The Journal o f Pediatrics Freeman et al. 4 7 9 Volume 123, Number 3

gand assay, and physiological dose-response curves. Am J Physiol 1978;235:E97-E102.

13. D'Argenio DZ, Schumitzky A. ADAPT 1I user's guide. Los Angeles: Biomedical Simulations Resource, University of Southern California, 1990.

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Clinical and laboratory observations

Intravenously administered immune globulin for the treatment of infection-associated hemophagocytic syndrome

Bridget Freeman, MD, Mobeen H. Rathore, MD, Emad Salman, MD, Michael J. Joyce, MD, PhD, and Paul Pitel, MD

From the Departments of Pediatrics, University of Florida Health Science Center and Nemours Children's Clinic, Jacksonville, Florida

Infection-associated hemophagocyt ic syndrome is an unusual disease with a high mortality rate. A variety of treatment modalities have been used with lim- ited success. We report three patients with infection-associated hemophago- cytic syndrome successfully treated with intravenously administered immune globulin. (J PEDIATR 1993;123:479-81)

Infection-associated hemophagocytic syndrome is charac-

terized by a benign proliferation of histiocytes throughout

the reticuloendothelial system in association with a systemic

infection, often viral. The immune mechanism is not clear,

Submitted for publication Jan. 13, 1993; accepted April 22, 1993.

Reprint requests: Mobeen H. Rathore, MD, 653-1 W. 8th St., De- ~partment of Pediatrics, Jacksonville, FL 32209.

Copyright �9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/26/48132

but if untreated, this disease has a high mortality rate.l

Numerous treatment modalities have been used, with lim-

ited success. We report three cases of I A H S in which intra-

venously administered immune globulin was used success-

fully.

CASE R E P O R T S Patient 1. A 7-year-old black girl had a 1 week history of fever

(up to 39.4 ~ C) and lethargy. Her examination on admission to the hospital showed a temperature of 38.3 ~ C. She was lethargic but responded appropriately to questioning and had no focal neurologic signs. There was no significant lymphadenopathy or bepatosple-

4 8 0 Freeman et al. The Journal o f Pediatrics September 1993

Table. L a b o r a t o r y da ta o f the th ree pa t ients

Patient No.

1 2 3

Leukocytes (109/L) 6.5 3.2 4.5 Hemoglobin (gm/L) 65 110 45 Platelet count (109/L) 314 80 96 Reticulocyte count (%) 0.006 0.001 0 Prothrombin time (sec) 11 14 13 Partial thromhoplastin time (sec) 24 150 42 Aspartate aminotransferase (#kat/L) 3.13 54.01 17.87 Lactic dehydrogenase (~kat/L) 37.67 183.70 72.56 Creatine phosphokinase (#kat/L) 42.68 155.76 166.88 Direct Coombs test - - - Indirect Coombs test - - - Fibrinogen (gm/L) ND 0.98 1.3 Fibrinogen split products (#g/ml) ND >40 <40 Lupus anticoagulant ND + + Antiplatelet antibody ND + ND

- , Negative result; +, positive result; ND, not done.

nomegaly. She had had chickenpox approximately 1 month earlier and had multiple residual scars. Shown in the Table are the labo- ratory data at the time of admission.

During the 24 hours after admission, she continued to have a fe- ver, and generalized lymphadenopathy and hepatomegaly devel- oped. Her hemoglobin level decreased to 46 gm/L, and she had re-

IAHS Infection-associated hemophagocytic syndrome IVIG Intravenously administered immune globulin

ticulocytopenia (Table). Hemoglobin electrophoresis showed a normal pattern, results of direct and indirect Coombs tests were uegative, and the peripheral blood smear was noncontributory. Results of serologic studies for Epstein-Barr virus and cytomega- lovirus were not consistent with a recent infection, and blood cul- tures were sterile. A bone marrow aspirate, obtained because of the patient's decreasing hemoglobin level and reticulocytopenia, showed an abnormal proliferation of histiocytes phagocytosing erythroid progenitor cells. The patient was given IVIG, 1 gm/kg, followed by a transfusion of packed erythrocytes. Within the next 24 hours, there was a significant increase in her reticulocyte count and a decrease in her tissue enzymes values. She has required no further therapy and is well 6 years later.

Patient 2. A 7-year-old black male patient had an acute febrile illness that was diagnosed as sinusitis. He was treated with an orally administered antibiotic by his physician. One week later he contin- ued to have fever, possible seizure activity, and intermittent confu- sion. When hospitalized, he had a fluctuating level of consciousness and intermittent decerebrate posturing. Examination showed a temperature of 39.4 ~ C, a pulse rate of 124 beats/min, a respira- tory rate of 38 breaths/rain, and a blood pressure of 100/60 mm Hg. He was obtunded, his pupils were sluggishly reactive to light, and he had intermittent spasticity of his lower extremities, espe- cially on the left, and intermittent decerebrate posturing. He also

had hepatomegaly. Shown in the Table are the laboratory data on admission.

During the next 12 hours the patient had disseminated intravas- cular coagulation, with blood oozing from both his upper airway and his gastrointestinal tract. He required multiple transfusions of fresh frozen plasma, cryoprecipitate, platelets, and packed eryth- rocytes. His liver enzyme values were markedly elevated (Table). Neurologically, he continued to deteriorate and required mechan- ical ventilation. Shortly after admission, an unenhanced computed tomography scan of the head showed mild ventricular dilation. Bone marrow aspiration showed histiocytic infiltration and he- mophagocytosis. His blood culture grew Escherichia coil Results of viral serologic studies for Epstein-Barr virus and cytomegatov- irus were not consistent with recent infections.

After bone marrow aspiration, the patient received IVIG, 1 gin/ kg, on two separate occasions, after which his transfusion require- ment of packed erythrocytes diminished considerably, the dissem- inated intravascular coagulation resolved, the lupus anticoagulant disappeared, and tissue enzyme values became normal. However, the patient's neurologic condition continued to worsen. A second computed tomography scan of the head showed multiple areas of cerebral infarction. The child died of neurologic complications.

Patient 3. A 3-year-old black girl was seen after a 3-week hos- pitalization for "fever of unknown origin." During that hospital- ization the results of extensive studies, including those of a bone marrow aspiration for cytology and cultures, were noncontributory. The patient was discharged with a tentative diagnosis of collagen vascular disease, and aspirin therapy was initiated. Her symptoms improved somewhat, and she became afebrile. However, 1 day be- fore her second hospitalization, she again became febrile. Her in- termittent fevers were now in their sixth week.

Examination on the patient's second admission to the hospital showed a temperature of 40.6 ~ C and a respiratory rate of 40 breaths/min. The patient was lethargic but arousable, recognized her parents, and had no focal neurologic deficits or meningeal signs.

The Journal of Pediatrics Freeman et al. 4 8 1 Volume 123, Number 3

Her liver was palpable 1 cm below the right costal margin, and the spleen tip was also palpable. Laboratory data on admission were profoundly abnormal and had changed significantly from those ob- tained during her initial hospitalization (Table). Bone marrow as- piration showed infiltration with benign-looking histiocytes, with evidence of hemophagocytosis.

Epstein-Barr virus IgG titer was 1:640; results of the remaining viral studies were negative, as were results of numerous blood cul- tures. The patient received IVIG. 1 gm/kg, and had a prompt de- crease in tissue enzyme values, followed by a gradual increase in platelet count and reticulocyte count. The patient's subsequem clinical course was uneventful, and she remains well 1 year later.

D I S C U S S I O N

Infection-associated hemophagocytic syndrome is an un- usual disease with multiple etiologic factors and typical clinical features. Most patients have high fevers, diffuse lymphadenopathy, and hepatosplenomegaly. The microor- ganisms implicated include viruses of the herpes family, as well as other viruses, bacteria, and parasites. 28 Laboratory

data show evidence of cytopenia, disseminated intravascu- lar coagulation, profound elevation of tissue enzyme values, and elevated serum triglyceride concentrations. 9 Bone

marrow examination usually reveals an excessive prolifer- ation of benign-looking histiocytes phagocytosing hemic cells. When first described, IAHS was identified mainly in immunocompromised patients, patients recewing chemo- therapy, and patients who had undergone organ transplan- tation. 9 Since then, it has been reported in patients with no recognized underlying immune dysfunction. The clinical course is usually fulminant, with mortality rates of 40% in the immunocompromised and 20% in immunocompetent patients. 1

The pathophysiology of IAHS remains obscure. This syndrome probably results from a defect in immune regu- lation such as excess cytokine production, as well as abnor- mal T-cell funct ion) ~ 11 The T-cell abnormalities range from the production of a lymphokine by CD4 lymphocytes 12

to excessive stimulation of cytotoxic T cells, resulting in in- creased production of interferon gamma, and in macroph- age stimulation and the subsequent release of tumor necro- sis factor. H, 13

Previously reported therapeutic approaches to IAHS have had limited efficacy. Therapy has been varied and has included corticosteroids, cyclosporine, 14 clinical support,

and withdrawal of immunosuppressant treatment. Treat- ment of specific infections reportedly has had some success. In some cases, plasmapheresis has ameliorated the course of the disease, suggesting the involvement of lymphokines in the disease process.l~ A single case of multiple infusions of IVIG to treat an apparent immune thrombocytopenia asso- ciated with IAHS, with a partial response and survival, has been reportedJ 5

In our patients, IVIG was utilized because of its efficacy in the treatment of pediatric autoimmune hematologic dis- orders: The mechanisms of action of IVIG are complex and include Fc receptor blockade, antiidiotype effects, and pos- sibly down-regulation of immunoglobulin synthesis and immune stimulation.ll The reported toxic effects of IVIG

have been minimal. We believe that IVIG improved the hematologic status of

all three of our patients. No other therapeutic modalities have demonstrated such success, and known mechanisms of action of IVIG are consistent with current knowledge regarding the pathophysiology of IAHS. We recommend

that IVIG be considered in the t reatment of this unusual and potentially fatal disorder.

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