Increased serum IgA
and IgM against LPS of enterobacteria
in chronic fatigue syndrome (CFS): Indication for the involvement of
gram-negative enterobacteria in the etiology of CFS
and for the presence of an increased gut-intestinal permeability.
Maes M, Mihaylova I, Leunis JC.
J Affect Disord. 2006 Sep 26;
There is
now evidence that chronic fatigue syndrome (CFS) is accompanied by immune
disorders and by increased oxidative stress. The present study has been
designed in order to examine the serum concentrations of IgA
and IgM to LPS of gram-negative enterobacteria,
i.e. Hafnia alvei;
Pseudomonas aeruginosa, Morganella
morganii, Proteus mirabilis, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in CFS patients, patients with partial CFS and
normal controls. We found that the prevalences and
median values for serum IgA against the LPS of enterobacteria are significantly greater in patients with
CFS than in normal volunteers and patients with partial CFS. Serum IgA levels were significantly correlated to the severity of
illness, as measured by the FibroFatigue scale and to
symptoms, such as irritable bowel, muscular tension, fatigue, concentration
difficulties, and failing memory. The results show that enterobacteria
are involved in the etiology of CFS and that an
increased gut-intestinal permeability has caused an immune response to the LPS
of gram-negative enterobacteria. It is suggested that
all patients with CFS should be checked by means of the IgA
panel used in the present study and accordingly should be treated for increased
gut permeability.
Multiple co-infections (Mycoplasma,
Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients:
association with signs and symptoms.
Nicolson GL, Gan
R, Haier J.
APMIS. 2003 May;111(5):557-66.
Previously
we and others found that a majority of chronic fatigue syndrome (CFS) patients
showed evidence of systemic mycoplasmal infections,
and their blood tested positive using a polymerase chain reaction assay for at
least one of the four following Mycoplasma species:
M. fermentans, M. hominis,
M. pneumoniae or M. penetrans.
Consistent with previous results, patients in the current study (n=200) showed
a high prevalence (overall 52%) of mycoplasmal
infections. Using forensic polymerase chain reaction we also examined whether
these same patients showed evidence of infections with Chlamydia pneumoniae (overall 7.5% positive) and/or active human
herpes virus-6 (HHV-6, overall 30.5% positive). Since the presence of one or
more infections may predispose patients to other infections, we examined the
prevalence of C. pneumoniae and HHV-6 active
infections in mycoplasma-positive and -negative
patients. Unexpectedly, we found that the incidence of C. pneumoniae
or HHV-6 was similar in Mycoplasma-positive and
-negative patients, and the converse was also found in active HHV-6-positive
and -negative patients. Control subjects (n=100) had low rates of mycoplasmal (6%), active HHV-6 (9%) or chlamydial
(1%) infections, and there were no co-infections in control subjects.
Differences in bacterial and/or viral infections in CFS patients compared to
control subjects were significant. Severity and incidence of patients' signs
and symptoms were compared within the above groups. Although there was a
tendency for patients with multiple infections to have more severe signs and
symptoms (p<0.01), the only significant differences found were in the
incidence and severity of certain signs and symptoms in patients with multiple
co-infections of any type compared to the other groups (p<0.01). There was
no correlation between the type of co-infection and severity of signs and
symptoms. The results indicate that a large subset of CFS patients show
evidence of bacterial and/or viral infection(s), and these infections may
contribute to the severity of signs and symptoms found in these patients.
Exercise capacity and immune function in male
and female patients with chronic fatigue syndrome (CFS).
Snell CR, Vanness JM, Strayer DR, Stevens SR.
In Vivo.
2005 Mar-Apr;19(2):387-90.
Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L
has been linked to reduced exercise capacity in persons with chronic fatigue
syndrome (CFS). This investigation compares exercise capacities of CFS patients
with deregulation of the RNase L pathway and CFS patients with normal
regulation, while controlling for potentially confounding gender effects.
Thirty-five male and seventy-one female CFS patients performed graded exercise
tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass
index, perceived exertion, and respiratory quotient were entered into a two-way
factorial analysis with gender and immune status as independent variables. A
significant multivariate main effect was found for immune status (p < 0.01),
with no gender effect or interaction. Follow-up analyses identified VO2(peak)
as contributing most to the difference. These results implicate abnormal immune
activity in the pathology of exercise intolerance in CFS and are consistent
with a channelopathy involving oxidative stress and
nitric oxide-related toxicity.
Lower serum zinc in Chronic Fatigue Syndrome
(CFS): relationships to immune dysfunctions and relevance for the oxidative
stress status in CFS.
Maes M, Mihaylova I, De Ruyter M.
J Affect Disord. 2006 Feb;90(2-3):141-7. Epub
2005 Dec 9.
The present
study examines serum zinc concentrations in patients with chronic fatigue
syndrome (CFS) versus normal volunteers. Serum zinc levels were determined by
means of an atomic absorption method. We found that serum zinc was
significantly lower in the CFS patients than in the normal controls. There was
a trend toward a significant negative correlation between serum zinc and the
severity of CFS and there was a significant and negative correlation between
serum zinc and the subjective experience of infection. We found that serum zinc
was significantly and negatively correlated to the increase in the alpha2
protein fraction and positively correlated to decreases in the expression of mitogen-induced CD69+ (a T cell activation marker) on CD3+
as well as CD3+CD8+ T cells. These results show that CFS is accompanied by a
low serum zinc status and that the latter is related to signs of inflammation
and defects in early T cell activation pathways. Since zinc is a strong
anti-oxidant, the present results further support the findings that CFS is
accompanied by increased oxidative stress. The results of these reports suggest
that some patients with CFS should be treated with specific antioxidants,
including zinc supplements.
The role of enterovirus
in chronic fatigue syndrome.
Chia JK.
J Clin Pathol. 2005
Nov;58(11):1126-32.
Two and a
half decades after coining of the term chronic fatigue syndrome (CFS), the
diagnosis of this illness is still symptom based and the aetiology
remains elusive. Enteroviruses are well known causes
of acute respiratory and gastrointestinal infections, with tropism for the
central nervous system, muscles, and heart. Initial reports of chronic enteroviral infections causing debilitating symptoms in
patients with CFS were met with skeptism, and had
been largely forgotten for the past decade. Observations from in vitro
experiments and from animal models clearly established a state of chronic
persistence through the formation of double stranded RNA, similar to findings
reported in muscle biopsies of patients with CFS. Recent evidence not only
confirmed the earlier studies, but also clarified the pathogenic role of viral
RNA through antiviral treatment. This review summarises
the available experimental and clinical evidence that supports the role of enterovirus in chronic fatigue syndrome.
Clinical activity of folinic
acid in patients with chronic fatigue syndrome.
Lundell K, Qazi S, Eddy L, Uckun
FM.
Arzneimittelforschung.
2006;56(6):399-404.
A high
incidence of severe B-cell immunodeficiency and chronic reactivated
Epstein-Barr virus (EBV) infection in patients with
chronic fatigue syndrome (CFS) is reported herein. Of the 58 patients
evaluated, 100% had evidence of prior EBV exposure
and 72% had evidence for reactivated EBV infection.
Notably, 94% of CFS patients had B-cell immunodeficiency with a marked depletion
of their CD19+IgM+ mature B-lymphocyte population. A remarkable 81% of CFS
patients experienced subjective improvement of their symptoms after treatment
with folinic acid (CAS
58-05-9, leucovorin). The findings provide
unprecedented evidence that CFS frequently is a folinic
acid responsive clinical entity accompanied by B-cell immunodeficiency and
inappropriate antibody responses to EBV.
Detection of antibody against Borna disease virus-p24 in the plasma of Chinese patients with
chronic fatigue syndrome by Western-blot analysis [Article in Chinese]
Li YJ, Wang DX, Zhang FM, Liu ZD,
Yang AY, Ykuta K.
Zhonghua
Shi Yan He Lin Chuang Bing Du Xue
Za Zhi. 2003
Dec;17(4):330-3.
OBJECTIVE:
To evaluate the prevalence of infection with Borna
disease virus (BDV) in Chinese patients with chronic
fatigue syndrome (CFS) and control subjects, and to discuss the etiological
association between CFS and infection with BDV.
METHODS: The CDC (1994) diagnostic criteria for CFS were used for case
definition. Sixty-one patients suffered from CFS were from 11 Provinces in
China. To detect the antibody against BDV-p24 on the plasma samples from all
cases and 73 healthy control subjects by Western-blotting analysis. RESULTS: 7
of the sixty-one cases and 0 of the controls were sero-positive
for BDV-p24 antibody, there was a statistical significant difference between
the two groups (11.48% vs 0%; P less than 0.010).
CONCLUSION: Chinese patients with CFS showed sero-positive
identifying BDV infection, by comparison,
anti.BDV-p24 antibody prevalence in patients was significantly higher than in
controls. An etiological association may exist between CFS and BDV infection.
Increased neutrophil
apoptosis in chronic fatigue syndrome.
Kennedy G, Spence V, Underwood C, Belch JJ.
J Clin Pathol. 2004 Aug;57(8):891-3
BACKGROUND/AIMS:
Many patients with chronic fatigue syndrome (CFS) have symptoms that are
consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection,
this study examined whether this phenomenon also occurs in patients with CFS.
METHODS: Apoptosis was assessed in patients with CFS in conjunction with
concentrations of the anti-inflammatory cytokine, transforming growth factor
beta1 (TGFbeta1). RESULTS: The 47 patients with CFS had higher numbers of
apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V
binding, and increased expression of the death receptor, tumour
necrosis factor receptor-I, on their neutrophils than
did the 34 healthy controls. Patients with CFS also had raised concentrations
of active TGFbeta1 (p < 0.005). CONCLUSIONS: These findings provide new
evidence that patients with CFS have an underlying detectable abnormality in
their immune cells.
Influenza vaccination: is it appropriate in
chronic fatigue syndrome?
Sleigh KM, Marra FH, Stiver HG.
Am J Respir Med. 2002;1(1):3-9.
Chronic
fatigue syndrome (CFS) is a recognized clinical illness of unknown cause and pathophysiologic mechanisms. Immunizing patients against
influenza would seem to be a prudent strategy since infection has been
associated with symptom exacerbation. However, patients with CFS have
demonstrated variable abnormalities in the immune system, the clinical
significance of which is unclear. Anecdotal information has suggested that, due
to the etiologic uncertainty surrounding CFS, many patients reject
immunization, fearful of untoward effects. This article attempts to clarify the
situation by reviewing immunologic findings in CFS and influenza vaccines in
current use. Results from a recent survey of perceptions of patients with CFS
regarding immunization revealed that 31% felt immunization was neither safe nor
beneficial. This opinion was universal in those patients who had never received
influenza vaccine. Among patients who had received vaccine and experienced an
adverse effect, 26% felt the vaccine was safe and 28% felt it was beneficial.
Among those who had received vaccine without an adverse effect, 45% believed
the vaccine was safe, and 55% felt it was effective. CFS patients as a group
expressed concern that influenza vaccine would alter an already dysfunctional
immune system, or worsen CFS symptoms. Significantly more patients with CFS who
had never received influenza vaccine voiced this opinion than did patients who
had received immunization for influenza in the past. Contrary to the opinions
expressed by the sample, clinical trials in CFS have yet to find that any type
of immunization has produced a deleterious effect on symptoms or functioning.
Moreover, patients with CFS in a randomized, placebo-controlled, double-blind
trial of influenza immunization produced an antibody titer in the protective
range to inactivated trivalent influenza vaccine, although the geometric mean
titer was slightly blunted compared with healthy vaccinees.
Although patients with CFS in placebo and active groups reported four times the
number of post-injection adverse effects of healthy vaccinees,
data re-analysis revealed that this finding was related to the overlap of
common, post-influenza immunization symptoms and CFS constitutional symptoms.
CFS is a poorly understood illness and some patients may believe in causal
theories that lead to the rejection of disease prevention strategies such as
immunization. However, influenza immunization appears to provide protective
antibody levels without worsening CFS symptoms or causing excessive adverse
effects. Efforts to motivate patients with CFS to obtain annual influenza
immunization should take into account illness perceptions and concentrate on
education based on placebo-controlled trials.
Diagnostic evaluation of 2', 5'-oligoadenylate synthetase activities and antibodies against Epstein-Barr
virus and Coxiella burnetii
in patients with chronic fatigue syndrome in Japan.
Ikuta K,
Yamada T, Shimomura T, Kuratsune H, Kawahara R, Ikawa S, Ohnishi E, Sokawa Y, Fukushi H, Hirai K, Watanabe Y, Kurata
T, Kitani T, Sairenji T.
Microbes
Infect. 2003 Oct;5(12):1096-102.
To
investigate the association of viral infections with chronic fatigue syndrome
(CFS), we assayed 2', 5'-oligoadenylate synthetase
(2-5AS) activities in peripheral blood mononuclear cells from CFS patients in
Japan. These patients were diagnosed in two hospitals, H1 and H2, located in
different areas of the country. The activities were detected in 19 (86%) and 7
(32%) of each of the 22 patients in H1 and H2, respectively, while they were
detected in only four (11%) out of the 38 healthy controls. IFN-alpha
was similarly detected in a few CFS patients and healthy controls. We also
assayed the antibody titers against Epstein-Barr virus (EBV)
and Coxiella burnetii in
these patients. The EBV anti-EA-IgG
antibodies were detected in two (9%) and seven (32%) of each of the 22 patients
in H1 and H2, respectively. Anti-C. burnetii IgG antibodies were detected in six (27%) out of 22
patients in H1 but not in 22 patients in H2, while they were detected in one
(11%) of the nine healthy controls. Some CFS patients may be associated with EBV or C. burnetii infection.
There were some statistical correlations between the 2-5AS activities and
antibody titers of EA-IgG (P < 0.05, Student's
t-test) but not to the antibody titers of C. burnetii.
The up-regulation of 2-5AS activities suggests immunological dysfunctions with
some virus infections in the CFS patients. Our results indicate that 2-5AS
activities are useful for a diagnostic marker of CFS and for exploring the
complicated pathogenesis of CFS.
Mycoplasma blood infection in chronic fatigue and fibromyalgia
syndromes.
Endresen
GK.
Department
of Rheumatology, University of Oslo, Norway.
Rheumatol Int. 2003 Sep;23(5):211-5. Epub 2003 Jul 16.
Chronic
fatigue syndrome (CFS) and fibromyalgia syndrome
(FMS) are characterised by a lack of consistent
laboratory and clinical abnormalities. Although they are distinguishable as
separate syndromes based on established criteria, a great number of patients
are diagnosed with both. In studies using polymerase chain reaction methods, mycoplasma blood infection has been detected in about 50%
of patients with CFS and/or FMS, including patients with Gulf War illnesses and
symptoms that overlap with one or both syndromes. Such infection is detected in
only about 10% of healthy individuals, significantly less than in patients.
Most patients with CFS/FMS who have mycoplasma
infection appear to recover and reach their pre-illness state after long-term
antibiotic therapy with doxycycline, and the
infection can not be detected after recovery. By means of causation and
therapy, mycoplasma blood infection may permit a
further subclassification of CFS and FMS. It is not
clear whether mycoplasmas are associated with CFS/FMS
as causal agents, cofactors, or opportunistic infections in patients with
immune disturbances. Whether mycoplasma infection can
be detected in about 50% of all patient populations with CFS and/or FMS is yet
to be determined.
RNase L levels in peripheral blood mononuclear
cells: 37-kilodalton/83-kilodalton isoform ratio is a
potential test for chronic fatigue syndrome.
Tiev KP, Demettre
E, Ercolano P, Bastide L, Lebleu B, Cabane J.
Service de
Medecine Interne, Hopital Saint Antoine, Paris, France.
Clin Diagn Lab Immunol. 2003
Mar;10(2):315-6.
Chronic
fatigue syndrome (CFS) is a disorder characterized by debilitating fatigue
associated with immunological abnormalities. The etiology remains unclear. A
low-molecular-mass (37 kDa) isoform
of RNase L has been described in peripheral blood mononuclear cell (PBMC) extracts, and the ratio of two isoforms
of RNase L (37 kDa/83 kDa) has been proposed as a
potential biochemical marker of CFS. In a prospective case-control study, we
tested whether the RNase L 37-kDa/83-kDa ratio could discriminate a SFC population. We compared the ratio of RNase L isoforms in PBMCs from 11
patients with CFS (6 women and 5 men; mean age +/- standard deviation, 43.2 +/-
13.8 years) and PBMCs from 14 healthy well-matched
volunteers (10 women and 4 men; age, 39.1 +/- 11.6 years). A ratio of RNase L
of 0.4 used as a threshold allowed diagnosis of CFS with high sensitivity (91%;
95% confidence interval [CI], 57 to 99%) and specificity (71%; 95% CI, 41 to
90%). The positive and negative prognostic values were 71% (95% CI, 41 to 90%)
and 91% (95% CI, 57 to 99%), respectively. In the absence of acute infection or
chronic inflammation, a high RNase L ratio could distinguish CFS patients from
healthy volunteers. Additional large studies and follow-up studies are required
to confirm the stability of this high ratio of RNase L isoforms
in a CFS group.
A six-month trial of valacyclovir
in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in
left ventricular function.
Lerner AM, Beqaj SH, Deeter
RG, Dworkin HJ, Zervos M, Chang CH,
Fitzgerald JT, Goldstein J, O'Neill W.
School of
Medicine, Wayne State University, Detroit, USA.
Drugs Today
(Barc). 2002 Aug;38(8):549-61.
This study
was designed to determine safety and efficacy of a 6-month trial of valacyclovir in single-virus Epstein-Barr virus (EBV) persistent infection. Phase I of this study used four
specific criteria to define a subset of patients with chronic fatigue syndrome
(CFS). In the second phase, myocardial dynamics were measured by MUGA rest/stress radionuclide ventriculographic
(RVG) examinations pre- and posttreatment
with valacyclovir. In phase I, a trial was performed
in 19 consecutive CFS patients with the following diagnostic conditions:
patients met criteria for diagnosis of CFS; they had had CFS for less than 1
year. They demonstrated repetitively abnormal oscillating T waves (ischemic or
flat) at 24-h Holter monitoring; and they had
elevated serum IgM antibody titers to EBV viral capsid antigen and/or
total diffuse early antigen as measured by the enzyme-linked immunosorbent assay method. The treatment group comprised
10 CFS patients with no serum antibodies to human cytomegalovirus, but the
control group (nine CFS patients) had, additionally, high titers of serum
antibodies (IgG) to conformational structural
antigens of human cytomegalovirus. Both the parallel treatment and control CFS
groups received valacyclovir 1.0-1.5 gm q.6.h. for 6
months. This valacyclovir dose achieved serum acyclovir
C(max) of > 7 microm and high antiviral activity
versus EBV (IC(50) of 4.4-13.3 m). In phase II, six
additional CFS patients met the same four criteria as the 19 CFS patients in
phase I. They had, however, been ill for a mean of 55.8 months. Thus, 25 CFS
patients comprise this study. The studies were carried out at a single
outpatient practice in Birmingham, MI, U.S.A. Before initiating valacyclovir, and after 6 months of treatment, clinical and
laboratory observations were made. The CFS Energy Index point score (Table I)
was used to record each CFS patient's functional capacity at baseline and after
1, 3 and 6 months of valacyclovir. Energy Index point
scores, as well as EBV and human cytomegalovirus
serum antibody titers were assessed. In the second phase, left ventricular
dynamics were repeated after 6 months of treatment with valacyclovir.
We concluded that the 16 CFS patients (included in both phases of this study)
with EBV-persistent infection (EBV
single-virus subset) are improved after 6 months of continuous pharmacokinetic
dosing with valacyclovir. Nine CFS patients with EBV/human cytomegalovirus co-infection did not benefit from
6 months of similar treatment. Valacyclovir is not an
effective anti-human cytomegalovirus antiviral drug. Unimproved CFS patients
with co-infections EBV and human cytomegalovirus may
require combined treatment with valacyclovir and
another drug more active against human cytomegalovirus. This preliminary trial,
with a small number of patients, may be critical to an appropriately designed
larger, double-blind, placebo-controlled trial. Copyright 2002 Prous Science
Prevalence of abnormal cardiac wall motion in
the cardiomyopathy associated with incomplete
multiplication of Epstein-barr Virus and/or
cytomegalovirus in patients with chronic fatigue syndrome.
Lerner AM, Dworkin HJ, Sayyed
T, Chang CH, Fitzgerald JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P, O'Neill W.
Department
of Medicine, William Beaumont Hospital, Michigan, USA.
In Vivo.
2004 Jul-Aug;18(4):417-24.
We reported
unique incomplete herpesvirus (Epstein-Barr Virus (EBV) and/or nonstructural (HCMV)
cytomegalovirus) multiplication in 2 distinct subsets of CFS patients. The CFS
subsets were identified by: a) presence of IgM serum
antibodies to HCMV nonstructural gene products p52
and CM2 (UL44 and UL57), and/or b) IgM serum
antibodies to Epstein-Barr virus viral capsid antigen
(EBV, VCA IgM). Diagnostic IgM serum
antibodies were found in two independent blinded studies involving 49 CFS patients,
but the same antibodies were absent in 170 control patients (p<0.05).
Abnormal 24 Hr-electrocardiographic monitoring, tachycardias at rest and, in severe chronic cases, abnormal
cardiac wall motion (ACWM) were seen in these same
CFS patients. We now report a prospective consecutive case control study from
1987--1999 of cardiac dynamics as measured by radionuclide ventriculography
in 98 CFS patients from 1987--1999. Controls were patients with various
malignancies who were evaluated in protocols requiring radionuclide ventriculography before initiation of cardiotoxic
chemotherapeutic agents. The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 out of 87 patients
(11.5%). With stress exercise, 21 patients (24.1%) demonstrated ACWM. Cardiac biopsies in 3 of these CFS patients with ACWM showed a cardiomyopathy.
Among the controls, ACWM at rest was present in 4 out
of 191 patients (2%) (p=0.0018). A progressive cardiomyopathy
caused by incomplete virus multiplication of EBV and/or
HCMV in CFS patients is present.
High prevalence of Mycoplasma
infections among European chronic fatigue syndrome patients. Examination of
four Mycoplasma species in blood of chronic fatigue
syndrome patients.
Nijs J,
Nicolson GL, De Becker P, Coomans D, De Meirleir K.
Department
of Human Physiology, Vrije Universiteit
Brussel, Belgium.
FEMS Immunol Med Microbiol. 2002 Nov
15;34(3):209-14.
Prevalence
of Mycoplasma species infections in chronic fatigue
syndrome (CFS) has been extensively reported in the scientific literature.
However, all previous reports highlighted the presence of Mycoplasmas
in American patients. In this prospective study, the presence of Mycoplasma fermentans, M. penetrans, M. pneumoniae and M. hominis in the blood of 261 European CFS patients and 36
healthy volunteers was examined using forensic polymerase chain reaction. One
hundred and seventy-nine (68.6%) patients were infected by at least one species
of Mycoplasma, compared to two out of 36 (5.6%) in
the control sample (P<0.001). Among Mycoplasma-infected
patients, M. hominis was the most frequently observed
infection (n=96; 36.8% of the overall sample), followed by M. pneumoniae and M. fermentans
infections (equal frequencies; n=67; 25.7%). M. penetrans
infections were not found. Multiple mycoplasmal
infections were detected in 45 patients (17.2%). Compared to American CFS
patients (M. pneumoniae>M. hominis>M.
penetrans), a slightly different pattern of mycoplasmal infections was found in European CFS patients
(M. hominis>M. pneumoniae,
M. fermentansz.Gt;M. penetrans).
Antiviral pathway
activation in patients with chronic fatigue syndrome and acute infection.
Gow JW,
Simpson K, Behan PO, Chaudhuri A, McKay IC, Behan WM.
Clin Infect Dis. 2001
Dec 15;33(12):2080-1. Epub 2001 Nov 6.
Gene
expression of key enzymes in 2 antiviral pathways (ribonuclease
latent [RNase L] and RNA-regulated protein kinase [PKR]) was compared in 22 patients with chronic fatigue
syndrome (CFS), 10 patients with acute gastroenteritis, and 21 healthy
volunteers. Pathway activation in the group of patients with infections differed
significantly from that of the other 2 groups, in whom there was no evidence of
upregulation. Therefore, assay of activation is
unlikely to provide the basis for a diagnostic test for CFS.
Studies on enterovirus in patients with chronic fatigue syndrome.
Gow JW,
Behan WM, Simpson K, McGarry F, Keir
S, Behan PO.
Clin Infect Dis. 1994
Jan;18 Suppl 1:S126-9.
A large
study on 121 patients with the chronic fatigue syndrome (CFS) that examined
muscle biopsy samples for enterovirus by means of
polymerase chain reaction analysis was carried out. The results were compared
with those obtained from 101 muscle biopsy specimens from patients with a
variety of other neuromuscular disorders (OND),
including neurogenic atrophies, dystrophies, and
mitochondrial, metabolic, and endocrine myopathies.
Thirty-two (26.4%) of the biopsy specimens from the group of patients with CFS
were positive, compared with 20 (19.8%) from the group of patients with OND, a difference that was not significant. This finding is
in contrast to those of our previous smaller study in which significantly more
patients with CFS than control subjects (53% [32 of 60] vs. 15% [6 of 41]) had enterovirus RNA sequences in their muscle. It was concluded
that it is unlikely that persistent enterovirus
infection plays a pathogenetic role in CFS, although
an effect in initiating the disease process cannot be excluded.
Impairments of the 2-5A synthetase/RNase
L pathway in chronic fatigue syndrome
Nijs J, De Meirleir K.
In Vivo. 2005 Nov-Dec;19(6):1013-21
This paper
provides an overview of the evidence addressing the impairments of the 2'-5' oligoadenylate (2-5 A) synthetase/RNase
L pathway in Chronic Fatigue Syndrome (CFS) patients. The 2-5A synthetase/RNase L pathway in CFS patients appears to be
both up-regulated (i.e. increased levels of bioactive 2-5A synthetase
and increased activity of the RNase L enzyme) and deregulated (elastase and calpain initiate 83 kDa RNase L proteolysis, generating two major fragments
with molecular masses of 37 and 30 kDa,
respectively). The deregulation of the 2-5A synthetase/RNase
L pathway in CFS accompanies decreased NK-function
and deregulation of apoptotic pathways. Since various components of the pathway
appear to be related to performance during a graded exercise stress test, some
evidence supportive of the clinical importance of the impaired pathway in CFS
patients has been provided. Studies addressing the treatment of the
deregulation of the 2-5A synthetase/RNase L pathway
in CFS are warranted.
Gene expression in
peripheral blood mononuclear cells from patients with chronic fatigue syndrome
N Kaushik, D Fear, S C M Richards, C R McDermott, E F Nuwaysir, P Kellam, T J Harrison,
R J Wilkinson, D A J Tyrrell, S T Holgate, J R Kerr.
Journal of Clinical Pathology 2005;58:826-832
http://jcp.bmjjournals.com/cgi/content/abstract/58/8/826
BACKGROUND:
Chronic fatigue syndrome (CFS) is a multisystem
disease, the pathogenesis of which remains undetermined. AIMS: To test the
hypothesis that there are reproducible abnormalities of gene expression in
patients with CFS compared with normal healthy persons.
METHODS: To
gain further insight into the pathogenesis of this disease, gene expression was
analysed in peripheral blood mononuclear cells from 25 patients with CFS
diagnosed according to the Centers for Disease
Control criteria and 25 normal blood donors matched for age, sex, and
geographical location, using a single colour microarray
representing 9522 human genes. After normalisation, average difference values
for each gene were compared between test and control groups using a cutoff fold difference of expression > or = 1.5 and a p
value of 0.001. Genes showing differential expression were further analysed
using Taqman real time polymerase chain reaction (PCR) in fresh samples.
RESULTS:
Analysis of microarray data revealed differential
expression of 35 genes. Real time PCR confirmed
differential expression in the same direction as array results for 16 of these
genes, 15 of which were upregulated (ABCD4, PRKCL1,
MRPL23, CD2BP2, GSN, NTE,
POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP,
BRMS1, and GABARAPL1) and one of which was downregulated
(IL-10RA). This profile suggests T cell activation and perturbation of neuronal
and mitochondrial function. Upregulation of
neuropathy target esterase and eukaryotic translation initiation factor 4G1 may
suggest links with organophosphate exposure and virus infection, respectively.
CONCLUSION: These results suggest that patients with CFS have reproducible
alterations in gene regulation.
Current
research priorities in Chronic Fatigue Syndrome / Myalgic Encephalomyelitis
(CFS/ME): disease mechanisms, a diagnostic test and specific treatments
Kerr JR,
Christian P, Hodgetts A, Langford PR, Devanur LD, Petty R, Burke B, Sinclair LI, Richards SC,
Montgomery J, McDermott C, Harrison TJ, Kellam P, Nutt DJ, Holgate ST.
J Clin Pathol. 2006 Aug 25
Chronic
fatigue syndrome (CFS) is an illness characterised by disabling fatigue of at least
6 months duration which is accompanied by various rheumatological,
infectious and neuropsychiatric symptoms. A
collaborative study group has been formed in order to address the current areas
for development in CFS research, namely, to develop an understanding of the
molecular pathogenesis of CFS, to develop a diagnostic test, and to develop
specific and curative treatments. Various groups have studied the gene
expression in peripheral blood of CFS patients and of those studies which have
been confirmed using polymerase chain reaction (PCR),
it is clear that the most predominant functional theme is that of immunity and defense. However, we do not yet know the precise gene
signature and metabolic pathways involved. Currently, this is being addressed
using a microarray representing 47,000 human genes
and variants, massive parallel signature sequencing (MPSS)
and real-time PCR. It will be important to ensure
that once a gene signature has been identified, that it is specific to CFS and
does not occur in other diseases and infections. A diagnostic test is being
developed using Surface-Enhanced, Laser-Desorption
and Ionisation - Time of Flight (SELDI-TOF) mass
spectrometry following a pilot study in which putative biomarkers were
identified. And, finally, clinical trials are being planned; novel treatments
which we believe are important to trial in CFS patients are interferon-a and
one of the anti-tumour necrosis factor-a drugs.
Chronic fatigue syndrome
Devanur LD, Kerr JR.
J Clin Virol. 2006 Sep 13
Chronic
fatigue syndrome (CFS) is thought to have a worldwide prevalence of 0.4-1% with
approximately 240,000 patients in the UK. Diagnosis is based on clinical
criteria and critically depends on exclusion of other physical and psychiatric
diseases. Studies of pathogenesis have revealed immune system abnormalities and
chronic immune activation, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, brain abnormalities, evidence of emotional
stress (comprising host aspects) and evidence of exogenous insults, for
example, various microbial infections (Epstein-Barr virus, enteroviruses,
parvovirus B19, Coxiella burnetii
and Chlamydia pneumoniae), vaccinations and exposure
to organophosphate chemicals and other toxins (comprising environmental
aspects). Emotional stress appears to be very important as it reduces the
ability of the immune system to clear infections, it's presence has been shown
to determine whether or not an individual develops symptoms upon virus
infection, and it leads to activation of the HPA
axis. But, emotional stress is distinct from depression, the presence of which
precludes a diagnosis of CFS. There is no specific treatment for CFS other than
the much underutilised approach of specific treatment of virus infections.
Current priorities are to understand the molecular pathogenesis of disease in
terms of human and virus gene expression, to develop a diagnostic test based on
protein biomarkers, and to develop specific curative treatments.
Detection
of Actin Fragments in Serum: A Rapid Screening Test
to Aid in the Diagnosis of Chronic Fatigue Syndrom.
The
Fragmented Actin Serum Test (FASTest™)
http://www.redlaboratories.be/2/printer.php?nummer=1&tabel=testen
In its
native form, actin exists in a monomeric
state with a molecular weight of 42 kDa (referred to
as G-actin). To form part of the cytoskeleton, actin polymerizes into long filaments (referred to as F-actin). Any degradation or abnormal proteolysis of actin protein could therefore have dramatic consequences on
the ability of an immune cell to perform its normal function, especially if
that function required motility (e.g., phagocytosis).
In PBMCs from patients with CFS, fragmentation of actin was detected. The amount of fragmentation correlated
significantly with the amount of fragmentation of RNase L protein (p <
0.001, n = 62 specimens).
Researchers
then examined the serum for actin protein fragments.
Normally, actin is released into the serum as a
consequence of cell turnover and/or necrosis and is cleared from circulation by
the vitamin D-binding protein (also referred to as the group-specific
component, or Gc)(6). Native actin
protein binds to the vitamin D-binding protein through actin's
C-terminal amino acid structure. However, the intracellular cleavage of actin results in fragments that do not contain the
identical C-terminal structure and thus these fragments are not cleared as
rapidly from the serum. Levels of actin protein
fragmentation in serum correlates significantly with the amount of both
intracellular actin- and RNase L- fragmentation (p
< 0.01, n = 175)(7)
Quantitative
Measurement of RNase L Proteins: The Confirmatory Test to Aid in the Diagnosis
of Chronic Fatigue Syndrome
http://www.redlaboratories.be/2/printer.php?nummer=2&tabel=testen
In 1995,
Dr. Robert Suhadolnik and his co-workers at Temple
University, Philadelphia, PA, detected a novel intracellular protein related to
RNase L, one of the interferon-inducible enzymes. These enzymes, which also
include 2'-5' Oligoadenylate Synthetase,
and double-stranded RNA dependent Protein Kinase,
play a key role in protecting the cell from viral infection.(2,3) The novel
protein was determined to have a molecular weight of approximately half of the
native RNase L (and is thus referred to as the Low Molecular Weight RNase L or
'LMW,' while the native RNase L protein is referred
to as the High Molecular Weight (HMW) species).
Working
together with clinicians Daniel Peterson and Paul Cheney, Dr. Suhadolnik was able to demonstrate the presence of this LMW protein in a subset of patients with CFS.(4,5) His
findings were independently confirmed by Dr. Bernard Lebleu,
at the Institute for Genetic Molecular Medicine, Montpellier University,
Montpellier, France, working together with clinician Kenny De Meirleir at the Free University of Brussels, Belgium.(6)
Detection
of Mycoplasma Infection. Using the Polymerase Chain
Reaction (PCR) Technique
http://www.redlaboratories.be/2/printer.php?nummer=3&tabel=testen
A number of
recent publications in the medical literature have reported an increased
incidence of Mycoplasma infection in patients with
Chronic Fatigue Syndrome (CFS).4,5 While chronic fatigue is reported by 20% of
all patients seeking medical care, CFS is distinguishable as a separate
syndrome based on established medical criteria, the hallmark of which is
chronic, debilitating fatigue of six months or more in duration.6 Patients with
CFS also suffer from a number of physical problems including myalgia, arthralgia, low grade
fever, enlarged lymph nodes, cognitive impairment, and sleep disorders.
Although it remains unclear as to whether or not infection with Mycoplasma is causal, opportunistic, or a co-factor of the
morbidity observed in patients with CFS, it is important to distinguish this
group of patients as treatment of this or any underlying infection must be
considered in the overall therapeutic strategy.