatment. Prompt KD diagnosis is crucial because IVIG administration within 10 days of the onset of fever results in a lower rate of coronary abnormalities and lowering of the risk of coronary artery aneurysm formation from 20-25% to 3-5% in those who are appropriately treated (9,31,32).
The etiology of KD remains unclear. Immunological responses are reported to be associated with KD, but the immunological profile associated with KD has yet to be defined (1). Furthermore, an infection-induced immunologic response may be considered a predisposing factor; according to some case reports, KD may be associated with M. pneumoniae infection (33)(34)(35). M. pneumoniae has several arrays for immunomodulation, including T cell and B cell activation and cytokine oversecretion, which are thought to trigger KD (36). M. pneumoniae infection can have a wide spectrum of extrapulmonary manifestations (including dermatological) that may mimic KD (37). A study reported that acute hepatitis can be included in the heterogeneous group of extrapulmonary diseases related to M. pneumoniae infection (38). The pathogenesis of hepatitis related to M. pneumoniae infection is likely to be immune mediated (38), but the clinical manifestations of KD, including strawberry tongue and jaundice, are not a clinical extrapulmonary manifestation of M. pneumoniae infection (1,37). M. pneumoniae infection may be a trigger for KD leading to hepatobiliary problems. The exact pathological mechanisms and whether M. pneumoniae infection is related to KD warrant further investigation. Notably, KD combined with M. pneumoniae infection may present as a more severe clinical condition; thus, early treatment of the infection is essential.
This study has limitations. Not all the cases that we reviewed had complete hepatobiliary data. The child in the reported case was not tested for hepatitis E, and complete work-up for autoimmune hepatitis was not performed. However, the presence of these conditions was unlikely.
Jaundice is a critical differential diagnosis of KD, a disease requiring prompt treatment with IVIG and aspirin to alleviate symptoms and prevent fatal cardiac complications. Even if coronary abnormalities are not initially observed, cardiac involvement is highly likely in patients with KD and hepatobiliary involvement and must be treated without delay. Physicians should consider the presence of this condition when examining children presenting with febrile cholestatic hepatitis.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Taipei Medical University-Joint Institutional Review Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

AUTHOR CONTRIBUTIONS
S-WH cared the patient, drafted the initial manuscript, and approved the final manuscript as submitted. S-CL diagnosed, cared and treated the patient, also conceived, drafted, reviewed, and revised the manuscript, and approved the final manuscript as submitted. S-YC and K-SH are consultants and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.