Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial

Abstract:

BACKGROUND: Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment.

METHODS: In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat.

FINDINGS: None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher’s exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo.

INTERPRETATION: In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

Comment in:

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

Chronic fatigue syndrome and functional hypoadrenia–fighting vainly the old ennui. [Lancet. 1999]

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

 

Source: Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999 Feb 6;353(9151):455-8. http://www.ncbi.nlm.nih.gov/pubmed/9989716

 

Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever

Abstract:

BACKGROUND: The role of viruses in the aetiology of both chronic fatigue syndrome (CFS) and depressive illness is uncertain.

METHOD: A prospective cohort study of 250 primary care patients, presenting with glandular fever or an ordinary upper respiratory tract infection (URTI).

RESULTS: The incidence of an acute fatigue syndrome was 47% at onset, after glandular fever, compared with 20% with an ordinary URTI (relative risk 2.3, 95% CI 1.3-4.1). The acute fatigue syndrome lasted a median (interquartile range) of eight weeks (4-16) after glandular fever, but only three weeks (2-4) after an URTI. The prevalence of CFS was 9-22% six months after glandular fever, compared with 0-6% following an ordinary URTI, with relative risks of 2.7-5.1. The most conservative measure of the incidence of CFS was 9% after glandular fever, compared with no cases after an URTI. A conservative estimate is that glandular fever accounts for 3113 (95% CI 1698-4528) new cases of CFS per annum in England and Wales. New episodes of major depressive disorder were triggered by infection, especially the Epstein-Barr virus, but lasted a median of only three weeks. No psychiatric disorder was significantly more prevalent six months after onset than before.

CONCLUSIONS: Glandular fever is a significant risk factor for both acute and chronic fatigue syndromes. Transient new major depressive disorders occur close to onset, but are not related to any particular infection if they last more than a month.

 

Source: White PD, Thomas JM, Amess J, Crawford DH, Grover SA, Kangro HO, Clare AW. Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever. Br J Psychiatry. 1998 Dec;173:475-81. http://www.ncbi.nlm.nih.gov/pubmed/9926075

 

Developing case definitions for symptom-based conditions: the problem of specificity

Symptom-based conditions are postulated organic diseases that are characterized primarily by chronic physical (somatic) symptoms (1, 2). Contemporary conditions associated with multisystem complaints are generally referred to as chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivities, silicone associated atypical rheumatic disease, sick building syndrome, and most recently, Gulf War syndrome (table 1). Possibly related disorders that will not be considered in the following analysis include epidemic neuromyasthenia, hyperventilation syndrome, reactive hypoglycemia, post-lyme disease syndrome, and irritable bowel syndrome (3).

Although the need to consistently define symptombased conditions has been repeatedly emphasized, there has been limited progress in establishing widely accepted diagnostic criteria (1,4). Based on reports in English-language publications, symptom-based conditions were analyzed to determine why it has been difficult to develop case definitions of unique diseases.

You can read the rest of this article here: http://epirev.oxfordjournals.org/content/20/2/148.long

 

Source: Hyams KC. Developing case definitions for symptom-based conditions: the problem of specificity. Epidemiol Rev. 1998;20(2):148-56. http://epirev.oxfordjournals.org/content/20/2/148.long (Full article)

Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during ‘natural fatigue’ but not following ‘experimental fatigue’ in patients with chronic fatigue syndrome

Abstract:

In an investigator-blinded study, adherent (monocytes) and non-adherent cells (lymphocytes) from patients with chronic fatigue syndrome (CFS) were examined on two separate occasions (when feeling ‘fatigued’ and when feeling ‘rested’) for in vitro spontaneous, phytohemagglutinin- (PHA, for lymphocytes), and lipopolysaccharide- (LPS, for monocytes) induced production of IL-6 by ELISA assay.

A group of CFS patients and controls were also subjected to exercise-induced fatigue (‘experimental fatigue’) and IL-6 production was compared, in a double-blinded manner, prior to and following induction of fatigue.

A significant increase in spontaneous, PHA- and LPS-induced IL-6 secretion by both lymphocytes and monocytes was observed in CFS patients during ‘natural fatigue’ as compared to during state. However, no such changes in IL-6 production were observed during ‘experimental fatigue’.

These data suggest a role of IL-6 in natural symptomatology and perhaps in the pathogenesis of CFS. In addition, the data demonstrate that laboratory-induced fatigue (experimental fatigue) may not be a good model to study immunological changes in CFS; immunological parameters should be studied in a longitudinal manner during the natural course of the disease.

 

Source: Gupta S, Aggarwal S, Starr A. Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during ‘natural fatigue’ but not following ‘experimental fatigue’ in patients with chronic fatigue syndrome. Int J Mol Med. 1999 Feb;3(2):209-13. http://www.ncbi.nlm.nih.gov/pubmed/9917531

 

Orthostatic intolerance in adolescent chronic fatigue syndrome

Abstract:

OBJECTIVES: To demonstrate the association between orthostatic intolerance and the chronic fatigue syndrome (CFS) in adolescents and to delineate the form that orthostatic intolerance takes in these children.

STUDY DESIGN: We investigated the heart rate and blood pressure (BP) responses to head-up tilt (HUT) in 26 adolescents aged 11 to 19 years with CFS compared with responses in adolescents referred for the evaluation of simple faint and to responses in 13 normal healthy control children of similar age.

RESULTS: A total of 4/13 of the controls and 18/26 simple faint patients experienced typical faints with an abrupt decrease in BP and heart rate associated with loss of consciousness. One CFS patient had a normal HUT. A total of 25/26 CFS patients experienced severe orthostatic symptoms associated with syncope in 7/25, orthostatic tachycardia with hypotension in 15/25, and orthostatic tachycardia without significant hypotension in 3/25. Acrocyanosis, cool extremities, and edema indicated venous pooling in 18/25. None of the control or simple faint patients experienced comparable acral or tachycardic findings.

CONCLUSIONS: We conclude that chronic fatigue syndrome is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS often has heart rate and BP responses similar to responses in the syndrome of orthostatic tachycardia suggesting that a partial autonomic defect may contribute to symptomatology in these patients.

 

Source: Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics. 1999 Jan;103(1):116-21. http://www.ncbi.nlm.nih.gov/pubmed/9917448

 

Prevalence of chronic fatigue syndrome in a community population in Japan

Abstract:

In order to know the prevalence of chronic fatigue syndrome (CFS) in a community population in Japan, we analyzed data from a population-based interview survey. Two cases out of 137 respondents experienced chronic fatigue during a period of nine months, suffered from 50% or more reduction of daily activity due to fatigue and had no other physical or psychiatric diagnosis. Both of the two cases fulfilled the 1994 Centers for Disease Control (CDC) criteria and the British criteria. The point and nine-month prevalence rates of CFS were both 1.5% (95% confidence intervals, 0.4-5.2%). None fulfilled the 1989 CDC criteria for CFS. The prevalence rate of CFS was higher than those in previous studies in the Western countries, suggesting a need for future research on cross-cultural differences in the definition, prevalence and symptomatology of CFS.

 

Source: Kawakami N, Iwata N, Fujihara S, Kitamura T. Prevalence of chronic fatigue syndrome in a community population in Japan. Tohoku J Exp Med. 1998 Sep;186(1):33-41. https://www.jstage.jst.go.jp/article/tjem/186/1/186_1_33/_article (Full article)

 

Cytokine dysregulation in the post-Q-fever fatigue syndrome

Abstract:

The post-Q-fever fatigue syndrome (QFS) (inappropriate fatigue, myalgia and arthralgia, night sweats, changes in mood and sleep patterns) follows about 20% of laboratory-proven, acute primary Q-fever cases. Cytokine dysregulation resulting from chronic immune stimulation and modulation by persistence of Coxiella burnetii cells or their antigens is hypothesized.

We studied cytokine release patterns of peripheral blood mononuclear cells (PBMC) stimulated with various ligands in short-term culture, from 18 patients with active QFS, and 27 controls: six with resolving QFS, five who had had acute primary Q-fever without subsequent QFS, eight healthy Q-fever vaccinees and eight healthy subjects without Q-fever antibody. Conditioned media (CM) from PBMC stimulated in short-term culture with Q-fever antigens, PHA or measles antigen (as an unrelated antigen) were assayed for IL-2, IL-4, IL-5, IL-6, IL-10 and IFN gamma by AgEIA, and for IL-1 and TNF alpha/beta by bioassay.

Aberrant cytokine release patterns were observed with PBMC from QFS patients when stimulated with Q-fever antigens: an accentuated release of IL-6 which was significantly [p = 0.01, non-parametric one-way analysis of variance (ANOVA)] in excess of medians for all four control groups. With IL-2, the number of responders in the active QFS group was decreased relative to control groups (Fisher’s exact test, p = 0.01) whereas the number of IFN gamma responders was increased (Fisher’s exact test, p = 0.0008). Significant correlations were observed between concentrations of IL-6 in CM, total symptom scores, and scores for other key symptoms.

Comment in: Fatigue syndromes. [QJM. 1999]

 

Source: Penttila IA, Harris RJ, Storm P, Haynes D, Worswick DA, Marmion BP. Cytokine dysregulation in the post-Q-fever fatigue syndrome. QJM. 1998 Aug;91(8):549-60. http://qjmed.oxfordjournals.org/content/91/8/549.long (Full article)

 

The non-specific environmental syndromes MCS (Multiple Chemical Sensitivity), IEI (Idiopathic Environmental Intolerance) and SBS (Sick Building Syndrome)

Abstract:

This review starts with a clinical description of the most common unspecific environmental diseases, such as Multiple Chemical Sensitivities (MCS), Idiopathic Environmental Intolerances (IEI) and Sick Building Syndrome (SBS). These syndromes are very controversial discussed between scientific medicine and “clinical ecology”. In addition, they have fundamental similarities to Chronic Fatigue Syndrome (CFS) and Fibromyalgia. Finally the spectrum of therapeutic approaches is discussed.

 

Source: Csef H. The non-specific environmental syndromes MCS (Multiple Chemical Sensitivity), IEI (Idiopathic Environmental Intolerance) and SBS (Sick Building Syndrome). Fortschr Med. 1998 Nov 30;116(33):18-20, 22, 24. [Article in German] http://www.ncbi.nlm.nih.gov/pubmed/9889460

 

Nasal secretion analysis in allergic rhinitis, cystic fibrosis, and nonallergic fibromyalgia/chronic fatigue syndrome subjects

Abstract:

Rhinitis symptoms are present in approximately 70% of subjects with fibromyalgia and chronic fatigue syndrome (FM/CFS). Because only 35% to 50% have positive allergy skin tests, nonallergic mechanisms may also play a role.

To better understand the mechanisms of nonallergic rhinitis in FM/CFS, nasal lavages were performed, and markers of vascular permeability, glandular secretion, and neutrophil and eosinophil infiltration measured in 27 nonallergic FM/CFS, 7 allergic rhinitis, 7 cystic fibrosis, and 9 normal subjects. Allergic rhinitis subjects had significantly increased vascular permeability (IgG) and ECP levels.

Cystic fibrosis subjects had significantly higher elastase and total protein levels. There were no significant differences between FM/CFS and normal lavage fluids. Analysis of the constituents of nasal mucus provides information about ongoing secretory processes in rhinitis.

There were no differences in the basal secretion of these markers of vascular permeability, submucosal gland serous cell secretion, eosinophil and neutrophil degranulation in nonallergic FM/CFS subjects. This suggests that constitutively active secretory processes that regulate continuous production of nasal secretions are not altered in FM/CFS. Future studies should examine alternative mechanisms such as inducible, irritant-activated, or reflex-mediated effects.

 

Source: Baraniuk JN, Clauw D, Yuta A, Ali M, Gaumond E, Upadhyayula N, Fujita K, Shimizu T. Nasal secretion analysis in allergic rhinitis, cystic fibrosis, and nonallergic fibromyalgia/chronic fatigue syndrome subjects. Am J Rhinol. 1998 Nov-Dec;12(6):435-40. http://www.ncbi.nlm.nih.gov/pubmed/9883301

 

Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome

Abstract:

Mycoplasma fermentans and other Mycoplasma species are colonizers of human mucosal surfaces and may be associated with human immunodeficiency virus infection. While many infectious agents have been described in different percentages of patients with Chronic Fatigue Syndrome (CFS), little is known about the prevalence of mycoplasmas and especially M. fermentans in CFS patients.

A polymerase chain reaction (PCR)-based assay was used to detect Mycoplasma genus and M. fermentans genomes in peripheral blood mononuclear cells (PBMC) of CFS patients. Blood was collected from 100 patients with CFS and 50 control subjects. The amplified products of 717 bp of Mycoplasma genus, and 206 bp of M. fermentans were detected in DNA purified from blood samples in 52% and 34% of CFS samples, respectively. In contrast, these genomes were found in only 14% and 8% of healthy control subjects respectively (P < 0.0001).

All samples were confirmed by Southern blot with a specific probe based on internal sequences of the expected amplification product. Several samples, which were positive for Mycoplasma genus, were negative for M. fermentans indicating that other Mycoplasma species are involved. A quantitative PCR was developed to determine the number of M. fermentans genome copies present in 1 microg of DNA for controls and CFS patients.

Mycoplasma copy numbers ranging from 130 to 880 and from 264 to 2400 were detected in controls and CFS positive subjects, respectively. An enzyme immunoassay was applied for the detection of antibodies against p29 surface lipoprotein of M. fermentans to determine the relationship between M. fermentans genome copy numbers and antibody levels. Individuals with high genome copy numbers exhibited higher IgG and IgM antibodies against M. fermentans specific peptides. Isolation of this organism by culture from clinical specimens is needed in order to demonstrate specificity of signal detected by PCR in this study.

 

Source: Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW. Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome. FEMS Immunol Med Microbiol. 1998 Dec;22(4):355-65. http://femsim.oxfordjournals.org/content/22/4/355.long (Full article)