Periodic Illness Associated With Epstein-Barr Virus: A New Diagnosis After a 22-Year Follow-up

To the Editor—In 1996, Lekstrom-Himes and colleagues published a case report of a 15-year old boy who presented with periodic fever accompanied by generalized lymphadenopathy, abdominal discomfort, and splenomegaly, which had occurred every 2–4 weeks since 19 months of age [1]. His initial workup at the National Institutes of Health in 1986 showed a persistently low-positive Epstein-Barr virus (EBV) immunoglobulin (Ig) M antibody to viral capsid antigen and early antigen, absence of antibody to EBV nuclear antigen, and elevated EBV viral capsid antigen IgA. A lymph node biopsy showed increased EBV-encoded RNA with 1%–5% of cells positive for EBV nuclear antigen. EBV DNA polymerase chain reaction performed retrospectively on cryopreserved blood mononuclear cells showed 1285 copies of EBV DNA per million cells in the blood. The patient's serum IgD level was normal (7.4 mg/dL), but his IgA level was moderately elevated (398–631 mg/dL). Periodic illness associated with EBV infection was diagnosed but did not respond to treatment with acyclovir, intravenous Ig, or interferon α. The patient had symptomatic relief with prednisone (40 mg/d) for 3 days at the onset of symptoms.

At follow-up at the National Institutes of Health in 2013, 22 years after his last evaluation in 1991, the patient reported continued episodes of fever up to 40°C with tender cervical lymphadenopathy, myalgias, and arthralgias. These episodes were triggered by stress and overexertion. He took prednisone (40 mg) at the onset of symptoms, which eliminated the fever within several hours and blunted the remaining symptoms. Laboratory evaluations showed normal white blood cell and differential counts, an inverted T4/T8 ratio, and levels of EBV DNA ranging from 1200 to 25 200 copies/mL of whole blood. Chest computed tomography showed diffuse bronchiectasis and apical bullae. The serum IgD level was elevated, at 86 mg/dL. and the IgA level was 860–974 mg/dL, consistent with hyperimmunoglobulin D syndrome (HIDS). Sequencing of the mevalonate kinase (MVK) gene showed amino acid mutations I268T and V337I. These mutations have been previously reported in patients with HIDS [2, 3]. Amplification of genomic DNA from the blood showed that the patient is a compound heterozygote with the mutations on different alleles of the MVK gene (Figure 1). Testing for genetic disorders associated with elevated levels of EBV DNA [4, 5] in the blood showed no evidence for mutations in SH2D1A, BIRC4, ITK, CD27, MAGT1, or PRF1.

Figure 1.

Mevalonate kinase (MVK) mutations in a patient with hyperimmunoglobulin D syndrome and elevated Epstein-Barr virus nucleic acid in lymph nodes and blood. The MVK gene contains 11 exons (line 1). The region encompassing exons 9 and 11 was amplified with polymerase chain reaction from the patient's genomic DNA, and cloned into plasmid pCR2.1. Individual plasmid clones (MVK-2,3,11,15,37), derived from cloning the region corresponding to exons 9–11 of the MVK gene from the patient's DNA, were sequenced, and mutations were present in both alleles. Three of 5 had a G→A mutation at nucleotide 1129 (which resulted in a change in valine at amino acid 337 to isoleucine) and 2 clones had a T→C mutation at nucleotide 803 (which resulted in a change of isoleucine at amino acid 268 to threonine), indicating that each allele had a different mutation. The chromatogram above the line drawing shows the direct sequencing in the region with the mutations. Observed mutations appear as mixed peaks of roughly half the height, indicating that the patient is a compound heterozygote.

Our patient presented with periodic fever and a normal IgD level, but 22 years later was found to have an elevated level of IgD, and HIDS was diagnosed. Some patients with HIDS have normal IgD levels [6, 7]. A literature review found no cases of EBV disease or elevated EBV DNA in patients with HIDS, and we did not find elevated levels of EBV in 2 other EBV-seropositive patients with HIDS. Thus, our patient's elevated EBV level is probably due to impaired immune surveillance and not the cause of his inflammatory condition. Therefore, it is important not to attribute EBV as the cause of an unexplained inflammatory disorder in the absence of a thorough evaluation, including genetic testing, for other potential causes.