Acholic Stools as a Primary Presenting Symptom of Incomplete Kawasaki Disease - Consultant360

A previously healthy 4-month-old boy presented to a tertiary pediatric emergency department with a 2-day history of cough, nasal congestion, and fever.

AFFILIATIONS:
¹Pediatric Residency Program, Children's National Health System, Washington, DC
²Division of Hospitalist Medicine, Children's National Health System, Washington, DC
³Division of Critical Care Medicine, Children's National Health System, Washington, DC

CITATION:
Crawford L, Korattiyil M, Dixon G, Siems A. Acholic stools as a primary presenting symptom of incomplete Kawasaki disease. Consultant. Published online July 14, 2022. doi:10.25270/con.2022.06.00008

Received December 18, 2021; accepted January 4, 2022.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Lexi M. Crawford, MD, Children's National Health System, Pediatric Residency Program, 111 Michigan Avenue NW, Washington, DC 20010 (LCrawford3@childrensnational.org)

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ABSTRACT:  

Kawasaki disease is an acute febrile vasculitis that affects medium-sized arteries and occurs predominantly in children. In many patients, the clinical manifestations of Kawasaki disease are atypical or incomplete which often leads to a delay in diagnosis. In some patients with Kawasaki disease, gastrointestinal symptoms and/or laboratory and radiological hepatobiliary abnormalities can be part of the initial presentation, masking the typical symptoms of Kawasaki disease. Here we present a case of an infant presenting with acholic stools, gallbladder hydrops, and rapid progression to synthetic liver dysfunction that was found to have incomplete Kawasaki disease. Despite timely administration of IVIG, our patient developed coronary artery aneurysms necessitating close follow-up with cardiology. This case highlights the need for a high index of suspicion for a diagnosis of Kawasaki disease in children presenting at the extremes of the age range with non-classical symptoms and discusses important risk factors for IVIG-resistance and development of coronary artery aneurysms.
 

Key words: Kawasaki disease, coronary artery aneurysm, IVIG-resistance

A previously healthy 4-month-old boy presented to a tertiary pediatric emergency department with a 2-day history of cough, nasal congestion, and fever.

Physical examination. In triage, he was febrile to 40.1°C, tachycardic, and tachypneic without hypoxemia. Initial examination revealed a nontoxic-appearing infant in mild respiratory distress with clear lungs on auscultation and a diffuse erythematous confluent macular rash covering his trunk. Initial workup was concerning for leukocytosis (white blood cell count [WBC], 25,000 cells/mcL (normal, 4000-11,000 cells/mcL]) with bandemia. Chest radiograph revealed no acute cardiopulmonary disease and respiratory pathogen panel was negative. Blood and urine cultures were obtained, a dose of intravenous ceftriaxone was given, and the patient was admitted to the acute care department for respiratory monitoring and to rule out sepsis. Despite administration of acetaminophen, he remained persistently febrile.

On the second day of hospitalization, his clinical status acutely worsened with the development of acholic stools and increased respiratory effort. On examination, he was found to be lethargic with decreased peripheral perfusion, significant abdominal distention, hepatomegaly, mild conjunctival injection, and erythroderma of the abdomen.

Diagnostic testing. Laboratory values revealed direct hyperbilirubinemia, significant coagulopathy (prothrombin time, 28 seconds [normal, 11.8-14.2 seconds], partial thromboplastin time of 41.4 seconds [normal, 24.4-35.4 seconds]), and transaminitis. His C-reactive protein level (CRP) was elevated at 19 mg/dL (normal, 0.08-1.2 mg/dL). Abdominal ultrasound revealed significant gallbladder distention with pericholecystic edema and wall thickening measuring 3.8 mm. There was no intrahepatic or extrahepatic biliary dilation. Liver, spleen, pancreas, bilateral kidneys, bladder, aorta, inferior vena cava, and hepatic veins were all within normal limits. He was transferred to the pediatric intensive care unit (PICU) given concern for uncompensated shock, acute liver failure, and cholestasis.

Upon transfer to the PICU, the patient was noted to be in hypoxemic respiratory failure and required intubation and mechanical ventilation. Due to hypotension in the setting of septic shock, a norepinephrine infusion was started. Antibiotics were broadened to include vancomycin and ceftazidime. Clindamycin was also initiated for a short period due to concerns for toxic shock syndrome. The patient was also noted to have been febrile for 5 days with nonblanching erythroderma and mild desquamation of his truncal region and interval development of bilateral bulbar conjunctivitis raising concern for incomplete Kawasaki disease (KD). The patient had supporting characteristics of gallbladder distention and wall swelling; laboratory values revealed a CRP level greater than 3.0 mg/dL, WBC count greater than 15,000 cells/mcL, albumin level less than 3 gm/dL, and anemia with hemoglobin level as low as 7.7 gm/dL (normal for his age [mean], 11.2-12.6 gm/dL).

Treatment and management. A dose of intravenous immunoglobulin (IVIG) 2 gm/kg was completed with subsequent resolution of fevers. Initial echocardiogram showed normal left ventricular systolic and diastolic function along with normal coronary arteries. Aspirin was not initiated at this time due to severe coagulopathy secondary to his acute liver failure.

Given the severity of clinical decompensation in the setting of acute liver failure and cholestasis, specialists in infectious disease, gastrointestinal/liver, and genetics were consulted. Abdominal computed tomography revealed moderate intra-abdominal ascites and pronounced distention of the gallbladder with mild pericholecystic edema with no evidence of focal gallbladder wall thickening or calcified cholelithiasis. Failure of hepatic function progressed to a severe coagulopathy requiring treatment with vitamin K and three fresh frozen plasma transfusions, thrombocytopenia requiring two platelet transfusions, and hypoalbuminemia requiring albumin infusions. Several laboratory tests were performed to rule out the source of infection and possible cause of liver failure. Extensive workup for infectious source or metabolic derangement as the source of liver failure was unrevealing. Given the patient's severe illness with liver dysfunction, a personalized gene sequencing panel was also performed during hospitalization.

The patient was eventually weaned off vasoactive infusions, extubated, and weaned to room air. Synthetic liver function improved over time and direct hyperbilirubinemia resolved. However, repeat echocardiogram 2 weeks after the initial echocardiogram was significant for small saccular aneurysms of left anterior descending coronary artery (Z-score 3.5), left main coronary artery (Z-score 4.7), and right coronary artery (Z-score 4.7), confirming the previous concern for incomplete KD. A second 2 gm/kg dose of IVIG was administered per American Heart Association guidelines due to the presence of coronary artery abnormalities and continued presence of systemic inflammation, with a CRP level of 3.58 mg/dL.

Patient outcome. The patient was discharged home on low-dose aspirin therapy. Subsequent echocardiograms revealed a decrease in size of saccular aneurysms. The patient followed up with a genetics specialist for gene sequencing panel results. He was found to have a heterozygous alteration of the POLG gene (heterozygous c.2857C>T [p.Arg953Cys], Exon 18 POLG). The decision was made to not initiate ubiquinol because the current literature on its use in POLG-related disorders is inconclusive.¹ The patient continues to be followed by a genetics specialist with the intent of starting ubiquinol if he has another severe episode of liver failure.

Discussion. In our case, we report an infant presenting with acholic stools, gallbladder hydrops, and rapid progression to liver dysfunction that was found to have incomplete KD. This case highlights the need for a high index of suspicion for a diagnosis of KD in children presenting at the extremes of the age range with nonclassical symptoms. The case also supports previous evidence that acute acalculous cholecystitis in setting of KD is an important risk factor for IVIG-resistance and development of coronary artery aneurysms.^2,3  

KD is an acute febrile vasculitis that affects medium-sized arteries.^2-5 It is the most common vasculitis in childhood, predominantly affecting children between the ages of 6 months and 6 years of age, and it represents the leading cause of acquired heart disease among children in developed countries.^2,6 In the absence of a diagnostic test, KD is diagnosed based on the following clinical criteria: 5 or more days of fever in addition to 4 of 5 signs of mucocutaneous inflammation—(1) bilateral bulbar nonexudative conjunctivitis, (2) oral mucosal changes, (3) diffuse rash, (4) changes in extremities, and (5) cervical lymphadenopathy [nodes larger than 1.5 cm]).^4,5,7 In many patients, the clinical manifestations of KD are atypical, which often leads to a delay in diagnosis. One multicenter study revealed incomplete KD as an independent predictor of delayed treatment.⁷ In some patients with KD or incomplete KD, gastrointestinal symptoms or laboratory and radiological hepatobiliary abnormalities, or both, can be the initial presentation, masking typical symptoms of KD. This sometimes leads to a misdiagnosis as a gastrointestinal disease.³ Another study revealed that patients at both extremes of the age spectrum were more likely to present with atypical or incomplete KD and found that children younger than 6 months or older than 5 years of age were at increased risk of delayed diagnosis and suboptimal outcomes, as our patient's case highlights.²

KD is the second most common cause of febrile cholestatic jaundice in children after viral illnesses; however, gastrointestinal symptoms, which are the presenting complaint in roughly 6% of KD patients,⁸ are not included in the diagnostic criteria for KD.⁷ Although our patient received prompt treatment with IVIG, his clinical presentation with severe gastrointestinal symptoms caused significant diagnostic uncertainty that led our team to pursue extensive workup and consultation with multiple pediatric subspecialists.

Despite appropriate treatment with IVIG, coronary artery abnormalities (CAA) will develop in 5% of patients with KD.^3,4 Extensive research has been performed to identify which elements of a patient's clinical presentation may place them at risk of developing CAA. In a study of 67 children with KD, acute acalculous cholecystitis (AAC) was found to be a statistically significant risk factor for the development of CAA especially when gallbladder distention was present.³ A diagnosis of AAC can be made if two or more of the four diagnostic criteria are met: (1) gallbladder distention, (2) gallbladder wall thickness more than 3.5 mm, (3) nonshadowing echogenic sludge, and (4) pericholecystic fluid collections.⁴ Abdominal imaging in our patient was consistent with a diagnosis of AAC, which contributed to his risk for and eventually the development of CAA. In addition, the presence of AAC and cholestasis as primary presenting symptoms of KD may also delay the diagnosis, thus leading to development of CAA due to delay in initiation of treatment.^3,6

Studies have validated the Harada score as a sensitive tool to stratify patients into risk categories for the development of CAA.⁹ The score consists of seven criteria, with a positive score defined as meeting four or more criteria (Table). Patients with a positive score are considered at risk of development of CAA. Our patient met all seven of the Harada score criteria. Thus, the presence of ACC and a high Harada score indicated that our patient was at high risk of developing CAA despite timely treatment with IVIG. The development of risk stratification tools is important in identifying patients that may benefit from adjuvant therapies for KD, including repeat doses of IVIG, high-dose pulse corticosteroids, and monoclonal antibodies for prevention of CAA.^4,9

The underlying monoallelic POLG gene mutation likely contributed to the severity of clinical decompensation and rapid progression to liver failure and cholestasis in our patient. The POLG gene codes for the formation of the active alpha subunit of polymerase gamma (pol γ), a DNA polymerase that functions within the mitochondria.¹⁰ DNA polymerases are enzymes that "read" and replicate sequences of DNA in addition to playing roles in DNA repair.¹⁰ Pol γ is the only DNA polymerase that can replicate mtDNA, which is essential for the normal function of mitochondria.¹⁰ Although individuals with homozygous mutations are more severely affected by POLG-related disorders, the geneticists involved in our patient's care believe that the mutation puts him at increased risk for decompensation and liver failure when he is ill or under severe stress.

Conclusion. This case highlights the need for a high index of suspicion for a diagnosis of KD in children presenting with nonclassical symptoms and supports previous evidence that acute acalculous cholecystitis in setting of KD is an important risk factor for IVIG-resistance and development of coronary artery aneurysms.³