Case 2. Infant with prolonged fever
The patient was a 7-month-old female, ex-32-week di-zygotic twin admitted to a tertiary care children™s hospital for 7 days of fever, diarrhea, emesis, and an erythematous papular rash on the torso, with no known ill contacts or travel.32 Clinical laboratory evaluation was notable for elevated inflammatory markers, leukocytosis with neutrophilia, microcytic anemia, and thrombocytosis. Her infectious workup was negative. She was diagnosed with atypical Kawasaki disease as multiple echocardiograms demonstrated persistent borderline dilation of multiple coronary arteries despite treatment with high-dose IVIG and infliximab.33 During the course of her hospitalization, her fever curve was noted to be bimodal with persistent signs of systemic inflammation. Further inquiry into the family history revealed that her mother and maternal uncle had similar recurrent episodes of fever, arthritis, rash, serositis, and conjunctivitis since infancy, and were diagnosed with systemic juvenile arthritis. For them, several treatments were partially successful including etanercept and anakinra, though infliximab caused severe disease flares in the mother. This new history was suggestive of an autosomal dominant autoinflammatory disease, most consistent with TNF-receptor associated periodic syndrome (TRAPS).34,35
In contrast to the inflammasomopathies, TRAPS is due to an accumulation of intracellular stressors which trigger pattern-recognition receptors. In TRAPS, autosomal dominant mutations in TNFRSF1A negatively affect the three-dimensional structure of the receptor. In the wild-type state, binding of TNF-∠to the TNF receptor leads to inflammatory, apoptotic, and cellular regulation pathways. In TRAPS, the mutated protein has been proposed to result in decreased levels of circulating inhibitor soluble TNFR1, constitutive activation of the receptor, decreased TNF-mediated apoptosis, and intracellular oxidative stress due to misfolding of the receptor in the endoplasmic reticulum.36-39 Resulting autoinflammatory flares may last from 5 days to several weeks, and may occur spontaneously or be triggered by a minor illness. Symptoms during acute attacks include fever, migrating myalgia, arthralgia or arthritis, centrifugal or urticaria-like rash, and serous membrane inflammation that manifests as chest and abdominal pain. Periorbital edema is also common and can be associated with uveitis or conjunctivitis.34,35 The most severe complication of TRAPS is secondary AA amyloidosis with morbidity and mortality associated due to nephrotic syndrome and renal failure, though other organ systems can be affected.35,40 Treatment options include IL-1 blockade, such as anakinra, or canakinumab, as first-line therapy, though short-term glucocorticoids, with or without nonsteroidal anti-inflammatory drugs, anti-TNF therapy with etanercept, have also been attempted.18