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22
The Possible Infectious Origins
of Myalgic Encephalomyelitis/ Chronic
Fatigue Syndrome and Fibromyalgia
and Other Infectious Diseases Causing
Cognitive Consequences
Kenneth J. Friedman, Ilene S. Ruhoy, Patricia A. Fennell, and Shane George
Introduction
e etiologies of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/ CFS)
and bromyalgia (FM) remain unknown despite an estimated 17– 24 million people
worldwide having ME/ CFS (Centers for Disease Control and Prevention, 2020) and
an estimated 160– 217 million having FM worldwide (Häuser & Fitzcharles, 2018).
e search for the causes of ME/ CFS and FM has been strongly inuenced by Koch’s
postulates, which propose that in diseases caused by infectious organisms removal
of the infectious agent from the body will restore health (Chesterton, 2019). For both
ME/ CFS and FM, a triggering infectious agent has not been denitively found. Under
these circumstances, other approaches to determining disease etiology have been
and are being applied: molecular and genetic techniques to determine the altered
physiology and biochemistry contributing to the diseased state and altered gene expression and cellular metabolism that contribute to the observed pathophysiology.
So far, no unique infectious organisms that cause the presenting symptoms of ME/
CFS and FM have been found. In addition, unique, altered metabolic processes that
can account for the presenting symptoms of ME/ CFS and FM have not been identied. Clinical diagnosis of both these conditions is primarily based upon patient
report of symptoms, which usually includes some form of cognitive impairment. For
these reasons, healthcare provider disbelief of the organic nature of these illnesses
has occurred.
Here, we propose that there are sucient ndings to suggest that in many cases,
both ME/ CFS and FM are associated with prior exposure to an infective agent.
Elsewhere, it has been argued that exposure to an infective agent may serve as the
Kenneth J. Friedman, Ilene S. Ruhoy, Patricia A. Fennell, and Shane George, The Possible Infectious Origins of Myalgic Encephalomyelitis/ Chronic
and Neuropsychiatric Medicine
© Oxford University Press 2024. DOI: 10.1093/ oso/ 9780192870414.003.0023
Fibromyalgia and Chronic Fatigue 349
trigger of at least one of these illnesses (Rasa et al., 2018). We further propose that
FM and ME/ CFS are two of several diseases whose precedent or comorbid infectious
agents are followed by subsequent physical symptoms and cognitive dysfunction
and argue that such diseases should be recognized, researched, and treated as postactive phase infectious syndromes (PAPIS).
Cognitive dysfunction is linked to both ME/ CFS and FM by patient report.
Patients commonly describe an inability to recall words, needing a longer time to
process new information, and having diculty keeping on task as they lose focus
and attention. Because there is also ample literature linking FM and ME/ CFS to viral
and bacterial comorbidity, there is the possibility that antecedent or comorbid infectious agents cause or contribute to the cognitive dysfunctions associated with ME/
CFS and FM. We evaluate those literatures in this chapter as well.
As discussed in greater detail below, the estimated global prevalence of ME/ CFS
is 17– 24 million (Centers for Disease Control and Prevention, 2020), and the estimated prevalence of FM is 160– 217 million (Häuser & Fitzcharles, 2018). Long
Covid (coronavirus disease 2019 (Covid- 19)), with its overlap of multiple symptoms
with ME/ CFS, was estimated to aect 122 million patients in 2022 (Hanson et al.,
2022) suggesting that as many as 363 million patients worldwide may be aected by
these diseases with similarities in onset and symptomology. is should serve as argument for increased eorts to understand the pathophysiologies of these diseases.
ME/ CFS and FM are frequently comorbid conditions and, therefore, may be considered by some as variants of the same condition (Abbi & Natelson, 2013; Brown &
Jason, 2007; Otero et al., 2023). We believe that the following analysis demonstrates
sucient dierences between the two, based upon preceding infection, to argue that
they are distinct from each other.
Relationship of infection to myalgic
encephalomyelitis/ chronic fatigue syndrome
ere are more research ndings linking ME/ CFS to infectious agents than there
are for associating FM with infectious diseases. As of 2023, searching PubMed using
ME/ CFS and its two other popular names (chronic fatigue syndrome and myalgic
encephalomyelitis) as text search terms results in over 7000 citations. We, therefore,
reran the search using the same terms but limiting their appearance to within the
titles of articles. at title- word search yielded 70 citations, of which we found 55
articles to be relevant to a discussion of a potential association between ME/ CFS and
infectious agents.
Inspection of the ME/ CFS- and- infection literature suggests that investigations
of the relationships between ME/ CFS and infectious organisms began in or around
1988, some 20 years aer the classication of ME/ CFS as a neurological disease by the
World Health Organization and some 50 years aer the initial Public Health Service
Report of the disease as a polio- like condition (Gilliam, 1938). More recently, the
2022
2020
2018
2016
2014
2012
2010
2008
2006
2004
2002
2000
1998
1988
Number of publications
567
1996
1994
1992
1990
Infectious Disease and Neurocognition
01234
Figure 22.1 The number of publications linking myalgic encephalomyelitis/ chronic fatigue
syndrome to infection published per year as estimated from a query of the PubMed database
for the years 1988 through 2021.
development of long Covid as a consequence of severe acute respiratory syndrome
coronavirus 2 (SARS- CoV- 2, Covid- 19) infection may have rekindled interest in the
potential link between ME/ CFS and an infectious origin despite the failure of previous eorts to identify a unique infectious agent as the cause of the disease. For the
years in which research literature on this topic has been published, we have plotted
the number of relevant publications per year, which demonstrates a modest number
of publications per year (Figure 22.1).
Prior to the Covid- 19 pandemic, an estimated 17– 24 million patients suered
from ME/ CFS worldwide (Centers for Disease Control and Prevention, 2020). In
consideration of the number of patients suering from ME/ CFS, its chronic nature,
the waxing and waning of symptom severity, and the likelihood of many patients’
symptoms improving somewhat, but the rare likelihood of patients being cured, the
number of investigations exploring ME/ CFS’s linkage to infection or infectious organisms seems modest.
Table 22.1 summarizes 57 articles relevant and representative of relationships between ME/ CFS and infectious agents.
Table 22.1 is not an exhaustive list but rather a sampling of the existing research
ndings with the intent to primarily list the studies focused on the theoretical correlation between infectious organisms and ME/ CFS. ese studies are of great interest
for further research goals. To assist in determining the strength of each research
study listed in Table 22.1, we provide the number of ME/ CFS patients involved in
that study as an indication of the power of that study, as those studies with a greater
number of patients enrolled provide conclusions that are more likely to be reliable.
We list the case denition (diagnostic criteria) used in each study, where possible.
Since the case denition for ME/ CFS has evolved with time and because there are
Fibromyalgia and Chronic Fatigue 351
Table 22.1 Summary of research articles linking myalgic encephalomyelitis/ chronic fatigue
syndrome to infection with studies organized by type and species of pathogen
Ref. Ye a r N Country Diagnostic
criteria
a
Viruses
Epstein– Barr virus
1 2012 eoretical Italy No clinical case
denition used
2 1992 14 Canada CFS: u- like illness
> 6 months
FM: tender point
count
3 1988 Review USA No clinical case
denition used
Results
Statistical mechanics shows how
EBV infection may drive the immune
system toward an out- of- equilibrium
metastable state
Patients with CFS do not show
evidence of a specic chronic EBV
infection. CFS was dened as the
onset of exhaustion and weakness
aer u- like illness that has persisted
for 6 months or more
Argues that since the vast majority
of the adult population is chronically
infected with EBV, there are both
infectious and non- infectious causes
of fatigue, and therefore there is no
clear, serologic evidence that chronic,
acute EBV correlates with increased
EBV markers. is is even true in
cluster cases. An etiological role of
EBV exists in occasional patients
4 1992 60 Sweden CDC 1988 Markers for T lymphocyte activation
(soluble IL- 2 and CD8) and for
monocyte activation (neopterin)
signicantly elevated in acute
infectious mononucleosis but not in
CFS
5 1990 Comment/
letter
Spain CDC 1988 ree letters to the editor reviewing
immunological similarities of
chronic infectious mononucleosis to
the presence of chronic EBV
6 1991 ree
families
studied
with three
aected
members
USA No clinical case
denition cited
228 sera examined from patients with
a diagnosis of CFS or chronic EBV.
Twenty sera were negative for all EB
antigens. Early antigen levels varied
in a majority of patients. Authors
concluded EBV reactivation may be
slightly more frequent in CFS patients
when considered as a group
7 1995 3 Spain CDC 1988 Fourteen foreign travelers returning
to Spain tested positive for either
EBV or CMV
(continued)
Infectious Disease and Neurocognition
Table 22.1 Continued
Ref. Ye a r N Country Diagnostic
criteria
a
Results
8 1991 USA CDC 1988 It is important to dierentiate
patients with CFS from patients
having a dual (viral) infection or an
underlying immunodeciency
9 1989 1 Spain CDC 1988 Report of one patient who fullled
CFS criteria aer well- documented
EBV infection
10 1993 Croatia Unknown CFS associated with EBV (from
translated title). Article in Serbian.
Unable to obtain
Parvovirus
11 2012 180 Latvia CDC 1994 Frequency of HHV- 6, HHV- 7,
and parvovirus B19 infection/
coinfection and its association with
the clinical course of ME/ CFS were
evaluated. Denite relationship
between active beta herpesvirus
infection and subfebrility,
lymphadenopathy, and malaise aer
exertion and between active B19
infection and multi- joint pain
12 2003 UK CDC 1994 CFS triggered by B19 virus is
clinically indistinguishable from
idiopathic CFS and exhibits similar
cytokine abnormalities and may
represent an accessible model for the
study of CFS
13 2008 18 Japan CDC 1994 CFS occurs in patients aer B19
infection and aer B19 DNA
disappears from their blood.
Consider CFS derived from “other
asp ects”
14 2002 31 UK Questionnaire Five patients fullled CDC criteria
for CFS. One patient was negative for
B19 in blood suggesting diculty in
attributing CFS to B19
15 2003 1 (case
report)
Japan CDC 1994 B19 present in patients’ blood for
9 months produced symptoms
of CFS
16 2009 Japan CDC 1994 ere was no apparent dierence
in the prevalence of parvovirus B19
infection between chronic fatigue
syndrome patients and healthy
controls in Japan
Table 22.1 Continued
Fibromyalgia and Chronic Fatigue 353
Ref. Ye a r N Country Diagnostic
17 1997 1 (case
USA CDC 1994 Woman with persistent B19 viremia
criteria
a
report)
Results
and symptoms indistinguishable from
CFS had symptoms resolved with IVIG
18 1995 7 USA CDC 1991 Bone marrow evidence of B19 not
found. Antibody evidence found in
one patient
Herpesviruses
11 2012 11/ 108 Latvia CDC 1994 Frequency of HHV- 6, HHV- 7, and
parvovirus B19 infection/ coinfection
and its association with clinical
course of ME/ CFS evaluated. Denite
relationship between active beta
herpesvirus infection and subfebrility,
lymphadenopathy, and malaise aer
exertion and between active B19
infection and multi- joint pain
19 2022 Systematic
review
Iran No clinical case
denition used
Systematic review and meta- analysis
of 17 HHV- 6 studies up to 2021.
e association between the HHV6 infection and CFS incidence was
substantiated
20 2012 72 USA CDC 1994 No statistically signicant dierences
in antibody levels or frequency of
HHV- 6A or HHV- 6B infection
were detected between the controls
and CFS patients in African and
American CFS patients
21 1992 Review Japan Straus et al. (1988) Review of viruses associated with
CFS: EBV, enterovirus, HTLV and
HTLV- 2, and HHV- 6
22 2001 10 USA German Ministry
1994
Elevated HHV- 6 DNA, increased
peripheral blood leukocytes,
apoptosis, CD4/ CD8 ratios
typical of autoimmune disease.
Conclusion: imbalanced immune
response rather than overt immune
deciency
23 2000 8 Sweden CDC 1994 Two of eight patients and two of
seven controls were positive for
HHV- 6. Conclusion: active infection
not associated with HHV
24 2012 Review/
hypothesis
UK Afari & Buchwald
(2003)
e ability of certain herpesviruses
to impair the development of Tcell memory may explain this viral
persistence
(continued)
Infectious Disease and Neurocognition
Table 22.1 Continued
Ref. Ye a r N Country Diagnostic
criteria
a
25 1993 Review USA No clinical case
denition cited
Results
Herpesviruses are not the dominant
cause of CFS and may not be
necessary to the perpetuation of the
illness
Enterovirus
26 2010 3 USA Reeves et al. (2003) ree representative patients in a
hospital population who presented
with dierent manifestations
of acute enterovirus infections
progressed to have chronic
symptoms of ME/ CFS
27 2007 135/ 165 USA CDC 1994 135/ 165 (82 percent) biopsies
stained positive for enterovirus
capsid protein, whereas 7/ 34
(20 percent) of the controls stained
positive. Conclusion: A subset of
CFS patients may have enteroviral
infection
28 1990 38/ 124; 205/
420
UK Authors’ own
“clinical criteria”
38/ 124 (30.6 percent) CFS patients
were positive for enterovirus. 205/
420 (48.8 percent) had signicant
Coxsackie B titers
29 1996 34 UK Oxford consensus
criteria 1991
None of the muscle samples from
34 patients contained detectable
amounts of enteroviral RNA. is
does not exclude a role of enterovirus
in initiating the disease process
Cytomegalovirus (CMV)
30 2008 1135 USA CDC 1994 517 patients (45.6 percent) were
positive for HCMV. (“Abortive
herpesvirus infection may be a major
aetiology of CFS” (p. 625))
31 1995 3 Spain CDC 1988 A cohort of 14 patients who
presented themselves at a travelers’
clinic subsequent to returning to
Spain tested positive for either EBV
or CMV satised CFS criteria
32 2002 22 USA CDC 1994 Twenty- two monozygotic twin
pairs studied. Results did not dier
between the twin with and without
CFS for HHV- 6, HHV- 7, HHV- 8,
CMV, EBV, herpes simplex virus,
varicella zoster virus, JC virus, BK
virus, and parvovirus B19
Table 22.1 Continued
Fibromyalgia and Chronic Fatigue 355
Ref. Ye a r N Country Diagnostic
criteria
a
Results
Borna virus
33 1999 10 Japan CDC 1988 Two family clusters of patients with
CFS. All the family members with
CFS were infected with Borna virus.
Healthy members were negative
34 1999 169 Sweden CDC 1994 No specic immunoreactivity to
Borna virus proteins was found in
sera in Swedish patients. Two 1996
studies suggest such an association
in Japan
35 1996 89 Japan CDC 1991 Seroprevalence of Borna virus in
CFS patients in Japan is two standard
deviations higher than in healthy
controls. Authors conclude Borna
virus is associated with CFS in Japan
Hepatitis C virus
36 1991 36 USA CDC 1988 Hepatitis C is uncommon in CFS
patients. One in 36 (2.8 percent)
patients and 0 of 14 controls were
seropositive
37 2011 39 Italy CDC 1994 irty- nine CFS and 49 chronic
hepatitis C patients examined using
Fatigue Impact Scale and 36- item
short form survey (SF- 36). A higher
score of fatigue and a lower healthrelated quality of life in CFS patients
than in chronic hepatitis C patients
Xenotropic murine leukemia virus (XMRV)
38 2010 Number
unspecied
USA No clinical case
denition cited
39 2010 51 USA International case
denition
1994
Inuenza (H1N1) virus
40 2015 Population
of Norway
Norway
USA
Institute of Medicine
2015
XMRV present in 85 percent of
ME/ CFS patients. Results could
not be duplicated by several
other laboratories per reference
immediately below
Blinded PCR and serologic testing
were performed at the US CDC and
at two additional laboratories. XMRV
not detected
Pandemic inuenza A (H1N1)
infection was associated with a more
than twofold increased risk of CFS/ ME
(continued)
Infectious Disease and Neurocognition
Table 22.1 Continued
Ref. Ye a r N Country Diagnostic
criteria
a
Results
Varicella zoster virus (VZV)
41 2009 Hypothesis USA None cited Posits that infection of peripheral
ganglia with a neurotropic
herpesvirus can cause cases of CFS.
VZV is the most likely candidate. No
supporting data provided
42 1994 21 USA CDC 1988 Lack of evidence of retrovirus
infection in CFS. Viruses tested
included human T- cell lymphotropic
virus types 1 and 2, human
spuma retrovirus, simian T- cell
lymphotropic virus type 1, simian
retrovirus types 1, 2, and 3, bovine
leukemia virus, feline leukemia virus,
and gibbon ape leukemia virus. All
samples tested negative
Virus unspecied
43 2022 Editorial Austria
Germany
Portugal
Not Specied Various viruses can trigger
ME/ CFS: herpes, enterovirus,
arboviruses, and SARS- CoV- 2
UK
44 1992 Review Japan CDC 1988 e causative role of viral infections
is reviewed, including EBV,
retrovirus, adenovirus, HHV- 6.
Cause(s) are enigmatic
45 1993 Review UK No 1 case denition
accepted
is paper reviews the viral origin of
CFS. CFS shows similarities to the
inammatory myopathies whether
the CFS is diagnosed by Holmes
et al. (1988) or Sharpe et al. (1988)
criteria. Postulates CFS caused by
a viral persistence similar to the
viral persistence believed to cause
polymyositis/ dermatomyositis.
Concludes that the viruses found
may be latent; reactivated viruses
caused by immune dysfunction but
not the actual cause of the disease
46 2011 Hypothesis USA CDC 1994 ere is evidence of CFS being
associated with abnormalities of the
CNS and ANS. ere is also evidence
linking several infectious agents
with CFS, suggesting CFS can be
triggered and perpetuated by several
chronic infections, which directly or
indirectly aect the nervous system
Table 22.1 Continued
Fibromyalgia and Chronic Fatigue 357
Ref. Ye a r N Country Diagnostic
criteria
a
Results
47 2013 Hypothesis USA CDC 1994 Hypothesizes CFS symptoms are a
pathologically exaggerated version
of normal sickness behavior when
ganglia or paraganglia infected
with any virus or bacteria release
neuroexcitatory substances
Viral infection of vagal nerve hypothesis
47 2013 Hypothesis USA CDC 1994 Hypothesizes CFS symptoms are a
pathologically exaggerated version
of normal sickness behavior when
ganglia or paraganglia infected
with any virus or bacteria release
neuroexcitatory substances
Negative virus
32 2002 22
monozygotic
twins
USA CDC 1994 Antibodies to HHV- 8, CMV, herpes
simplex virus 1 and 2, and hepatitis C
virus did not dier between CFS and
healthy twin
48 2001 22 UK CDC 1994 Gene expression of two antiviral
pathway enzymes was not elevated in
CFS patients but was elevated in ten
acute gastroenteritis patients
Bacteria
Mycobacterium tuberculosis
49 2022 7666 Taiwan CDC 1994 Incidence density found to be 3.04 and
3.69 per 1000 person- years among
Mycobacterium tuberculosis (−) and (+ )
infection populations, respectively
Coxiella
50 2005 8 Japan CDC 1994 Tests whether post Q fever is CFS by
administering tetracycline to CFS
and Q- fever patients. Q- fever patients
improved; CFS patients did not
Bartonella
51 1994 51 USA CDC 1991 Some patients with cat- scratch fever
have symptoms in common with CFS,
and some do not. Only one patient
tested positive for the two organisms
(Bartonella (formerly Rochalimaea)
henselae or Apia felis), which cause catscratch fever. Conclusion: Bartonella is
not a likely cause of CFS
(continued)