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Infectious Disease and Neurocognition
Table 22.1 Continued
Ref. Ye a r N Country Diagnostic
criteria
a
Results
Borrelia
52 1995 138 USA CDC 1988 15.8 percent of patients were
borderline IgG antibody positive, but
no sera contained specic antigen for
Borrelia
Mycoplasma
53 2003 Belgium
USA
No case denition
cited
Two research groups in the United
States and one in Belgium have
detected Mycoplasma DNA products
in 52– 68 percent of several hundred
patients with CFS and/ or FM as
opposed to detecting Mycoplasma
DNA products in 0– 15. percent of
controls
Chlamydia
54 1992 50 USA CDC 1991 Antibodies to Chlamydia not found
in sera of CFS patients. Chlamydia is
unlikely to explain the cough present
in patients
55 1999 10/ 171 USA CDC 1994 10 of 171 (5.8 percent) patients
with CFS symptoms had elevated
Chlamydia pneumonia titers long
aer respiratory infection. Most had
favorable clinical and serological
responses to a 1– 2- month course of
azithromycin
Notes: a e diagnostic criteria here are listed according to their commonly referred to names. eir descriptions
appear in Appendix 1 and their full citations appear in the references section.
Abbreviations: ANS, autonomic nervous system; BK virus, a member of the polyomavirus family also known as
human polyomavirus 1; CDC, Centers for Disease Control and Prevention (USA); CD4, cluster of dierentiation
glycoprotein 4 that serves as a co- receptor for the T- cell receptor; CD- 8, cluster of dierentiation 8 transmembrane
glycoprotein; CFS, chronic fatigue syndrome; CMV, cytomegalovirus; CNS, central nervous system; EBV, Epstein–
Barr virus; FM, bromyalgia; H1N1, a subtype of inuence A virus; HHV, human herpesvirus; HTLV, human T- cell
lymphotropic virus; IgG, immunoglobulin G, a type of antibody; IL- 2, interleukin- 2; IVIG, intravenous immunoglobulin; JC virus, John Cunningham virus, a type of human polyomavirus (formerly known as papovavirus); N,
number of subjects; PCR, polymerase chain reaction; Ref., reference; USA, United States of America; VZV, varicella
zoster virus; XMRV, xenotropic murine leukemia virus.
Reference citation key: 1. Agliari et al., 2012; 2. Whelton et al., 1992; 3. Schooley, 1988; 4. Linde et al., 1992; 5. Navidad
et al., 1990; 6. Joncas, 1991; 7. Gascón et al., 1995; 8. Purtilo, 1991; 9. Parras et al., 1989; 10. Bojić et al., 1993; 11.
Chapenko et al., 2012; 12. Kerr and Tyrell, 2003; 13. Seishima et al., 2008; 14. Kerr et al., 2002; 15. Matano et al.,
2003; 16. Kato et al., 2009; 17. Jacobson et al., 1997; 18. Ilaria et al., 1995; 19. Mozhgani et al., 2022; 20. Burbelo et al.,
2012; 21. Yamanishi, 1992; 22. Krueger et al., 2001; 23. Enbom et al., 2000; 24. Bansal et al., 2012; 25. Straus, 1993; 26.
Chia et al., 2010; 27. Chia and Chia, 2007; 28. Dowsett et al., 1990; 29. McArdle et al., 1996; 30. Beqaj et al., 2008; 31.
Gascón et al., 1995; 32. Koelle et al., 2002; 33. Nakaya et al., 1999; 34. Evengård et al., 1999; 35. Kitani et al., 1996; 36.
Dale et al., 1991; 37. Racciatti et al., 2011; 38. Mikovits et al., 2010; 39. Switzer et al., 2010; 40. Magnus et al., 2015; 41.
Shapiro, 2009; 42. Heneine et al., 1994; 43. Westermeier et al., 2022; 44. Okano, 1992; 45. Behan and Behan, 1993; 46.
Komaro and Cho, 2011; 47. VanElzakker, 2013; 48. Gow et al., 2001; 49. Yang et al., 2022; 50. Iwakami et al., 2005;
51. Bennett et al., 1994; 52. Pollark, 1995; 53. Endresen, 2004; 54. Komaro et al., 1992; 55. Chia and Chia, 1999.
Fibromyalgia and Chronic Fatigue 359
multiple case denitions for ME/ CFS, comparison of results with dierent case definitions is dicult. For the interested reader, a summary of the most frequently cited
ME/ CFS case denitions criteria appears in Appendix 1. In addition, an indication
of the number of ME/ CFS case denitions may be found in Lim and Son (2020).
We have listed the countries in which this research has been conducted and have
provided Figure 22.2, which displays in dark grey the countries in which this research has occurred on a world map. Finally, we provide summary ndings: a summary and/ or conclusion for each article listed.
A review of the worldwide, decades- long, investigations into the possible association of ME/ CFS with infective organisms permits us to make several observations.
If there is an association between ME/ CFS and infective organisms, that association appears to be strongest for an association of ME/ CFS and viruses. And if an
association exists between ME/ CFS and viruses, that association appears strongest
for ME/ CFS and the Epstein– Barr virus (EBV). While Table 22.1 reviews some of
the existing literature linking EBV to ME/ CFS, a recent summary of the pathophysiological ndings linking EBV to ME/ CFS is provided by Ruiz- Pablos et al. (2021),
which include signicant elevation of anti- EBV antibodies, defective EBV- specic
B- and T- cell response, a high rate of active EBV infection, serologic evidence of
EBV reactivation, and a positive upregulation of EBV- induced gene 2 (EBI2) mRNA
in peripheral blood mononuclear cells of patients with ME/ CFS. Another unproven
possibility related to Ruiz- Pablos et al. (2021) is that EBV may exist in an abortive/
lytic/ leaky replication state, which could explain the presence of certain EBV proteins (BRRF1 and BLLF3) that contribute to the symptomology of ME/ CFS. RuizPablos et al. (2021) also review the associations of EBV with multiple sclerosis and
Alzheimer’s disease, making it increasingly dicult to dispute the ability of EBV to
induce disease despite the mechanism or mechanisms of causation currently being
Figure 22.2 Countries in which studies suggesting linkage of myalgic encephalomyelitis/
chronic fatigue syndrome to infection have been conducted and are cited in this manuscript are
shown in dark grey.
Infectious Disease and Neurocognition
unclear. If we accept EBV’s ability to induce multiple diseases, then it becomes increasingly dicult to accept Koch’s postulates, which imply that one organism
causes one disease. One organism may contribute to more than one disease and one
disease as we currently dene it may be the consequence of infection caused by more
than one organism. e association of EBV with ME/ CFS is further supported by the
relatively recent work of Shikova et al. (2020), who screened 58 ME/ CFS patients for
active or latent EBV, CMV, and human herpesvirus (HHV)- 6 and found a high prevalence of active EBV but no active CMV or HHV- 6.
Similar arguments may be made for the relationship between enterovirus and ME/
CFS. Enteroviruses have been found in ME/ CFS patients, but they may or may not
be causative. If not causative, enteroviruses may be contributory to ME/ CFS. An alternative explanation for the frequent occurrence of enterovirus in ME/ CFS patients
is that its presence is permitted when the patient has an underlying case of ME/ CFS.
Enteroviruses have long been associated with human disease and in some cases are
thought to be causative, but for the most part, enteroviruses seem to be contributory to the vulnerability of humans to develop post- infectious sequelae such as ME/
CFS. O’Neal and Hanson (2021) provide a review of the relationship between enteroviruses and diseases with special mention of ME/ CFS, concluding that several of
the cluster outbreaks of ME/ CFS were most likely caused by one or more enterovirus
groups.
e Borna virus literature listed in Table 22.1 raises the possibility of ethnic and
geographic factors aecting the associations of ME/ CFS and viruses. us far, it
appears that Borna virus may be associated with ME/ CFS in Japan. Li et al. (2005)
found that 17 of 82 patients diagnosed using the 1994 Centers for Disease Control
and Prevention CFS criteria had Borna virus antibodies signicantly higher than
controls (prevalence of 20.73 percent versus 0 percent). Since similar results have
not been reported in other regions of the world, the possibility exists that this nding
is unique to Japan and that population, genetic, or geographical dierences in the
viruses that either trigger ME/ CFS or are comorbid in ME/ CFS patients exist. Such
a nding could possibly explain why some individuals, communities, or geographic
regions are at greater risk for developing ME/ CFS or suer more severe consequences than others.
Further support for the possibility of a virus- induced increased risk of contracting
ME/ CFS comes from Norway: people who contracted pandemic inuenza (H1N1)
reportedly more than doubled their risk of developing ME/ CFS, suggesting that the
role of some viruses is to create the opportunity in which ME/ CFS may later occur
(Magnus et al., 2015).
While some viruses appear supportive of or contributory to the development of
ME/ CFS, other viruses are less likely to do so— if at all. For example, parvovirus has
been thought to have a possible association with ME/ CFS. We note the existence of
some studies that were unable to nd such linkage and note further that there are
no recent studies exploring the relationship between ME/ CFS and parvovirus. Such
studies suggest that ME/ CFS is not a consequence of viral infection or infection per
Fibromyalgia and Chronic Fatigue 361
se, but rather is associated with specic infectious agents. Two studies suggest an association between cytomegalovirus and ME/ CFS. However, in the 2020 study cited
above, no active cytomegalovirus was found in either ME/ CFS patients or healthy
controls. is nding, however, does not preclude the possibility of a latent cytomegalovirus infection. Results of herpesvirus studies are mixed with some studies
nding an association and others not. In this regard, hepatitis C does not appear to
be associated with ME/ CFS despite an overlap of symptoms, suggesting some viruses are possibly associated with ME/ CFS while others are not. Several investigators have put forward theories of viral infection without naming a specic virus. It
should be noted that there is an existing, albeit small, literature indicating that viral
infection of peripheral nerves can trigger chronic illness, but a clear demonstration
of viral infection of a particular nerve ber producing ME/ CFS has not been made
(Bachor et al., 1996; Irie et al., 1989; Joo et al., 2019; Morrison et al., 1991).
We believe that one path forward to resolve the role relationship of infectious
agents to ME/ CFS would be a repeat of the monozygotic twin study of Koelle et al.
(2002), in which levels of viral load were found to be similar in both twins despite
one twin having ME/ CFS and the other not. e sets of twins were tested for HHV- 6,
HHV- 7, HHV- 8, cytomegalovirus, EBV, herpes simplex virus, varicella zoster virus,
John Cunningham virus, BK virus, and parvovirus B19.
Viruses are not the only infectious agents that have been investigated for an association with ME/ CFS. A few investigations have focused on relationships between
bacteria and ME/ CFS, including preliminary investigations into relationships between ME/ CFS and Bartonella (Bennett et al., 1994), Borellia (Pollark et al., 1995),
Chlamydia (Chia et al., 2010; Komaro et al., 1992), Coxiella (Iwakami et al., 2005),
Mycobacterium tuberculosis (Yang et al., 2022), and Mycoplasma (Endresen, 2003).
While most of these studies do not provide strong support for linkage between ME/
CFS and bacteria, those for the Mycobacterium tuberculosis and Mycoplasma suggest possible relationships. One possibility is that bacteria, as has been proposed for
some viruses, may be a predisposing factor to or a comorbidity of ME/ CFS.
Relationship of infection to fibromyalgia
Searching PubMed using the text search terms “bromyalgia” and “infection” resulted in 80 citations as compared to the over 7000 citations for a similar ME/ CFS
search, suggesting a far less robust investigation of linkage between FM and infection. Of the 80 citations identied, 68 were selected as relevant to the topic of exploring the relationship between FM and infection. ese studies were conducted
in the countries indicated in Figure 22.3 and support a worldwide, albeit modest,
investigation of linkage between infection and FM.
e concept of FM as a syndrome or disease entity evolved in the 1970s but its
association with previous and/ or comorbid infection was not initially apparent as
evidenced by the rst publication exploring such a relationship appearing in 1987
Infectious Disease and Neurocognition
Figure 22.3 Countries in which studies suggesting linkage of fibromyalgia to infection have
occurred and are cited in this manuscript are shown in dark grey.
(Buchwald et al., 1987). e complexity of the relationship is shown by the continuous albeit modest rate of publications exploring these relationships up to the current time (2023).
Table 22.2 provides a summary of retrieved articles linking FM to infection and
suggests a large variation in study design. Further, most studies employed small
sample sizes and unfortunately do not provide the methodology or criteria used to
determine if the included patients satised the same FM case denition of the disease or even an acceptable case denition of FM. Small sample size reduces the condence that can be placed in the conclusions to be drawn from the study, and the
usage of dierent case denitions makes comparisons of study subjects used in different studies problematic.
We have grouped the studies by the suspected infective organism being investigated. Note that for hepatitis C studies, we have grouped seven studies nding a relationship together, and two studies not nding such a relationship together for ease
of comparison.
From the data presented in Table 22.2, several observations are possible about any
associations between FM and infectious diseases. e strongest association of FM
with infectious agents is between FM and viruses. We note that the viruses most
likely associated with FM are dierent from the viruses associated with ME/ CFS.
Hepatitis C appears to have the strongest association with FM, with hepatitis B
showing a more modest association. FM has a more than random chance of being
present in HIV patients, and we note that such an association was not found for ME/
CFS. EBV does not appear to be associated with FM, whereas it appears to have a
strong association with ME/ CFS. Reports of a relationship between FM and with
parvovirus or herpesviruses are mixed. Available ndings suggest the possibility of
a stronger linkage between parvovirus and herpesviruses to ME/ CFS than to FM.
Although we found only two reports suggesting an association between human
Fibromyalgia and Chronic Fatigue 363
Table 22.2 Summary of articles linking fibromyalgia to infection
Ref. Ye a r N Country Diagnostic
criteria
a
Results
Hepatitis C positive
1 2003 Review USA No clinical case
denition cited
Titled, “Fibromyalgia, Hepatitis
C Infection, and the Cytokine
Connection,” this paper discusses
alterations of cytokines, and
mechanisms by which alterations in
cytokines in FM and chronic hepatitis C
infection can produce hyperalgesia. e
association between chronic hepatitis C
infection and FM is discussed
2 2001 77 Ireland Hx, PE, FIM,
HADS
5 percent of patients fullled FM
criteria. Concludes that there is a higher
prevalence of FM in HCV patients
3 2012 185 Ireland Hx, CE, FA 57 percent of HCV subjects fulll
FM criteria, one- third of whom
reported some degree of functional
impairment
4 2003 95 Tur k e y ACR 1990 FM found in 18.9 percent of patients
and 5.3 percent of HCs.
5 1997 112 Spain ACR 1990 HCV found in 15.2 percent of FM
patients and 5.3 percent of RA
controls. Concluded that there was
an association in some patients
6 1997 90 Israel ACR 1990 16 percent of HCV patients diagnosed
with FMS and none of the HCs
7 2008 Review Israel No case
denition cited
HCV, HIV, and Lyme disease are
associated with FMS
Hepatitis C negative
8 2005 115 Spain ACR 1990 FM conrmed in 2.6 percent of HCV
patients, which was only slightly
higher than in the control population
Hepatitis B
9 2005 50 Tur k e y ACR 1990 Chronic hepatitis B increases risk of FM
10 2013 77 Tur k e y ACR 1990 22 percent of HBV infected patients
diagnosed with FM; 23 percent of
HBV carriers diagnosed with FM
HIV
11 2021 160 Nigeria ACR 2010 Prevalence of 10.6 percent in HIV
patients versus 3.1 percent in
controls. No association of FM with
age, sex, or occupation.
(continued)
Infectious Disease and Neurocognition
Table 22.2 Continued
Ref. Ye a r N Country Diagnostic
criteria
a
12 2015 Review UK No clinical case
denition cited
Results
e methodology used to explore
FM in HIV patients has varied
widely, particularly in the case
denitions utilized, although the
prevalence of FM in HIV patients
is estimated to be between 1 and
17 percent, with the highest in the
United States and the lower ones in
India and China
13 2019 225 Tu r ke y ACR 2016, BDI,
FIQ, PSQI, FSS,
FM diagnosed in 20 percent of HIV
patients
SF- 36
14 1992 140 USA ACR 1990 FM diagnosed in 11 percent of
HIV patients and in 41 percent of
HIV patients with musculoskeletal
symptoms
15 1990 51 Canada 10 of 14 tender
points
29 percent of HIV patients satised
the criteria for FM, 24 percent of
psoriatic arthritis patients, and
57 percent of rheumatoid arthritis
patients
16 2005 Systematic
review
Spain No clinical case
denition cited
FM patients show greater
comorbidity. High presence in HIV
and hepatitis C patients
Parvovirus
17 1991 3 USA ACR 1990 ree patients developed symptoms
of FM aer acute parvovirus B19
infections
18 2009 75 Tur k e y ACR 1990 Parvovirus B19 IgG was found to be
signicantly higher in FM patients.
B19 may be a triggering factoring or
play a role in the etiology of FM
Herpes simplex 1
19 2022 30 USA ACR 2010 HSV- 1 found in patients with and
without FM. Larger studies are
warranted
HHV- 6 & - 7
20 2019 43 Latvia ACR 1990
ACR 2010
No dierence in frequency of HHV6 or HHV- 7 in FM patients versus
controls; however, higher loads of
HHV- 6 and HHV- 7 found in FM
patients
Table 22.2 Continued
Fibromyalgia and Chronic Fatigue 365
Ref. Ye a r N Country Diagnostic
criteria
a
Results
Parvovirus negative
21 2005 60 Spain ACR 1990 No serological evidence that FM
is linked with exposure to human
parvovirus B19
22 1993 15 USA No clinical case
denition cited
For all FM patients, the prevalence of
prior B19 infection was comparable
to that of healthy controls (11/
26 versus 12/ 26). None of the
FM patients showed evidence of
persistent B19 viremia
Human T- cell lymphotropic virus (HTV- 1)
23 2006 100 Brazil ACR 1990 irty- eight percent of HTLV- 1
patients versus 4.8 percent of controls
had FM, suggesting that FM is
associated with viral infection
24 2020 Review Australia No clinical case
denition cited
Meta- analysis of the health eects of
HTLV- 1 infection. Of 3318 studies,
39 met inclusion criteria. FM had a
“signicant association” with HTLV1 infection
Muscle enterovirus
25 2003 30 France Buchwald (1996) Four of 30 (13 percent) patients with
FM/ CFS found to have enterovirus
in skeletal muscle by reverse
transcription polymerase chain
reaction
Epstein– Barr negative
26 1987 50 USA Yunus et al.
(1981)
Antibody titers to Epstein– Barr
virus in FM patients are similar to
those in “healthy” and “unhealthy”
controls
27 1999 150 USA ACR 1990 Tender points are a common,
transient nding of acute, infectious
mononucleosis, but FM is an unusual
long- term outcome
Other infectious agents
Giardia
28 2021 572 Norway ACR 2016 FM in 8.6 percent (49/ 572) of Giardia
patients versus 3.1 percent (21/ 673)
of controls
(continued)
Infectious Disease and Neurocognition
Table 22.2 Continued
Ref. Ye a r N Country Diagnostic
criteria
a
Mycoplasma
29 1999 91 USA CDC 1988
ACR 1990
30 2003 Review Norway No clinical case
denition cited
Lyme disease negative
31 1993 Review USA No clinical case
denition cited
Rhinosinusitis
32 2008 283 USA Patient’s report
of physician’s
diagnosis
Results
Ninety- one patients with CFS/ FM
and positive for any Mycoplasma
investigated. Found M. pneumonia
in 54/ 91, M. fermentans in 44/
91, M. hominis in 28/ 91, and
M. penetrans in 18/ 91. Double
infections in 30.8 percent; triple
infections in 22 percent
Mycoplasma is found in
approximately 50 percent of FM/ CFS
patients
Questions the value of using
parenteral antibiotic treatment in
Lyme patients with nonspecic
myalgia and fatigue (FM and CFS)
as these symptoms are not abated by
such treatment (contrast to reference
41 below)
Endoscopic sinus surgery improves
the quality of life of chronic sinusitis
patients with comorbid FM
33 1992 47 USA ACR 1990 Of 47 consecutive patients with
either allergic or seasonal rhinitis,
38 percent satised FM criteria
versus the expected 4– 5 percent.
Rhinitis may be an underdiagnosed
but a causative factor of FM
Periodontitis
34 2022 196,428 &
141,439
Taiwan
USA
ACR 2016 Female and male patients with
periodontitis of all age groups were at
greater risk of developing FM. Most
susceptible were males and those <
30 years of age
Osteomyelitis
35 2017 1,244 Taiwan ICD- 9- CM- 729.1 Patients with chronic osteomyelitis
have a greater risk of FM than control
subjects with an adjusted hazard ratio
(aHR) of 1.32; people < 35 years have
an even greater risk: aHR = 1.58; ≥ 60
have an aHR = 1.03
Table 22.2 Continued
Fibromyalgia and Chronic Fatigue 367
Ref. Ye a r N Country Diagnostic
criteria
a
Results
Staphylococcus vaccine
36 2004 14 CFS/ FMSweden ACR unspecied
CDC
Vaccine causes serological response
in FM/ CFS patients
unspecied
37 2002 100 CFS/ FMSweden ACR 1990 Treatment of FM and CFS patients
with weekly Staphylococcus injections
over 6 months signicantly reduces
symptoms. Maintenance is required
to prevent relapse
Other triggers of FM
38 2015 939 China
USA
ACR 1990 Only 27 percent of patients report a
precipitating factor for their FM. e
rest report idiopathic FM. Twentyve percent of patients reported
trauma or infection as precipitant of
their FM
39 2011 Review
paper
Italy No clinical case
denition cited
ere is no clear- cut evidence
that FM is due to infections or
vaccinations, no correlations with
persistent infection, and no proven
relationship between infection,
antimicrobial therapies, and pain
improvement. A higher prevalence of
FM has been found in patients with
Lyme disease, HIV, or HCV infection,
and, perhaps, also in patients with
Mycoplasma, HBV, HTLV- 1, and
parvovirus B19 infections. Some
reports suggest that vaccinations may
trigger FM
Notes: a e diagnostic criteria here are listed according to their commonly referred to names. eir descriptions
appear in Appendix 1 and their full citations appear in the references section.
Abbreviations: ACR, American College of Rheumatology; aHR, adjusted hazard ratio; BDI, Beck Depression
Inventory; CE, clinical exam; CM, country modied; FA, functional assessment; FIM, Functional Independence
Measure; FIQ, Fibromyalgia Impact Questionnaire; FM, bromyalgia; FSS, Fatigue Severity Scale; Hx, history;
HADS, Hospital Anxiety and Depression Score; HBV, hepatitis B virus; HCs, healthy controls; HCV, hepatitis C
virus; HIV, human immunodeciency virus; HSV, herpes simplex virus; HTLV, human T- lymphotropic virus; ICD,
International Classication of Diseases; IgG, immunoglobulin G; N, number of subjects; N/ A, not applicable; PE,
physical exam; PSQI, Pittsburg Sleep Quality Index; RA, rheumatoid arthritis; Ref., reference; SF- 36, Short Form
Survey 36; UIA, unspecied in abstract.
References: 1. ompson and Barkhuizen, 2003; 2. Goulding et al., 2001; 3. Mohammad et al., 2012; 4. Kozanoglu
et al., 2003; 5. Rivera et al., 1997; 6. Buskila et al., 1997; 7. Buskila et al., 2008; 8. Narvaez et al., 2005b; 9. Adak et al.,
2005; 10. Ozsahin et al., 2013; 11. Emorinken et al., 2021; 12. Fox and Walker- Bone, 2015; 13. Demirdal et al., 2019;
14. Simms et al., 1992; 15. Buskila et al., 1990; 16. Chamizo- Carmona, 2005; 17. Leventhal et al., 1991; 18. Buyukkose
et al., 2009; 19. Duy et al., 2022; 20. Krumina et al., 2019; 21. Narvaez et al., 2005; 22. Berg et al., 1993; 23. Cruz et al.,
2006; 24. Schierhout et al., 2020; 25. Douche- Aourik et al., 2003; 26. Buchwald et al., 1987; 27. Rea et al., 1999; 28.
Hunskar et al., 2021; 29. Nasralla et al., 1999; 30. Endresen, 2003; 31. Lightfoot et al., 1993; 32. Soler et al., 2008; 33.
Cleveland et al., 1992; 34. Ma et al., 2022; 35. Chen et al., 2017; 36. Zachrisson et al., 2004; 37. Zachrisson et al., 2002;
38. Jiao et al., 2015; 39. Cassisi et al., 2011.