Hemophagocytic syndrome after Kawasaki disease

Hemophagocytic syndrome (HPS) is a rare and life-threatening disease in which a generalized histiocytic proliferation results in hemophagocytosis and up-regulation of inflammatory cytokines. This syndrome has been associated with infections, malignancy, drugs and immunologic triggers such as Kawasaki disease (KD). We describe the clinical and laboratory features of two children with HPS after KD and review the three previously reported pediatric cases of recrudescence of KD leading to HPS. Hemophagocytic syndrome (HPS) is a nonmalignant disorder characterized by uncontrolled histiocytic proliferation, hemophagocytosis and up-regulation of inflammatory cytokines. 1–3 Diagnostic criteria for HPS include fever, splenomegaly, cytopenia in two or more cell lines, hypertriglyceridemia or hypofibrinogenemia and hemophagocytosis in bone marrow, spleen, lymph nodes or other organs. 4 HPS encompasses both primary (familial) and secondary (reactive) disease. Clinical presentations of patients with primary and secondary HPS may be indistinguishable. 1, 4–6 Secondary HPS may develop from strong immunologic activation associated with severe bacterial or parasitic infection (infection-associated hemophagocytic syndrome), viral infection, malignancy, drugs (phenytoin) or prolonged administration of fat-soluble lipids in parenteral nutrition (fat overload syndrome). 7, 8 HPS has been reported after conditions associated with significant immunologic stress such as acute lupus erythematosus and Kawasaki disease (KD). 9–12 We report two additional cases of the rare but important occurrence of HPS after Kawasaki disease. Case 1. An 11-year-old previously healthy Asian boy was admitted to Texas Children’s Hospital (TCH) with a 2-week history of fatigue, fever to 103°F and pharyngitis. At the onset of illness he also had nonexudative conjunctival injection and was believed to have a viral illness. Fever persisted despite scheduled antipyretics. Before admission he developed an erythematous, polymorphous, nonpruritic rash on his shoulders, arms and legs that evolved during the ensuing days to affect most of his body. He was evaluated in the outpatient setting where his physician noted a 1.5-cm right posterior cervical lymph node. A white blood cell count at that time was 16 000/mm3. The patient received a steroid injection, and oral prednisone was prescribed. He was afebrile for 1 day, but the rash worsened. He presented to TCH the following day with a fever to 103°F and myalgias. Because the patient had fever above 102°F for >5 days, an enlarged cervical lymph node measuring 1.5 cm, rash, a history of conjunctival injection and red, cracked lips, he fulfilled the diagnostic criteria for Kawasaki disease. Platelet count was 294 000/mm3. The patient was given 2 g/kg intravenous immunoglobulin (IVIG) and high dose (100 mg/kg/day) aspirin. An echocardiogram revealed no coronary artery aneurysms. The patient continued to have fever for 48 h, but the rash slowly improved. Three days after receiving IVIG, the patient was afebrile, but fever to 101°F returned the next day, and he was given a second dose of 2 g/kg IVIG. Two days after the second dose of IVIG, his fever increased to 103–104°F. Serum aspirin concentration was 29.6 mg/dl (therapeutic concentration, 20–30 mg/dl). The rash again worsened, and the posterior cervical lymph node measured 2 by 2 cm. A repeat echocardiogram was normal. An abdominal ultrasound demonstrated splenomegaly, gallbladder wall thickening and bile duct wall thickening or periportal edema. The patient’s hemoglobin decreased from 12.2 g/dl at admission to 10.6 g/dl. A platelet count was 109 000/mm3. His clinical course prompted an evaluation for HPS. The patient’s initial serum ferritin concentration was 4023 μg/l and increased to 11 158 μg/l the following day. Viral, bacterial and other infectious diseases studies did not reveal an infectious cause for HPS. Case 2. A 10-year-old previously healthy Hispanic girl was admitted to TCH with a 2- to 3-week history of fever and an erythematous polymorphous, pruritic rash starting on her extremities and progressing centrally. She did not have sore throat, congestion or cough. She complained of myalgias and arthralgias. A physician prescribed an antibiotic and oral steroid for these complaints, and some improvement of her symptoms was noted. Several days later the rash and fever recurred, and she developed red eyes, red lips and enlarged cervical lymph nodes. She was admitted to the hospital. Her erythrocyte sedimentation rate was 91 mm/h. The patient met the criteria for Kawasaki disease, and 2 g/kg IVIG and high dose aspirin were given. Her fever defervesced, and the rash slowly improved. She was discharged home on low dose (3 to 5 mg/kg/day) aspirin 6 days after admission at which time the platelet count was 301 000/mm3. Four days after discharge she returned with a 2-day history of fever to 103.6°F and recurrence of a rash. She was given a second 2-g/kg dose of IVIG, and high dose aspirin was restarted. Abdominal ultrasound examination revealed marked gallbladder wall edema and splenomegaly. Two days after readmission she continued to have fever to 104°F and developed increased breathing exertion, hepatosplenomegaly and marked diffuse lymphadenopathy. Her hemoglobin and platelet count decreased from 11.7 g/dl and 320 000/mm3, respectively, the day before to 9.9 g/dl and 115 000/mm3. These clinical and laboratory changes prompted the infectious diseases service to consider the diagnosis of HPS. The patient’s initial serum ferritin value was 9338 μg/l. Viral, bacterial and other infectious diseases studies (including leptospirosis) were negative. Table 1 summarizes the clinical and laboratory data in these two patients compared with the three patients previously reported in the literature.TABLE 1: Clinical and laboratory findings in five patients with HPS following KDDiscussion. The association between KD and HPS has been reported previously in three children. 10–12 The mechanism by which KD evolves into or triggers HPS is unknown. Abnormal immunoregulation of T cells resulting in hypercytokinemia has been proposed to contribute to the pathogenesis of both syndromes. 13, 14 However, distinct hypercytokinemias have been reported for HPS and KD, suggesting differing mechanisms of T cell activation. 11, 15–18 Our two patients share clinical and laboratory features similar to those in the three previously reported children. 10–12 All five children had fever, hepatosplenomegaly and cytopenia in at least two cell lines as well as hemophagocytosis in bone marrow or liver biopsy. Serum lactate dehydrogenase and ferritin concentrations were elevated in all cases. Similar to what has been reported by other investigators, 4, 19–21 the most frequent missing criteria for the diagnosis of HPS were hypertriglyceridemia and hypofibrinogenemia. Two of the four children in whom serum triglycerides were measured demonstrated hypertriglyceridemia. None of the three patients tested had hypofibrinogenemia. All five children experienced the clinical deterioration of HPS near the fourth week of illness. In addition all patients had several days of improvement in fever and rash after one or more doses of IVIG and aspirin before their clinical deterioration associated with HPS. Interestingly four of the five children were not treated with IVIG until ∼2 weeks into their illness. The significance of this delay in IVIG treatment as it relates to the subsequent development of HPS is unknown. Unlike the three children previously reported in the literature, our two patients each received short courses of steroid therapy during their first week of illness. One patient had some initial improvement in a rash coincident with administration of steroids whereas the other child did not show any improvement in symptoms. The significance of this antecedent steroid therapy as it relates to our patients’ clinical courses is unclear. Another difference between our patients and those previously reported in the literature is that our patients were adolescents who developed KD whereas the other children were 6 years of age or younger. Although most children diagnosed with KD are <5 years of age, adolescent patients comprise 3 to 5% of KD patients. 22–24 Adolescents are more likely to present with atypical Kawasaki disease; therefore investigation into other causes of illness is necessary. In our patients the diagnostic criteria for KD were fulfilled, and no other cause of illness was found despite thorough investigation. In addition both patients initially responded to IVIG before their clinical deterioration associated with HPS. For patients with HPS an appropriate chemotherapeutic regimen in the form of etoposide, Decadron and cyclosporine therapy, recommended by the Hemophagocytic Lymphohistiocytosis Study Group, is best pursued under the guidance of a hematology oncology specialist. 25, 26 Four of the five patients with HPS after KD responded to therapy with etoposide and steroids (Decadron or prednisone) for HPS, and one patient received steroids without etoposide. Our two patients also received the cyclosporine therapy as recommended by the Hemophagocytic Lymphohistiocytosis Study Group. 25, 26 All five patients survived, whereas HPS from all causes has a survival rate of 10 to 55%. 25–29 After high dose IVIG and aspirin therapy, 10 to 15% of children with KD have persistent or recrudescent fever. 30 We agree with Al-Eid et al. 10 that children presenting with presumed recrudescence of KD, but accompanied by generalized lymphadenopathy; falling red blood cell, white blood cell or platelet counts; and coagulopathy should be evaluated for HPS. Because HPS is a potentially severe and life-threatening illness, its prompt recognition is necessary to initiate appropriate therapy. 21, 25, 26