Variability of the RNase L Isoform Ratio (37 Kilodaltons/83 Kilodaltons) in Diagnosis of Chronic Fatigue Syndrome

Abstract

Chronic fatigue syndrome (CFS) is a disorder characterized by debilitating fatigue whose etiology and pathophysiology remain unclear. Previous studies showed abnormalities of the RNase L pathway in peripheral blood mononuclear cells (PBMC) from patients with CFS (1, 2). The ratio of RNase L isoforms (37 kDa/83 kDa ratio [37/83 R]) has therefore been proposed as a potential biochemical marker of CFS, with a sensitivity of 91% and a specificity of 71% when the cutoff ratio was 0.4 (3).In order to evaluate the variability and reproducibility of the 37/83 R in the diagnosis of CFS, we assayed it in duplicate as described by Demettre et al. (2) once a month for 3 months with nine patients fulfilling CFS criteria (mean age Ϯ standard deviation ϭ 43.1 Ϯ 10.4 years). The accuracy of this ratio in the diagnosis of CFS was also tested and correlated with a clinical tool, the Multidimensional Fatigue Inventory (MFI) score, in a case-control study involving 28 CFS patients (mean age, 43.1 Ϯ 10.4 years; MFI, 60.9 Ϯ 14.6) and 24 healthy volunteers (mean age, 40.5 Ϯ 9.9 years; MFI, 27.1 Ϯ 7.7).The results of these two assays were correlated by the Spearman test for each sample; the means of the results of the assays were calculated, and the results from 3 consecutive months were correlated. Sensitivities, specificities, and positive and negative prognostic values were calculated with different threshold ratios of RNase L isoforms (0.4, 0.45, and 0.5). Ninety-five percent confidence intervals (95% CIs) were estimated. The ages of subjects in the two groups were comparable, and the MFI scores of the CFS group were higher than those of the control group (Mann-Whitney U test; P Ͻ 0.05).The correlation between two 37/83 R assays from the PBMC sample was lower for the CFS group than for the control group. Moreover, the correlation decreased with time (r ϭ 0.69, 0.69, and 0.33 at the first, second, and third months, respectively) for the CFS group while staying unchanged for the control group (r ϭ 0.95). The correlations between two average results of 37/83 R at two different months were low. The correlations between the two first two months, the second and third months, and the first and third months were 0.16, 0.14, and Ϫ0.03, respectively. The 37/83 R cutoff of 0.4 yielded the best discrimination of CFS patients from controls, with 78.6% sensitivity (95% CI, 20.5 to 46.1%) and 33.3% specificity (95% CI, 46.2 to 72.8%). The positive and negative prognostic values were 59.5% (95% CI, 67.5 to 89.7%) and 53.3% (95% CI, 39.7 to 66.9%), respectively. Finally, the correlations between the MFI and 37/83 R were very weak: 0.14 at the first month, 0.51 at the second month, and -0.3 at the last month.Our data suggest a high variability and poor reproducibility of the 37/83 R for CFS patients and variations of the 37 kDa/ 83kDa R results while fatigue remains stable. This variability might be due to the increased proteolytic activity reported for PMBC of patients with CFS (2). Thus, we draw attention to the use of this test. The small sample ...

Diverse functions of RNase L and implications in pathology

“…It has been proposed that this polypeptide could be a biochemical marker for CFS [148,149]. However, levels of the 37 kDa polypeptide appeared to vary with time within individual patients [150]. The polypeptide is an apparent degradation product of the native RNase L due to an increased proteolytic activity in CFS PBMC extracts.…”

37-Kilodalton/83-Kilodalton RNase L Isoform Ratio in Peripheral Blood Mononuclear Cells: Analytical Performance and Relevance for Chronic Fatigue Syndrome

“…During validation, the lowest detectable ratio measured with a sample containing the 83-kDa isoform only was estimated (3 independent experiments with 26 replicates each) to be 0.13 Ϯ 0.06 (average Ϯ three standard deviations). Thus, the clinical cutoff ratio of 0.4 found by the authors (5,6) to best discriminate CFS patients from controls falls within the measurable range.…”

“…In our opinion, both fatigue and RNase L cleavage result from similar dysfunctions in the interferon-activated pathways that occur upstream of RNase L activation and exert their effects on different targets (3). Consequently, we do not feel particularly concerned by the weak correlations observed between the MFI and 37/83 R (6). The poor reproducibility of the test results over time (6) might reflect changes in the immune inflammatory status rather than in fatigue.…”

“…Consequently, we do not feel particularly concerned by the weak correlations observed between the MFI and 37/83 R (6). The poor reproducibility of the test results over time (6) might reflect changes in the immune inflammatory status rather than in fatigue. In particular, the authors do not provide any information concerning the drugs CFS patient might have been using during the longitudinal study, which is critical as some drugs may act on the inflammatory response.…”

“…A French group has reported results (5) supporting the use of the RNase L 37-kDa/83-kDa ratio (37/83 R) in peripheral blood mononuclear cells (PBMC) as a diagnostic test for chronic fatigue syndrome (CFS). More recently (6), the same group cautioned about the diagnostic value of the 37/83 R, based on a small patient follow-up study which was likely to indicate analytical variability among duplicate assays, lack of reproducibility over time, and a weak correlation with the multidimensional fatigue inventory (MFI) score. Because of our long-term experience with this assay, we would like to offer some comments.…”