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Causes of Death Among Patients With Chronic Fatigue Syndrome

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Chronic fatigue syndrome (CFS) is a debilitating illness affecting thousands of individuals. At the present time, there are few studies that have investigated causes of death for those with this syndrome. The authors analyzed a memorial list tabulated by the National CFIDS Foundation of 166 deceased individuals who had had CFS. There were approximately three times more women than men on the list. The three most prevalent causes of death were heart failure, suicide, and cancer, which accounted for 59.6% of all deaths. The mean age of those who died from cancer and suicide was 47.8 and 39.3 years, respectively, which is considerably younger than those who died from cancer and suicide in the general population. The implications of these findings are discussed.
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Health Care for Women International, 27:615–626, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 0739-9332 print / 1096-4665 online
DOI: 10.1080/07399330600803766
Causes of Death Among Patients With Chronic
Fatigue Syndrome
LEONARD A. JASON, KARINA CORRADI, SARA GRESS,
SARAH WILLIAMS, and SUSAN TORRES-HARDING
DePaul University, Chicago, Illinois, USA
Chronic fatigue syndrome (CFS) is a debilitating illness affecting
thousands of individuals. At the present time, there are few studies
that have investigated causes of death for those with this syndrome.
The authors analyzed a memorial list tabulated by the National
CFIDS Foundation of 166 deceased individuals who had had CFS.
There were approximately three times more women than men on
the list. The three most prevalent causes of death were heart failure,
suicide, and cancer, which accounted for 59.6% of all deaths. The
mean age of those who died from cancer and suicide was 47.8 and
39.3 years, respectively, which is considerably younger than those
who died from cancer and suicide in the general population. The
implications of these findings are discussed.
Chronic fatigue syndrome (CFS) is a severe illness, affecting a higher
proportion of women than men, and it can affect virtually every major
system of the body. Neurological, immunological, hormonal, gastrointestinal,
and musculoskeletal problems are all common among people with CFS
(Friedberg & Jason, 1998). Descriptions of symptom complexes similar to
CFS have occurred in the medical literature for centuries (Hyde, 2003), and
it is a condition that occurs throughout the world. Because it is one of the
more prevalent chronic health conditions (Jason et al., 1999), it is important
to better understand whether those with this condition have a higher risk of
mortality. Because few investigators have examined the issue of mortality and
Received 16 December 2004; accepted 16 March 2005.
The authors appreciate the assistance of Jill McLaughlin of the National CIFDS Foundation
in conducting this study. We also thank Connie Van der Eb, Gloria Njoku, Amber Jurgens,
Michael Fries, and Fred Friedberg for their editorial help.
Address correspondence to Leonard A. Jason, Center for Community Research, DePaul
University, 990 W. Fullerton Ave., Suite 3100, Chicago, IL 60614, USA. E-mail: Ljason@
depaul.edu
615
616 L. A. Jason et al.
CFS, databases that can provide estimates would be of particular importance
to public health officials and scientists from around the world.
Since the mid-1990s, the Fukuda and colleagues’ (1994) case definition
has been used by most researchers and health care personnel to define
this syndrome. This CFS case definition stipulates that a person needs to
experience chronic fatigue of new or definite onset, that is not substantially
alleviated by rest, is not the result of ongoing exertion, and results in
substantial reductions in occupational, social, and personal activities. This
case definition also requires the concurrent occurrence of at least four to eight
other symptoms (i.e., impaired memory or concentration, sore throat, tender
lymph nodes, muscle pain, multiple joint pain, new headaches, unrefreshing
sleep, and postexertional malaise).
This case definition, however, has been criticized by several researchers.
As an example, Jason and Taylor (2002) used cluster analysis to define
typologies of chronic fatigue symptomatology. They found that a majority of
individuals with moderate to severe symptoms were accurately classified into
two distinct subgroups: one distinguished by severe postexertional fatigue
and generalized fatigue that is alleviated by rest; and one characterized
by severe overall symptomatology, severe postexertional fatigue, and
generalized fatigue that is not alleviated by rest. Markedly high severity of
postexertional fatigue was a key symptom that distinguished the two clusters
that contained almost all participants with CFS from a third cluster containing
almost none of the CFS participants. This symptom has been designated as
a major criterion for the London definition of myalgic encephalomyelitis
(ME; Dowsett, Goudsmit, Macintyre, & Shepherd, 1994), but as only one of
eight possible symptoms within the Fukuda et al. (1994) criteria. In other
words, some individuals who are diagnosed with CFS according to the
Fukuda et al. case definition do not have one of the central features of this
illness.
Jason and colleagues (2003) investigated differences between CFS as
defined by Fukuda et al. (1994) and a set of criteria that has been stipulated
for ME, which requires postexertional malaise. The ME and the 1994 Fukuda
et al. criteria were compared with a group having chronic fatigue due to
psychiatric reasons (CF-psychiatric). There were 22 significant symptom
differences between the ME and CF-psychiatric group, but only eight
significant symptom differences between the CFS and CF-psychiatric group.
Those meeting the ME criteria were more symptomatic than those meeting
only the 1994 criteria, especially in the neurological and neuropsychiatric
areas. Chronic fatigue syndrome case definitions would be improved if more
attention was devoted to developing operationally explicit, objective criteria
and standardized interviews.
In spite of the debate in some quarters over the most appropriate
criteria for CFS (Brimacombe, Zhang, Lange, & Natelson, 2002–2003; Linder,
Dinser, Wagner, Krueger, & Hoffmann, 2002), other investigations have
Patients With Chronic Fatigue Syndrome 617
been able to isolate CFS as an illness distinct from other syndromes. For
example, Taylor, Jason, and Schoeny (2001) found diagnostic distinctions
between CFS, fibromyalgia, somatic depression, somatic anxiety, and irritable
bowel syndrome when employing a confirmatory factor analysis. In addition,
Naschitz and colleagues (2003) found a particular dysautonomia in CFS
that differs significantly from dysautonomia in patients with non-CFS fatigue,
fibromyalgia, syncope, and hypertensives, as well as healthy controls, but not
generalized anxiety disorder. In this study, the researchers computed blood
pressure and heart rate changes during a head-up tilt test, and processed the
data by image analysis methods.
Because other investigators have found cardiac and immunological
dysfunction in patients with CFS (Evengard, Schacterle, & Komaroff, 1999;
Lerner et al., 2003; Peckerman et al., 2003), it is possible that CFS might
be associated with the occurrence of other health conditions and, as a
result, perhaps decrease a patient’s life expectancy. Macfarlane, McBeth,
and Silman’s (2001) prospective follow-up study over eight years in England
found that mortality was higher in people with regional pain and widespread
pain than in those who reported no pain at baseline. The excess mortality
was almost entirely related to deaths from cancer, but there were also more
deaths from causes other than disease (e.g., accidents, suicide, violence)
among people with widespread pain. These findings may have implications
for the long-term follow-up of patients with CFS, who often report chronic
pain syndromes.
In the CFS area, several investigators have explored links between
CFS and other diseases (Levine, 1994). Endicott (1998) found patients with
CFS had significantly poorer health up to the time of onset of CFS than a
healthy control group, and that parents of patients with CFS had an increased
prevalence of cancer and autoimmune disorders (Endicott, 1999). Grufferman
and colleagues (1988) reported an outbreak of CFS in the Raleigh, North
Carolina Symphony orchestra. Three of these members were later reported
to have developed cancer (Johnson, 1996). Levine, Atherton, Fears, and
Hoover (1994) reviewed data from the Nevada State Cancer Registry
following an outbreak of a CFS-like illness in Nevada. These investigators
found an upward trend in the incidence of brain/CNS tumors, although this
could have been related to a national upward trend for this disease. Levine,
Fears, Cummings, and Hoover (1998) also analyzed data from the Nevada
Cancer Registry and found a higher incidence of non-Hodgkin lymphoma
and primary brain tumors in two northern Nevada counties where an
unexplained fatiguing illness was reported during 1984–1986. The higher
incidence rate was in comparison with another county where no such illness
had been reported. Finally, Joyce, Hotopf, and Wessely (1997) reported
that among 2,075 people followed up in 19 published outcome studies of
prolonged fatigue and CFS, there was one death by suicide and two unrelated
deaths. In a more recent review, Cairns and Hotopf (2005) found eight
618 L. A. Jason et al.
reported deaths in 12 studies. These mortality figures may underestimate
the true number of deaths because not all of these investigators had either
reported mortalities or had collected data on this topic.
The authors of a technical report issued by the Agency for Healthcare Re-
search and Quality (2001) concluded that estimates of recovery/improvement
or relapse from CFS are not possible because there are so few natural
history studies and those that are available have involved selected referral
populations. The authors recommended that studies need to be done to
determine the long-term natural history of CFS in longitudinal cohorts that
included representative samples.
Most CFS investigators believe that CFS can be a devastating and
debilitating illness, but not a fatal one. Despite this common belief, it is
conceivable that people with CFS might develop other serious secondary or
cooccurring health problems. In populations with poor health, we would
expect to find an increased susceptibility to many common diseases. Clearly,
it is important to establish if CFS leads to other illnesses or a shorter life
expectancy. In the present preliminary study, we reviewed the memorial
list published by the National CFIDS Foundation, and we used this as a
source for examining reasons for mortality in people with CFS. This database
of information is limited due to the nature of the informal collection and
presentation of data, but it still might provide intriguing data to warrant
future scientific investigations.
METHOD
Participants
Participants in this sample included individuals who had been entered in the
memorial list compiled by the National CFIDS Foundation. This list included
individuals with ME Chronic fatigue immune dysfunction (CFIDS) who have
died up to the summer of 2003. There are several other memorial lists
available on the Internet, but the list from the National CIFDS Foundation
was the most comprehensive. We decided not to pool entries from more
than one list as this might have resulted in counting individuals twice. The
National CFIDS Foundation Memorial List included both individuals who
had been members of the National CFIDS Foundation as well nonmembers.
Individual information for each entry was submitted by family or friends
of the deceased. The sample totaled 166, with 164 reporting the sex of
the individual, 145 reporting the cause of death of the individual, and 99
reporting the age of the individual.
Procedure
Each individual report was entered into a database to record the entry,
age, sex, and cause of death. Many causes of death were listed. To enable
Patients With Chronic Fatigue Syndrome 619
appropriate statistical analyses, cause of death was coded into categories.
The final categories included deaths caused by suicide, cancer (of all types),
heart failure (of all types), infections, complications due to CFS/ME, liver
or spleen or both failure, kidney failure, accidents and murder, other, and
unknown. The other conditions included entries where there was only one
individual in the category (i.e., ulceric gastritis, subdermal hematoma, abcess
on groin/sepsis, unrelated to ME/CFS, under anesthesia for minor surgery,
drug interaction/alcohol and medications, atypical pneumonia, pneumonia,
aneurysm, adult onset asthma attack, blood clot following fracture, diabetes).
The unknown condition referred to reports that specifically stated that the
cause of death was unknown.
RESULTS
Table 1 presents the reason for death among the 144 individuals where this
information was available. The three leading causes of death were heart
failure, suicide, and cancer, accounting for 59.6% of cases. In regard to
gender, 74.4% of this sample were female and 25.6% were male, and this
difference was significant at the p < .01 level using a binomial test. There
were also significant differences between males and females at the p < .01
level for deaths due to suicide and cancer. Small sample sizes probably led
to lack of significance on other variables.
Table 2 presents mean ages of death for individuals in the memorial list.
Due to small sample sizes, only the three largest categories were examined.
For heart failure, cancer, and suicide, employing an ANOVA, there was a
significant difference in ages (F (2,52) = 7.88, p < .01). In addition, those
who died from suicide were significantly younger than those who died from
heart failure.
Table 1 Causes of Death in Individuals With Chronic Fatigue Syndrome
Cause of death n
Percent of
total sample
Percent
male
Percent
female Significance
Suicide 29 20.1 17.2 82.8
Heart failure 29 20.1 34.5 65.5
Cancer 28 19.4 17.9 82.1
Complications of CFS/ME 16 11.1 31.3 68.8
Unknown 14 9.7 28.6 71.4
Other 12 8.3 25.0 75.0
Infections 5 3.5 100.0
Accidents/murder 5 3.5 20.0 80.0
Liver and/or spleen 4 2.8 75.0 25.0
Kidney failure 2 1.4 50.0 50.0
Total 144 100
Significant at <.01.
620 L. A. Jason et al.
Table 2 Mean Age and Standard Deviation by Cause of Death
Cause of death n Age (mean) Standard deviation
Suicide 17 39.3 12.69
Heart failure 21 58.7 15.57
Cancer 17 47.8 16.68
Complications of CFS/ME 7 35.6 13.73
Unknown 10 46.6 13.70
Other 9 44.4 3.84
Infections 3 48.3 17.62
Accidents/murder 4 46.2 20.76
Liver and/or spleen 1 69.0
Kidney failure 2 50.0 4.24
DISCUSSION
The authors examined causes of death in a sample of individuals that were
listed on a memorial list from the National CFIDS Foundation. Among those
listed, approximately 20% died from each of the following three causes:
heart failure, suicide, and cancer. The number deaths of women reported
was approximately three times the number deaths of men reported. Further,
those who died from suicide were significantly younger than those who
died from heart failure. Overall, at least among this group of individuals,
there were increased risks of death associated with heart failure, suicide,
and cancer.
The fact that approximately 20% of the sample died of heart failure is of
importance given the growing evidence of cardiac problems among patients
with CFS. For example, Streeten and Bell (2000) found that the majority of
patients with CFS had striking decreases in circulating blood volume. The
blood vessels in patients with CFS were constricted dramatically, and efforts
to restore normal volume have met with limited success. Martinez-Lavin and
colleagues (1997) studied 19 fibromyalgia patients, of whom 10 had CFS. The
patients were asked to stand upright after they had been resting in a supine
position, which represents a stressful challenge to the body. The patients
showed a decrease in the intensity of the sympathetic transmission to the
heart, and this reduction was even more pronounced for the patients with
comorbid CFS. By comparison, controls evidenced increases in the intensity
of sympathetic transmission to the heart. When lying down, there was a
trend among patients for an elevated heart rate, whereas when standing
up, there was a drop in sympathetic output. The authors suggest that
the sympathetic system might be incapable of responding to a stressful
challenge. Another line of research has been pursued by the Natelson
et al. research group at New Jersey Medical School. They recently found
that in response to postural stress, 81% of patients with CFS, but none of
controls, experienced ejection fraction decreases (suggesting left ventricular
Patients With Chronic Fatigue Syndrome 621
dysfunction in the heart) and those with more severe symptoms had greater
decreases (Peckerman, Chemitiganti, e t al., 2003). Patients with CFS might
have lower cardiac output, and the resulting low flow circulatory state could
make it difficult for patients to meet the demands of everyday activity, and it
could also lead to fatigue and other symptoms (Peckerman, LaManca, et al.,
2003).
The present study found that approximately 20% of the sample had died
from cancer, and this is of theoretical interest given the immune abnormalities
reported in patients. People with CFS appear to have two basic problems
with immune function: immune activitation as demonstrated by elevations
of activated T lymphocytes, including cytotoxic T cells and elevations of
circulating cytokines; and poor cellular function, with low natural killer
cell cytotoxicity and frequent immunoglobulin deficiencies (most often IgG1
and IgG3; Patarca-Montero, Mark, Fletcher, & Klimas, 2000). For example,
Antoni, Fletcher, Weiss, Maher, Siegel, and Klimas, (2003) found that patients
with low natural killer cell activity (NKCA) and a state of overactivation of
lymphocyte subsets (e.g., CD2+CD26+% activation markers) had the greatest
fatigue intensity and greatest fatigue-related impairments in emotional and
mental functioning. It seems that the Th2 cytokines are dominant over the
Th1 cytokines. In addition, Suhadolnik and colleagues (1997) found a novel
low-molecular-weight (37 kDa) binding protein in a subset of individuals
with CFS who are severely disabled by their disease. A European team
(De Meirleir et al., 2000) has also found increased levels of 80 kDa and 37
kDa RNase L in patients with CFS. The ratio of this 37 kDa protein to the
normal 80 kDa protein was high in 72% of patients with CFS but only in
1% of the healthy controls and in none of the depression and fibromyalgia
control patients.
Another 20% of patients died of suicide, possibly due to the losses
that patients with this illness experience from family, friends, coworkers,
and health care workers (Friedberg & Jason, 1998). Anderson and Ferrans
(1997) found that 77% of individuals with CFS reported past negative
experiences with health care providers, and 35% indicated that they no
longer sought treatment because of minimal benefits. David, Wessely, and
Pelosi (1991) found that 57% of respondents were treated badly or very
badly by their doctors. Green, Romei, and Natelson (1999) also found that
95% of individuals seeking medical treatment for CFS reported feelings of
estrangement, and 70% believed that others wrongly attributed their CFS
symptoms to psychological causes. Asbring and Narvanen (2003) found
that physicians regarded the illness as less serious than the patients. The
physicians characterized the patients with CFS and fibromyalgia as illness
focused, demanding, and medicalizing. Twemlow, Bradshaw, Coyne, and
Lerma (1997) found that 66% of individuals with CFS stated that they were
made worse by their doctors’ care. Clearly, individuals who are extremely
sick with an illness will feel even more alienated and demoralized if those
622 L. A. Jason et al.
who are responsible for helping them are insensitive to their needs. Certainly,
all of these factors, including demoralization, estrangement from the medical
establishment, and unsympathetic responses may cause some individuals to
develop depression as well. A sense of hopelessness concerning the illness
and comorbid depression may also increase the risk for developing suicidal
thoughts or behavior.
The fact that more women were reported to have died than men was
not unexpected, given that there is a higher percentage of women with CFS
than men. When examining individual cause of death categories, the authors
found significant gender differences were found only for suicide and cancer.
Analyses for gender differences in other causes of death, however, could
not be done due to low sample sizes. Of interest, the only category where
men had a higher reported percentage than women was with liver or spleen
or both problems; yet the very low number of individuals in this category
requires this finding to be viewed with caution.
When examining ages of death, we found that those dying of suicide
were significantly younger than those dying of heart failure. Another
intriguing finding was the overall ages of death for those dying of cancer,
suicide, and heart failure. If one examines national rates of death for these
conditions, the ages of death for these three conditions among the patients
with CFS are considerable earlier. The median age of death for cancer in
the United States is 72 (Reis et al., 2003, versus an average age of 47.8 for
the CFS sample), the average age of death for suicide in the United States is
48 (Centers for Disease Control, 2003, versus an average age of 39.3 for the
CFS sample), and the average age of heart failure is 83.1 (CDC, 2003, versus
an average age of 58.7 years for the CFS sample). What this suggests is that
those from this memorial list who did die of cancer, suicide, and heart failure
were considerable younger than what would have been expected from the
general population, which means that CFS might have increased the risk of
death for at least this sample.
CFS is a condition that affects individuals throughout the world (Hyde,
2003). Most research on the epidemiology and pathophysiology of this
syndrome, however, has occurred in either the United States, Europe,
or Japan (Jason, Fennell, & Taylor, 2003). Given that CFS is one of the
more common chronic health conditions, affecting potentially.42% of the
population (Jason et al., 1999), it is imperative for international researchers
and public health officials throughout the world to seriously study potential
factors that might influence functioning and mortality of those with this
condition.
The authors of the present study employed a sample from a self-help
advocacy organization in the United States. It is probably the case that most
individuals on this list were from the United States, but it is also likely that
there were individuals on this list from other countries. The authors, before
embarking on this investigation, did inspect lists that had been generated
Patients With Chronic Fatigue Syndrome 623
from other self-help organizations in different locations, but the authors felt
that the list from the United States was the most comprehensive. Unfortu-
nately, the authors are not able to list the different countries where mortalities
occurred, but this is an important task for future investigations. If mortality
rates for CFS did differ by geographic location, this might have implications
for either service delivery issues or for the etiology of the syndrome.
There are a number of methodological limitations in the present study.
First, there was no independent confirmation of cause of death, and self-
report data might have been inaccurate. It was not possible to interview
the family members or seek independent confirmation of cause of death.
In addition, data available from the memorial list often was not complete.
Even when a cause of death was provided, more specific information was
frequently missing (e.g., what type of heart failure or cancer caused the
death). It also was unclear how representative the memorial list is and from
what population it draws its data. Clearly, it is not possible to generalize the
data from this memorial list to the overall population of patients w ith CFS.
We cannot underestimate this methodological flaw to the present
study. In other words, it is possible that some of the deaths were either
misdiagnosed or that the individuals did not even have CFS. We would urge
future investigators on this topic to place more attention on the diagnostic
criteria. Clearly, a study on causes of death related to a condition that may
have been unreliably diagnosed is a serious issue. There are so few published
findings in this area, however, that the current study could at minimum serve
to stimulate additional, better controlled studies.
In spite of the above limitations, among this sample of participants with
CFS, causes of death appear to cluster in three general domains: heart failure,
suicide, and cancer. For each of these areas, there is supportive evidence
that might help explain why heart failure, cancer, and suicide might be
associated with deaths among people with CFS in this sample. Longitudinal
prospective studies with community-based samples are needed in order to
better understand the unique health risks associated with having CFS.
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... This may be due to a combination of autonomic dysfunction and maladaptive functional and structural cardiovascular responses to stressors. Evidence shows that ME/CFS patients die significantly earlier than the United States general population from cardiac failure (58.7 years vs. 83.1 years) [127]. Furthermore, ventricular dysfunction and increased arterial stiffness are noted in ME/CFS [104,127]. ...
... Evidence shows that ME/CFS patients die significantly earlier than the United States general population from cardiac failure (58.7 years vs. 83.1 years) [127]. Furthermore, ventricular dysfunction and increased arterial stiffness are noted in ME/CFS [104,127]. ...
Article
Full-text available
The transient receptor potential (TRP) superfamily of ion channels is involved in the molecular mechanisms that mediate neuroimmune interactions and activities. Recent advancements in neuroimmunology have identified a role for TRP cation channels in several neuroimmune disorders including amyotropic lateral sclerosis, multiple sclerosis, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating disorder with an obscure aetiology, hence considerable examination of its pathobiology is warranted. Dysregulation of TRP melastatin (TRPM) subfamily members and calcium signalling processes are implicated in the neurological, immunological, cardiovascular, and metabolic impairments inherent in ME/CFS. In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review. TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.
... [35]. Patients with severe ME/CFS usually die from underlying health complications such as cardiovascular diseases and cancer [36][37][38]. ...
Article
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities. Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity. Currently, there is no validated cure of biomarker signature for this illness. Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS. TRYP is an important precursor for serotonin and the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). TRYP has been associated with the development of some parts of the brain responsible for behavioural functions. The main catabolic route for TRYP is the kynurenine pathway (KP). The KP produces NAD+ and several neuroactive metabolites with neuroprotective (i.e., kynurenic acid (KYNA)) and neurotoxic (i.e., quinolinic acid (QUIN)) activities. Hyperactivation of the KP, whether compensatory or a driving mechanism of degeneration can limit the availability of NAD+ and exacerbate the symptoms of ME/CFS. This review discusses the potential association of altered KP metabolism in ME/CFS. The review also evaluates the role of the patient's gut microbiota on TRYP availability and KP activation. We propose that strategies aimed at raising the levels of NAD+ (e.g., using nicotinamide mononucleotide and nicotinamide riboside) may be a promising intervention to overcome symptoms of fatigue and to improve the quality of life in patients with ME/CFS. Future clinical trials should further assess the potential benefits of NAD+ supplements for reducing some of the clinical features of ME/CFS.
... The new model of CFAS-D proposed here is shown in Figure 7. Disorders in the cross-talks among these three key pathways mediate the effects of a variety of trigger factors in the onset of CFAS-D. These findings also support the theory that once CFAS-D is present, the abovementioned pathways may increase morbidity and even mortality of IO&NS-associated medical disorders through the detrimental effects of disorders in redox, NF-κB, and Wnt axis (24,26,(86)(87)(88). The model also explains that the acute phase of inflammatory conditions may lead to CFAS-D via disorders in this axis, oxidative damage and the neurotoxic effects of LPS, proinflammatory cytokines, and TRYCATs. ...
Article
Full-text available
There is evidence that chronic fatigue spectrum disorders (CFAS-Ds), including myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease, are characterized by neuroimmune and neuro-oxidative biomarkers. This study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns, and domains enriched in their PPI network. We performed network, enrichment, and annotation analyses using differentially expressed proteins and metabolics, which were established in patients with CFAS-D. The PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, tumor necrosis factor (TNF), and interleukin-6 (IL-6) and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/β-catenin subnetworks. Multiomics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, interleukin-10 (IL-10) anti-inflammatory signaling and neurodegenerative canonical Wnt, the β-catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways, and the transcription factors nuclear factor kappa B (NF-κB) and RELA. The top 10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer, and infectious disease. The custom Gene Ontology (GO) term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium, or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/β-catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.
... If the hypotheses described above were to be true, the subgroup of ME/CFS patients with EBV infection could have increased risk of developing autoimmune diseases (19,100,101), latent viral reactivations (e.g., herpesviruses, Parvovirus B19) and cancer (83,(102)(103)(104)(105)(106)(107), namely EBV-associated lymphoma (108). Additionally, HLA-II alleles associated with increased EBV susceptibility may also explain the higher prevalence of cancer and autoimmune disorders ( Figure 1C), such as rheumatoid arthritis and type 1 diabetes, in first-degree relatives of patients with ME/CFS (15,19,100,109,110). ...
Article
Full-text available
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.
... Our new model shows that disorders in cross-talks among these three key pathways mediate the effects of a variety of trigger factors in the onset of CFAS-D. These findings also support the theory that once CFAS-D is present the abovementioned pathways may increase morbidity and even mortality of IO&NS-associated medical disorders through the detrimental effects of disorders in redox, NF-κB and Wnt axis [81,82]. The model also explains that the acute phase of inflammatory conditions may lead to CFAS-D via disorders in this axis, oxidative damage and the neurotoxic effects of LPS, pro-inflammatory cytokines and TRYCATs. ...
Preprint
There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers. The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network. We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which we established in CFAS-D patients. PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks. MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA. The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease. Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.
... Our new model shows that disorders in cross-talks among these three key pathways mediate the effects of a variety of trigger factors in the onset of CFAS-D. These findings also support the theory that once CFAS-D is present the abovementioned pathways may increase morbidity and even mortality of IO&NS-associated medical disorders through the detrimental effects of disorders in redox, NF-κB and Wnt axis [81,82]. The model also explains that the acute phase of inflammatory conditions may lead to CFAS-D via disorders in this axis, oxidative damage and the neurotoxic effects of LPS, pro-inflammatory cytokines and TRYCATs. ...
Preprint
Full-text available
There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers. The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network. We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which we established in CFAS-D patients. PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks. MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA. The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease. Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.
... Most participants appreciated that ME is painful. However, only 25% knew that ME can kill, though research indicates increased mortality from cardiovascular disease, cancer and suicide [38,39], the latter being particularly tragic [40,41]. A recent paper has pointed out that there is a considerable risk to life from malnutrition among patients with very severe ME [42]. ...
Article
Full-text available
Background and Objectives: There is some evidence that knowledge and understanding of ME among doctors is limited. Consequently, an audit study was carried out on a group of hospital doctors attending a training event to establish how much they knew about ME and their attitudes towards it. Materials and Methods: Participants at the training event were asked to complete a questionnaire, enquiring about prior knowledge and experience of ME and their approaches to diagnosis and treatment. A total of 44 completed questionnaires were returned. Responses were tabulated, proportions selecting available options determined, 95% confidence limits calculated, and the significance of associations determined by Fisher’s exact test. Results: Few respondents had any formal teaching on ME, though most had some experience of it. Few knew how to diagnose it and most lacked confidence in managing it. None of the respondents who had had teaching or prior experience of ME considered it a purely physical illness. Overall, 91% of participants believed ME was at least in part psychological. Most participants responded correctly to a series of propositions about the general epidemiology and chronicity of ME. There was little knowledge of definitions of ME, diagnosis, or of clinical manifestations. Understanding about appropriate management was very deficient. Similarly, there was little appreciation of the impact of the disease on daily living or quality of life. Where some doctors expressed confidence diagnosing or managing ME, this was misplaced as they were incorrect on the nature of ME, its diagnostic criteria and its treatment. Conclusion: This audit demonstrates that most doctors lack training and clinical expertise in ME. Nevertheless, participants recognised a need for further training and indicated a wish to participate in this. It is strongly recommended that factually correct and up-to-date medical education on ME be made a priority at undergraduate and postgraduate levels. It is also recommended that this audit be repeated following a period of medical education
... Another study, despite not finding an increased suicide risk, discovered an increased risk of non-fatal self-harm [7], which is a robust predictor of future suicide attempt [8]. A retrospective convenience sample implicated suicide as one of the three leading causes of death in people with ME/CFS, alongside heart failure and cancer [9]. Compared to the general population, the median age at completed suicide was ...
Article
Full-text available
Adult patients affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are at an increased risk of death by suicide. Based on the scientific literature and our clinical/research experiences, we identify risk and protective factors and provide a guide to assessing and managing suicidality in an outpatient medical setting. A clinical case is used to illustrate how information from this article can be applied. Characteristics of ME/CFS that make addressing suicidality challenging include absence of any disease-modifying treatments, severe functional limitations, and symptoms which limit therapies. Decades-long misattribution of ME/CFS to physical deconditioning or psychiatric disorders have resulted in undereducated healthcare professionals, public stigma, and unsupportive social interactions. Consequently, some patients may be reluctant to engage with mental health care. Outpatient medical professionals play a vital role in mitigating these effects. By combining evidence-based interventions aimed at all suicidal patients with those adapted to individual patients’ circumstances, suffering and suicidality can be alleviated in ME/CFS. Increased access to newer virtual or asynchronous modalities of psychiatric/psychological care, especially for severely ill patients, may be a silver lining of the COVID-19 pandemic.
... Given the susceptibility of ME/CFS patients to experience threats to their identity and role confusion, afflicted patients who feel stigmatized may turn to suicide due to a reduction in their self-esteem. Indeed, evidence supports this conclusion, as suicide has been identified as a cause of death for a significant number of ME/CFS patients [105,106]. Additionally, patients who commit suicide appear to lack sufficient depressive symptoms to qualify for a depression diagnosis, as their depressive symptoms may better be associated with grief [107]. Evidence suggests that losses associated with ME/CFS and perceived stigma may be likely risk factors for suicidal ideation [42]. ...
Article
Full-text available
People who are severely and very severely affected by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience profound suffering. This suffering comes from the myriad of losses these patients experience, the grief that comes from these losses, the ongoing stigma that is often experienced as a person with a poorly understood, controversial chronic illness, and the trauma that can result from how other people and the health care community respond to this illness. This review article examines the suffering of patients with ME/CFS through the lens of the Fennell Four-Phase Model of chronic illness. Using a systems approach, this phase framework illustrates the effects of suffering on the patient and can be utilized to help the clinician, patient, family, and caregivers understand and respond to the patient’s experiences. We highlight the constructs of severity, uncertainty, ambiguity, and chronicity and their role in the suffering endured by patients with ME/CFS. A composite case example is used to illustrate the lives of severely and very severely affected patients. Recommendations for health care providers treating patients with ME/CFS are given and underscore the importance of providers understanding the intense suffering that the severely and very severely affected patients experience.
... [11] CFS patients mean age of death is considerably younger than those who died from cancer and suicide in the general population. [12] Although researchers pay substantial efforts to understand CFS better, diagnosing the disease is still a challenge because patients often struggle with their illness for years before an identification is made. [1,2] Due to CFS diagnosis uncertainties and a lack of clinical guidance for clinicians, many patients do not receive appropriate healthcare. ...
Article
Full-text available
Background: Chronic fatigue syndrome (CFS) is a relatively complex and disabling illness with a substantial economic burden and functional impairment. Until now, many CFS patients lack appropriate healthcare. Acupoint catgut embedding is an effective and emerging alternative therapy for CFE. With this research, we endeavor to investigate the effect and safety of ACE for CFS. Methods: Eight databases will be searched from inception to December 2020: PubMed, EMBASE, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chong-Qing VIP database, and Wan-fang database. We regard studies as eligible for inclusion if they were RCTs done in CFS patients, compare acupoint catgut embedding to another treatment strategy, and report fatigue changes at the end of the intervention period. Two independent reviewers complete the study selection, data extraction, and the risk of bias assessment. We assess pooled data using a random-effects model through Revman software (v.5.3) and Stata (version 15.0). Ethics and dissemination: Ethics approval is not required because the individual patient data will not be involved, with no privacy concerns. This systematic review and meta-analysis will provide a reference for CFS patients and clinicians on the non-drug interventions. We will publish and disseminate the results of this review in a peer-reviewed journal or relevant conference. Osf registration number: 10.17605/OSF.IO/7SHD9 (https://osf.io/7shd9).
Article
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• The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, system­ atic, and integrated approach to the evaluation, classi­ fication, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations.
Article
The prognosis of chronic fatigue syndrome and chronic fatigue has been studied in numerous small case series. We performed a systematic review of all studies to determine the proportion of individuals with the conditions who recovered at follow-up, the risk of developing alternative physical diagnoses, and the risk factors for poor prognosis. A literature search of all published studies which included a follow-up of patients with chronic fatigue syndrome or chronic fatigue were performed. Of 26 studies identified, four studied fatigue in children, and found that 54-94% of children recovered over the periods of follow-up. Another five studies operationally defined chronic fatigue syndrome in adults and found that < 10% of subjects return to pre-morbid levels of functioning, and the majority remain significantly impaired. The remaining studies used less stringent criteria to define their cohorts. Among patients in primary care with fatigue lasting < 6 months, at least 40% of patients improved. As the definition becomes more stringent the prognosis appears to worsen. Consistently reported risk factors for poor prognosis are older age, more chronic illness, having a comorbid psychiatric disorder and holding a belief that the illness is due to physical causes.
Article
This study evaluated the diagnostic validity of conditions that have been labeled functional somatic syndromes. In an effort to replicate prior work in this area, latent variable models of functional somatic distress were estimated from the responses of 213 community members to a medical questionnaire. Medical questionnaire items that closely conformed to formal diagnostic criteria for the conditions were used in model estimation. Results of confirmatory factor analysis supported diagnostic distinctions between five syndromes (fibromyalgia, chronic fatigue syndrome, somatic depression, somatic anxiety, and irritable bowel syndrome). Discrete diagnostic categories of fibromyalgia and chronic fatigue syndrome were then tested using logistic regression analysis, in which the outcome involved independent diagnosis of these conditions based upon physician evaluation. Evidence for the existence of discrete diagnoses of fibromyalgia and chronic fatigue syndrome was particularly strong, since these diagnoses were cross-validated using findings from physician evaluation tailored to diagnose these conditions. Findings can assist mental health practitioners in drawing theoretical and symptom-based distinctions between different types of syndromes characterized by physical complaints.
Article
A review of the literature on the immunology of CFS reveals that people who have Chronic Fatigue Syndrome (CFS) have two basic problems with immune function that have been documented by most research groups: 1. immune activation, as demonstrated by elevation of activated T lymphocytes, including cytotoxic T cells, as well as elevations of circulating cytokines; and 2. poor cellular function, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgGl and IgG3. These findings have a waxing and waning temporal pattern which is consistent with episodic immune dysfunction (with predominance of so called T-helper type 2 and proinflammatory cytokines and low NKCC and lymphoproliferation) that can be associated as cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens. The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status is discussed.
Article
Forty-five psychiatric patients with chronic fatigue syndrome (CFS) were compared, using the case–control method, to two control groups selected from the same practice and matched on age, gender, and psychiatric diagnosis. The first control group (C-I, N=90) was selected on the basis of relatively good physical health. The second control group (C-II, N=45) was selected without regard to physical health. The reported family history of physical health revealed: the CFS mothers died at a younger age than the C-II mothers; both parents died before age 65 among the CFS parents more frequently than did the C-I parents; and the CFS parents had an increased prevalence of cancer, autoimmune disorders, and CFS-like conditions as compared to the families of one or both control groups. The reported family history of mental disorders revealed no significant differences in any of these conditions between the CFS patients and either control group.
Article
This study involved a randomly selected, medically-evaluated, community-based sample of 166 individuals with chronic fatigue. Participants diagnosed with chronic fatigue syndrome and medically-explained chronic fatigue reported significantly more severe fatigue following exertion than the idiopathic chronic fatigue group, and participants with medically-explained chronic fatigue also reported significantly more severe fatigue following exertion than the psychiatrically-explained chronic fatigue group. A cluster analysis was performed to define a typology of chronic fatigue symptomatology for participants diagnosed with chronic fatigue syndrome. Three clusters emerged. Cluster 1 contained only one participant with chronic fatigue syndrome and was characterized by relatively low post-exertional fatigue. Cluster 2 contained a small proportion of individuals with chronic fatigue syndrome and was characterized by most severe post-exertional fatigue and most improvement in fatigue following rest. Cluster 3 contained the highest proportion of individuals with chronic fatigue syndrome, and was characterized by high post-exertional fatigue and fatigue not alleviated by rest.
Article
Surveyed a group of 67 Ss (80% female, aged 18–57 yrs) seeking relief from the incapacitating symptoms of chronic fatigue syndrome (CFS) concerning their feelings of stigma and perceptions of physician attributions of CFS symptoms to psychological causes as a contributor to CFS-related stigma. Most Ss scored high on measures of stigma: 95% had feelings of estrangement, 70% believed that others attributed their CFS symptoms to psychological causes, 77% coped by using an educational strategy (disclosure), and 39% saw a need to be secretive about their symptoms in some circumstances. Most Ss (77%) were labeled as "psychological cases" by one or more of the physicians consulted, but of the 4 stigma measures, only disclosure was related to physician labeling. Such factors as duration of illness and unemployment, dissatisfaction with spouse, and symptom severity correlated significantly with measures of stigma. That many physicians were reportedly ignorant or skeptical of CFS (males more so than females) may influence attempts of CFS patients to legitimize their symptoms by disclosure and lead to high rates of health care system use. (PsycINFO Database Record (c) 2012 APA, all rights reserved)