The findings of history, examination, and laboratory investigations performed immediately before commencement of IVIG therapy are summarized in table 1. During examination, the patient was flushed and sleepy, with no evidence of synovitis, and 4 of 18 tender points were present. The findings of routine blood investigations, including a complete blood cell count, determination of urea and electrolyte levels, liver function tests, and determination of the ESR, were normal. Serological investigations revealed that the patient was positive for serum parvovirus B19 DNA but negative for leukocyte parvovirus B19 DNA, serum antiparvovirus B19 VP1/2 IgG, antiparvovirus B19 NS1 IgG, RF, and ANA.
In January 2001, the patient was admitted to the hospital for a 5-day course of IVIG (Sandoglobulin) at a dosage of 400 mg/kg per day. On day 2 of this treatment, he developed a severe headache that lasted 48 h, and, on day 3, his joint pains began to improve. This improvement continued over the ensuing 2 weeks, by which time his fatigue had lessened.
The arthritis was somewhat slower to resolve, but a marked improvement occurred at 3 months after treatment. At this time, his hips, knees, and ankles were virtually free of pain. This improvement continued until he achieved a complete recovery. This treatment has enabled the man to participate again in family and social activities that were not possible during his illness. In particular, he could walk on flat surfaces without a stick. He no longer needed daytime naps after receiving treatment. At the time of this writing, his condition remains in remission. Serial serum samples obtained at intervals of 129 months from the onset of his illness were tested for parvovirus B19 markers and cytokines.
Results.
In all cases, serum samples contained parvovirus B19 DNA that decreased to less than the limit of detection by our nested PCR assay after IVIG treatment (figures 13). The acute phase of each patient's illness began with a typical acute parvovirus B19 infection coincident with a positive test result for serum antiparvovirus B19 IgM. Patients 2 and 8 mounted IgG responses to parvovirus B19; however, patient 32 did not switch class and tested negative for antiparvovirus B19 IgG antibodies until he was treated with IVIG. In this patient, specific IgG antibodies were detected for the first time after completion of IVIG therapy.
Although many cytokines were quantified, only those that were significantly elevated above normal levels are discussed and included in figures 13. Before initiation of IVIG treatment, all patients had increased levels of MCP-1 and TNF-. After IVIG therapy, MCP-1 and TNF-levels decreased and were consistently less than the limit of detection for the Bioplex protein array system within 36 months of IVIG treatment in patients 2 and 8; however, the decrease was somewhat slower in patient 32.
Patients 2 and 8 had intermittent increases in levels of IFN- and IL-6 during the disease phase, which decreased to baseline levels after the introduction of IVIG treatment. Patient 32 had a slightly different cytokine profile, with an elevated IL-4 concentration before receipt of IVIG therapy, which peaked 6 weeks afterward and then slowly returned to the baseline value. The decrease in the IL-4 concentration after administration of IVIG was similar to that noted for TNF- and MCP-1.
A smaller peak in the IL-2 level also occurred in this patient after administration of IVIG treatment, coincident with the peak in the IL-4 level. An important limitation of the cytokine data was that antigen-specific responses were not assessed, and serum values may not accurately reflect cytokine concentration in the secondary lymphoid compartment. Further studies will be required to address these issues.
Discussion. IVIG treatment led to a significant improvement in symptoms and functional outcome in 3 patients with parvovirus-associated CFS. We hypothesized that IVIG therapy would be effective in this patient population for the following reasons. IgG antibody prevents in vitro infection of erythroid progenitor cells by parvovirus B19 [14], and volunteer studies have shown it to be protective [15].
Individuals with persistent parvovirus infection have a specific defect in humoral immunity to this virus [10]. Because parvovirus is a common infection in the population, with a seroprevalence of 60%70% in blood donors [16], IVIG is a good means to neutralize antibodies [17]. Finally, IVIG has been shown to be an effective therapy for other clinical syndromes associated with persistent parvovirus infection, such as pure RBC aplasia in immunocompromised individuals [11] and in sporadic cases of parvovirus B19associated arthritis [18], vasculitis [19], fetal anemia [20], meningoencephalitis [13], and CFS [12].
We have previously shown that parvovirus-associated CFS was associated with increased circulating levels of TNF- and IFN- [6]. In this study, all patients had persistent elevations of TNF- and MCP-1 levels that returned to baseline values after IVIG therapy was administered. In one individual, parvovirus-specific IgG was detected for the first time after administration of IVIG treatment. This was associated with an isolated increase in levels of both IL-2 and IL-4 (figure 3), cytokines that are known to be important in immunoglobulin class switching [21, 22].
IVIG has been used to treat idiopathic CFS, and individual trials have shown benefit [2426]. However, some trials do not show clinical benefit [27, 28], and a meta-analysis of all of the randomized controlled trials of IVIG therapy for idiopathic CFS was unable to determine whether this treatment had a clear-cut benefit [29]. One possible reason for the conflicting results of individual trials may lie in the heterogeneity of the population of patients with CFS; it is possible that some individuals with idiopathic CFS may have persistent viral illnesses similar to parvovirus that are responsive to IVIG.
However, another possibility is the heterogeneity of IVIG preparations. Notwithstanding, one goal for future studies is to determine what proportion of patients with idiopathic CFS have persistent parvovirus infection and whether screening for this should be routinely performed.
In conclusion, IVIG appears to be a promising treatment for parvovirus-associated CFS. It leads to a significant improvement in symptoms and to functional outcome and clearance of persistent viremia. Our findings provide support for the use of this therapy in parvovirus-associated CFS.
Acknowledgments:
We thank Alex Liversage of Bio-Rad, Hemel Hempstead, United Kingdom, for assistance with cytokine testing, and David Tyrrell, for helpful comments on the article in manuscript.