Wolf at the Door

Posted by Sara Fazio • June 8th, 2012

In the latest Clinical Problem-Solving article, a 29-year-old man presented with a 1-week history of fever, night sweats, reduced appetite, and left upper abdominal pain exacerbated by inspiration. He reported no weight loss, cough, dyspnea, nausea, diarrhea, rash, mouth ulcers, arthralgias, or ocular or urinary symptoms.

Systemic lupus erythematosus (SLE) and the hemophagocytic syndrome are two important and related causes of fever and pancytopenia.

Clinical Pearls

• What laboratory abnormalities are commonly seen in SLE?

Whereas many connective-tissue diseases are associated with increases in both the erythrocyte sedimentation rate and the C-reactive protein level, SLE is often associated with an elevated erythrocyte sedimentation rate and a near-normal C-reactive protein level. The presence of antinuclear antibodies as well as antibodies to extractable nuclear antigens (e.g., anti-Smith, anti-RNP) and double-stranded DNA (anti-dsDNA) are very helpful in making the diagnosis of SLE; anti-dsDNA and anti-Smith are very specific for SLE. Complement levels (particularly C3 and C4) are often depressed. Lupus anticoagulant and anticardiolipin antibodies are commonly seen in SLE. Cytopenias are also frequent in SLE and reflect heterogeneous mechanisms that include anemia of chronic disease, peripheral immune-mediated destruction, primary bone marrow involvement, and therapy-related hematologic toxicity. If renal involvement is present, proteinuria may be found.

• What findings are suggestive of hemophagocytic syndrome?

The findings of fever, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and hemophagocytosis are all consistent with the hemophagocytic syndrome. Secondary hemophagocytic syndrome, sometimes known as the macrophage activation syndrome, can present at any age and in rare cases is a complication of infection, hematologic cancer, drug exposure (particularly exposure to immunomodulatory drugs), and autoimmune disease. This clinical presentation is also commonly referred to as hemophagocytic lymphohistiocytosis. Bone marrow examination usually shows hemophagocytosis, but this finding may initially be absent or confined to other organs, such as the spleen or lymph nodes.

Morning Report Questions

Q: What are common triggers for secondary hemophagocytic syndrome?

A: The most common infectious trigger is EBV, but HIV is increasingly implicated, and many other viral, bacterial, and protozoal infections have also been associated with secondary hemophagocytic syndrome. Of the autoimmune diseases associated with the hemophagocytic syndrome in adults, SLE is by far the most common, accounting for about 60% of cases; the estimated prevalence of the hemophagocytic syndrome among patients with SLE is up to 2.4%. Adult-onset Still’s disease is responsible for 10 to 15% of cases. There is considerable overlap between the features of adult-onset Still’s disease and those of secondary hemophagocytic syndrome, and the possibility of hemophagocytosis should be considered in any patient with adult-onset Still’s disease in whom cytopenias develop.

Q: How should hemophagocytic syndrome be managed?

A: Management of secondary hemophagocytic syndrome is based on control of the cytokine storm, treatment of possible triggers, and supportive care. In patients with associated autoimmune diseases, immunosuppression may be indicated. Reports on case series have described good outcomes in patients treated with a variety of immunosuppressive agents, including glucocorticoids (the most commonly used agents for this condition), cyclophosphamide, cyclosporine, and intravenous immune globulin; the use of etoposide, biologic agents, and plasmapheresis has been reported in refractory cases. Caution must be exercised in prescribing immunosuppressive  therapy, since infectious triggers are identified in more than 50% of these patients, and concurrent antimicrobial therapy should be considered.

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