The admitting diagnosis was septic arthritis. Bilateral arthrocenteses appeared inflammatory. Naproxen and low-dose prednisone were added.

Cultures and liver function were normal, as were WBC and platelet counts. However, WBC bands increased to 56% from 15%, and hemoglobin dropped from 3g to 8.6 g/dL in the first 3 days of admission. Serologies for rheumatic diseases, HIV, and other viruses were negative.

Acute renal failure and liver function abnormalities developed concurrently. Naproxen was discontinued.

After admission to the ICU, “in the course of 10 days, everything worsened,” noted Paulo B. Pinho, M.D., a Staten Island, N.Y., pediatrician and internist. Dr. Pinho reported the case in a poster session at the annual meeting of the Federation of Clinical Immunological Societies in Boston.

The patient's first few days in the ICU were marked by hypotension (BP 90s/30s), tachycardia (110–115 bpm), persistent fevers (>101° F), pancytopenia with bands of 88%, and coagulopathy. Her erythrocyte sedimentation rate (ESR) was low (5 mm/hr), but C-reactive protein (CRP) was elevated (24 mg/dL). Transaminases had climbed to an aspartate transferase level of 2653U/L and alanine transferase of 504 U/L. Ferritin increased to >2,000 ng/mL (fractionated 152,197).

Given right upper quadrant pain and hepatosplenomegaly, an abdominal ultrasound was performed to look for intra-abdominal causes of presumed septic shock. It revealed only sludging.

Admitting diagnosis to the ICU was septic shock. Other diagnoses considered included adrenal insufficiency (potentially induced by corticosteroid withdrawal), thrombotic thrombocytopenia purpura (TTP, worsening renal function and altered mental state), and macrophage activation syndrome (MAS).

All cultures were negative; sepsis was rejected. The absence of microangiopathic hemolytic anemia ruled out TTP. Cortisol levels were consistent with the level of systemic inflammation, so adrenal insufficiency was also abandoned.

A bone marrow biopsy showed variable cellularity (40%–60%) with prominent hemophagocytosis. This finding, along with the markedly elevated ferritin, low ESR, yet elevated CRP suggested that the patient's previously uncharacterized febrile illnesses may have been a subtle presentation of systemic onset juvenile idiopathic arthritis (S-JIA).

The physician team entertained a diagnosis of JIA flare at this point, but the decreased counts of platelets and other cell lines, massive coagulopathy, and markedly elevated ferritin suggested macrophage activation syndrome (MAS), according to Dr. Pinho.

MAS is a relatively rare but potentially fatal complication of S-JIA and other chronic rheumatologic diseases. Its incidence is uncertain; the literature documents only hundreds of cases in patients with S-JIA, said Dr. Pinho. Reported mortality rates range from 8% to 22%.

The cause of MAS is also unclear, but it may be precipitated by infection or medication changes. “The clinical signs and symptoms can be easily explained by the surge of numerous cytokines and chemokines produced by activated macrophages and T cells,” said Dr. Pinho.

MAS presents as a confusing constellation of signs and symptoms. It is often characterized by well-differentiated hallmark macrophages showing hemophagocytosis in the bone marrow. But there are no firm diagnostic criteria.

Angelo Ravelli, M.D., and colleagues recently proposed preliminary diagnostic criteria for differentiating MAS from a disease flare in patients with S-JIA.

The researchers performed a systematic evaluation of the sensitivity and specificity of findings in 74 patients with MAS and 37 patients with S-JIA who had disease flares (J. Pediatr. 2005;146:598–604).

Their criteria focus on laboratory findings, since clinical symptoms of MAS often arrive late. They suggest the presence of any two of the following four criteria is diagnostic: decreased platelet count (≤262 × 109/L); elevated levels of aspartate transferase (>59 U/L); decreased WBC count (≤4.0 × 109/L); or hypofibrinogenemia (≤2.5 g/L).

Hyperferritinemia may also be highly diagnostic. Bone marrow biopsy for macrophage hemophagocytosis should be reserved for confirmation of only doubtful cases because hemophagocytosis is not always present in MAS, they wrote.

Other clinical criteria include CNS dysfunction, hemorrhages, and hepatomegaly.

The patient was bolused with intravenous methylprednisolone and started on cyclosporin A. Intense blood product, ventilatory, and fluid support were essential. Not until day 14 did she begin to improve. By day 18 she was extubated and on day 31 discharged from the hospital with a prednisone taper and cyclosporin.

The extraordinary and swift transformation of a healthy-appearing, young female with a sore knee and sore throat to a desperately ill patient with multiple organ failure points out the need for early recognition and prompt action, two essential components to good outcomes in this disease, according to Dr. Pinho.

His colleagues included Miguel Rodriguez, M.D.; Davida Menasha, M.D.; Manal Youssef-Bessler, M.D.; Bhavna Suri, M.D.; Allen Blaivas, M.D.; Ralph K. Messo Jr., D.O.; Rajendra Kapila, M.D.; and Leonard Bielory, M.D., of New Jersey Medical School and Staten Island University Hospital, New York.

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A bone marrow biopsy done at ICU admission showed variable cellularity with prominent hemophagocytosis. Courtesy Dr. Paulo B. Pinho

Joint Decisions