"Have you covered all the bases?/Is the problem cholestasis?/After days of pyrexia/Does the case still perplex ya?/When what's under your nose is Not the diagnosis"

You've been approached by a surgeon at your local hospital to consult on a perplexing patient: an 8-year-old African-American boy who yesterday was brought to the emergency department with a 20-hour history of abdominal pain. The child could neither localize the pain nor describe its quality. He did not have testicular pain. He had eaten dinner without difficulty the night before presentation but had two episodes of nonbloody, nonbilious emesis on his way to the ED. His mother thought that he felt warm; in the ED, the temperature was 38.4° C.

The chart shows that the patient has a medical history remarkable only for "sinus problems" and seasonal allergy. Homeless, he lives with his mother and three sisters in a shelter.

Can't think of a diagnosis The surgeon admitted the boy for possible appendicitis. He was observed overnight and treated with intravenous fluids. Routine lab tests were run on admission, including a CBC. The white blood cell count was 19.7 x 10³/μL; hemoglobin, 12.5 g/dL; hematocrit, 36.5%; and platelet count, 286 x 10³/μL. Urinalysis revealed a specific gravity of 1.027; pH, 6.5; 2+ bilirubin; 1+ ketones; 2+ urobilinogen; trace leukocyte esterase; and a negative microscopic analysis.

Overnight, the patient spiked a temperature to 40.4° C. Because a repeat CBC showed a WBC count of 20.2 x 10³/μL, blood was drawn for culture. Because of the high fever, he was started on ampicillin-sulbactam.

On your examination, the boy appears ill. Heart rate is 101/min; respirations, 24/min. Blood pressure is 100/62 mm Hg. The conjunctivae are mildly to moderately injected bilaterally, without exudate. Sclera are icteric. Mucous membranes are somewhat dry, but his posterior oropharynx appears normal. The neck is supple, and there is a tender, 1.5 centimeter right-side anterior cervical lymph node.

The chest is clear, and the cardiovascular exam is normal. The abdomen is soft and nondistended. There is mild-to-moderate tenderness with guarding, mostly in the right upper quadrant. Genitourinary exam shows Tanner stage I development; the genitalia are normal and no hernia is detected. The skin and extremities are normal.

Wanting more information Right upper-quadrant pain with fever and elevated liver function point to hepatitis or cholecystitis. The surgeon has already obtained an abdominal sonogram that shows a normal liver and an enlarged gallbladder with a thickened wall- but no gallstones. Furthermore, the gallbladder did not appear very tender when the ultrasound probe was pressed firmly into it. Diffuse periportal edema is seen in the liver; the common bile duct appears normal.

The surgeon is reluctant to operate without seeing the stones that would explain cholecystitis. He is also concerned that the child is now febrile, and wants to wait for the "hot" gallbladder to cool down with antibiotics. He has ordered a HIDA scan of the gallbladder for this morning, to further examine gallbladder function, and, at this point, asks for your help in reaching a diagnosis.

Certainly, the boy could have viral hepatitis-if so, it would most likely be A. Hepatitis B or C presenting acutely at this age would be unusual. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are also likely causes of hepatitis in this age group; these infections can be associated with high fever and lymphadenopathy. Adenovirus infection of the liver is also a possibility. Autoimmune hepatitis is less common in a school-age child and is more likely to have a chronic presentation. Toxins that cause hepatitis are, again, unusual in this age group. Last, metabolic causes of hepatitis, such as Wilson disease and hemochromatosis, are unlikely to present with high fever.

But would the liver appear normal on the CT scan and sonogram if there is active hepatitis? The gallbladder was large on the sonogram, so you ponder the differential diagnosis of this finding. First, cholecystitis is what your surgical colleague is wondering about. No stones are visible on the sonogram- is it possible they were just not seen? Two types of stones can obstruct the neck of the gallbladder: cholesterol stones and pigment stones. For this thin 8-year-old to have cholesterol stones would be very unusual, unless he had undiagnosed familial hypercholesterolemia. You want more family history to see if any of his relatives have had a myocardial infarction or stroke at a young age, but the mother has not been seen since admission, and you're unable to reach her by telephone. It's simple enough to order a lipid profile while the patient is hospitalized.

What about pigment stones? The patient's race puts him at high risk of a hemoglobinopathy that can cause chronic hemolysis. In your state, screening for sickle cell disease is performed at birth, and you assume that this would have come up in the history; nevertheless, you keep this in your differential for now because the family is unavailable for questioning.

Other red blood cell membrane defects, such as hereditary spherocytosis and elliptocytosis, are also possible. You examine the peripheral smear in the lab but find no abnormally shaped RBCs or sickle cells. Interestingly, you can't see evidence of hemolysis, either. CBC indices are also normal, making a thalassemia unlikely. Because the hyperbilirubinemia is mostly direct, an obstructive hepatic or biliary process is the more likely cause.

Now, you're handed the report of the HIDA scan. There is no uptake of tracer by the gallbladder, which, the radiologist says, is consistent with cholecystitis.

What causes an enlarged gallbladder without stones? A search of the literature reveals little. An obstructing tumor is a rare possibility, but you already have a negative abdominal CT scan. The surgical literature has old articles on an entity called acute acalculous cholecystitis, but most patients with this condition are described as more acutely ill than your patient.

You consider that your patient is homeless, and may therefore be more likely to have been exposed to rodents. Leptospirosis can cause high fever and gallbladder hydrops. Fortunately, a blood culture was taken the night before and the antibiotic that was ordered will cover Leptospira interrogans. You alert the microbiology lab that this is a possibility so that they can culture for the spirochete.

Last, Kawasaki disease (KD) can cause gallbladder hydrops. Your patient is beyond the typical age range for Kawasaki, however, and has had only two days of fever. He does have conjunctival changes and an enlarged cervical lymph node, but lacks the other required diagnostic criteria: mucous membrane changes, changes to the extremities, and rash.

Saved from the scalpel! The surgeon says that he plans to continue the antibiotics and wait for the fever and bilirubin level to come down, and then proceed to laproscopic cholecystectomy in three to four days. This gives you time to investigate the medical possibilities and continue observation. You decide to order serologic studies for hepatitis, including EBV and CMV; mononucleosis can cause fever, anorexia, lymphadenopathy, and elevated liver enzymes. You also order a lipid profile.

On the third hospital day, the patient develops an erythematous, papular rash immediately after infusion of the antibiotic. This is likely a drug rash, although it also appears typical of the rash in EBV infections that have been treated with ampicillin. Drug rashes are usually pruritic, however, and your patient isn't scratching or complaining of an itch. The rash does not fade, so you change the antibiotic to cefotaxime. Blood cultures have not grown anything.

The surgeon is concerned. The boy is persistently febrile-as high as 39.4° C-even while on antibiotic therapy that would cover gallbladder infection. Also of concern is that the total bilirubin level continues to rise: Today, it is up to 4.7 mg/dL (total). That is not typical of acute cholecystitis.

Keeps getting more interesting The next day-hospital day 4-your patient continues to run a fever, and the total bilirubin level is now 5.4 mg/dL. Titers return for EBV, CMV, and hepatitis A, B, C infection: There is evidence of prior CMV infection only. An HIV antibody test obtained at admission is negative. You note that child has had persistently mild hyponatremia since admission-all checks of sodium have come back in the neighborhood of 130 mEq/L. The patient appears more comfortable and has managed to eat some. He has, however, been whining and complaining persistently, nursing staff report- about nothing in particular.

When you arrive to see the boy on the fifth hospital day, he has become increasingly irritable. Oral mucosa are reddened and lips are cracked and peeling. This face looks familiar and, with the injected conjunctivae, you move Kawasaki disease to the top of your differential. Add to that five days of fever now. The erythrocyte sedimentation rate is 72 mm/hr; C-reactive protein, 9.9 mg/dL. You obtain an echocardiogram, which shows coronary artery diameters at the upper limit of normal for age. You move to treat presumptive KD: intravenous immune globulin (IVIG) and high-dose aspirin until the fever abates.

A description of Kawasaki disease, also known as mucocutaneous lymph node syndrome, was first published in the English language literature in 1974.¹ The disease is a vasculitis of small vessels, affecting mostly children between 6 months and 5 years old. The cause is unknown. Diagnostic criteria are clear: The patient must have five days of fever, usually over 104°, and four of five of the following:

The most feared complication of KD is coronary artery aneurysm, which occurs in about 25% of untreated patients. IVIG and aspirin are used in the acute phase to prevent this complication. Administered within the first 10 days of illness, the two agents reduce the incidence of coronary aneurysm to 3% to 5%.³

Gallbladder hydrops in children has an interesting history if one looks back to cases reported in the surgical literature before the description of KD.^4-10 Many such patients were brought for medical attention in the context of what was considered a viral illness with rash and fever. After KD was described, case series of patients with gallbladder hydrops have been reported within that context. In all but very rare cases, gallbladder disease abates during the convalescent phase of KD and generally does not require surgical treatment.

All is well (once again, readers) Over the next few days, after immune globulin treatment, the patient's fever falls and his ESR and CRP level drop. He proceeds to peeling and desquamation of the hands and feet. At six-week cardiology follow-up, coronary artery diameters are still at the upper limit of normal.

The road Kawasaki/Can turn out . . . rocky.

REFERENCES

1. Kawasaki T, Kosaki F, Okawa S, et al: A new infantile acute febrile mucocutaneous lymph node syndrome (MCLS) prevailing in Japan. Pediatrics 1974;54:271

2. Morens DM, O’Brien RJ: Kawasaki disease: A ‘new’ pediatric enigma. Hosp Pract 1978;13:109

3. Burns JC, Kushner HI, Bastian JF, et al: Kawasaki disease: A brief history. Pediatrics 2000;106:e27

4. Ternberg JL, Keating JP: Acute acalculous cholecystitis. Complication of other illnesses in childhood. Arch Surg 1975;110:543

5. Slovis TL, Hight DW, Philippart AI, et al: Sonography in the diagnosis and management of hydrops of the gallbladder in children with mucocutaneous lymph node syndrome. Pediatrics 1980;65:789

6. Mercer S, Carpenter B: Surgical complications of Kawasaki disease. J Pediatr Surg 1981;16:444

7. Grisoni E, Fisher R, Izant R: Kawasaki syndrome: Report of four cases with acute gallbladder hydrops. J Pediatr Surg 1984;19:9

8. Suddleson EA, Reid B, Woolley MM, et al: Hydrops of the gallbladder associated with Kawasaki syndrome. J Pediatr Surg 1987;22:956

9. Wheeler RA, Najmaldin AS, Soubra M, et al: Surgical presentation of Kawasaki disease (mucocutaneous lymph node syndrome). Br J Surg 1990;77:1273

10. Falcini F: Acute febrile cholestasis as an inaugural manifestation of Kawasaki’s disease. Clin Exp Rheum 2000;18:779