Chronic fatigue syndrome: Identification of distinct subgroups on the basis of allergy and psychologic variables,☆☆,,★★

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Abstract

Background: We investigated a role for allergic inflammation and psychologic parameters in the development of chronic fatigue syndrome (CFS). Methods: The design was a comparison between subjects with CFS and age- and sex-matched control cohorts. Studies were performed on CFS subjects (n = 18) and control cohorts consisting of normal subjects (n = 11), allergic subjects (n = 14), and individuals with primary depression (n = 12). We quantified cytokines at baseline as cell-associated immunoreactive peptides and as transcripts evaluated by means of semiquantitative RNA-based polymerase chain reactions. Psychologic evaluations included administration of the Diagnostic Interview Schedule, the Structured Clinical Interview, and the Symptom Checklist 90–Revised. Results: Increases in tumor necrosis factor (TNF)-α were identified in individual subjects with CFS (50.1 ± 14.4 pg TNF-α per 107 peripheral blood mononuclear cells [PBMCs]; mean ± SEM) and allergic subjects (41.6 ± 7.6) in comparison with normal subjects (13.1 ± 8.8) (P < .01 and P < .05, respectively). Similar trends were observed for interferon (IFN)-α in allergic subjects (3.0 ± 1.7 pg/107 PBMCs) and subjects with CFS (6.4 ± 3.4) compared with normal subjects (1.9 ± 1.4). A significant increase (P < .05) in TNF-α transcripts was demonstrated between subjects with CFS and depressed subjects. In contrast to these proinflammatory cytokines, both subjects with CFS (2.6 ± 1.8 pg/107 PBMCs) and allergic subjects (3.4 ± 2.8) were associated with a statistically significant (P < .01) decrease in IL-10 concentrations compared with normal subjects (60.2 ± 18.2). As shown in other studies, most of our subjects with CFS were allergic (15 of 18) and therefore presumably demonstrated cytokine gene activation on that basis. The seasonal exacerbation of allergy was associated with a further increase in cellular IFN-α (from 2.1 ± 1.2 to 14.2 ± 4.5 pg/107 PBMCs; P < .05) but no further modulation of TNF-α or IL-10. Similarly, self-reported exacerbations of CFS were associated with a further increase in IFN-α (from 2.5 ± 1.0 to 21.9 ± 7.8; P < .05) and occurred at times of seasonal exposures to allergens. This linkage does not permit making any definitive conclusions regarding a causative influence of either seasonal allergies or the increase in cellular IFN-α with the increase in CFS symptoms. The close association between atopy and CFS led us to speculate that CFS may arise from an abnormal psychologic response to the disordered expression of these proinflammatory and antiinflammatory cytokines. Psychologic variables were predictive of immune status within the CFS sample (65.9% of the variance in immune status; F (3,10) = 6.44, P < .05). Specifically, the absence of a personality disorder but greater endorsement of global psychiatric symptoms was predictive of immune activation. Conclusions: Most of our subjects with CFS were allergic, and the CFS and allergy cohorts were similar in terms of their immune status. However, the CFS subjects could be discriminated by the distinct psychologic profiles among subjects with and without immune activation. We propose that in at least a large subgroup of subjects with CFS who had allergies, the concomitant influences of immune activation brought on by allergic inflammation in an individual with the appropriate psychologic profile may interact to produce the symptoms of CFS. In a psychologically predisposed individual, symptoms associated with allergic inflammation are recognized as illness. (J Allergy Clin Immunol 1998;102:222-30.)

Section snippets

Center model

The data collected for this study were generated as part of a study examining possible pathophysiologic mechanisms of the production of CFS.

Subjects

Studies were performed on age- and sex-matched normal subjects (n = 11) and subjects with CFS (n = 18). CFS was defined according to the original Centers for Disease Control and Prevention definition,14 which requires a history of debilitating idiopathic fatigue producing a greater than 50% reduction in activity from the premorbid state. To optimize

RESULTS

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ELISA

We investigated activation of the proinflammatory cytokines TNF-α, IFN-α, and IL-1β in PBMCs in subjects with CFS. As has been previously reported,1, 2, 3, 4, 5 most (15 of 18) of the subjects with CFS were atopic as demonstrated by skin test reactivity. Most of the depressed patients were also atopic (7 of 10 on whom skin testing could be performed).21 Concentrations of cell-associated cytokines were assayed by means of ELISA, and data are normalized to cell (PBMC) number. Individual data

RT-PCR

In addition to intracellular immunoreactive protein, we identified cytokine involvement in CFS as mRNA transcripts in the PBMCs of subjects with CFS. Data were quantified by means of densitometric analyses of cytokine transcript product that was normalized to the level of expression of β-actin as described. Representative data obtained by using nested 32P-labeled probes for TNF-α are displayed in Fig. 5.

. RT-PCR. PBMCs were obtained from subjects as described, and total RNA was isolated. After

DISCUSSION

We investigated the role of allergic inflammation in the pathophysiology of CFS. This was based on the surprisingly high association of CFS with allergy (10% to 20% of the general population is atopic compared with 55% to 80% of subjects with CSF)1, 2, 3, 4, 5 and the association of allergic conditions such as allergic rhinitis with fatigue. Allergies are the only consistent immune abnormality present in CFS and suggest a role for allergic inflammation in the development of CFS. In one of the

References (32)

  • R Patarca et al.

    Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression

    Clin Infect Dis

    (1991)
  • CC Chao et al.

    Serum neopterin and interleukin-6 levels in chronic fatigue syndrome

    Infect Dis

    (1990)
  • AR Lloyd

    Immunological studies of chronic fatigue syndrome

    Clin Infect Dis

    (1994)
  • A Linde et al.

    Serum levels of lymphokines and soluble cellular receptors in primary Epstein-Barr virus infection and in patients with chronic fatigue syndrome

    J Infect Dis

    (1992)
  • GP Holmes et al.

    Chronic fatigue syndrome: a working case definition

    Ann Intern Med

    (1988)
  • S Fontaine et al.

    Monoclonal antibodies to human interleukin-1β and their use in a sensitive two-site enzyme linked immunosorbent assay

    Lymphokine Res

    (1989)
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    From the Departments of aMedicine and bPediatrics, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver; and cthe Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.

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    Supported by National Institutes of Health grant AI32244 and General Clinical Research Center grant MO1 RR00051.

    Reprint requests: James F. Jones, MD, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St, University of Colorado Health Sciences Center, Denver, CO 80206.

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