372 Chronic Fatigue Syndrome
RNase-L. Viral infections and interferon that is induced by
viral infections increase levels of RNase-L, and this RNase-L
selectively degrades viral RNA. Patients with CFS have
higher levels of RNase-L (an 80 kDa polypeptide) than pa-
tients with any other disease, according to Suhadolnik et al.
(1997), who has also 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 37 kDa protein to the normal 80 kDa protein was high in
72% of patients with CFS and only 1% in healthy controls and
none in depression and “bromyalgia control patients. Herst
et al. (2001) treated two patients with CFS who were HHV-6
positive and had a high ratio of 37/80 kDa activity. Three to
four months after Ampligen treatment, their RNase-L cell low
molecular weight protein dropped and no HHV-6 infection
was detectable, suggesting that these two biomarkers might be
used in monitoring patients• response to treatment. Gow et al.
(2001), however, did not “nd any evidence of upregulation of
the antiviral pathway in a group with CFS and healthy con-
trols, but a group with a group of patients with infections evi-
denced upregulation.
Another group of researchers (Bou-Holaigah, Rowe,
Kan, & Calkins, 1995) found that 22 of 23 patients with CFS
had an abnormal response consistent with neurally mediated
hypotension. This condition occurs when the central nervous
system misinterprets the body•s needs when it is in an upright
position. Then it sends a message to the heart to slow down
and lower the blood pressure, responses that are directly op-
posite the responses the body needs. Other investigators,
however, have not found neurally mediated hypotension to
play a major role in CFS (Poole et al., 2000). In another study
(Streeten & Bell, 2000), the majority of patients had striking
decreases in circulating blood volume. It appears that the
blood vessels in patients with CFS are constricted dramati-
cally, and efforts to restore normal volume have met with
limited success.
Other investigators have noted cardiac dysfunction
(Lerner, Lawrie, & Dworkin, 1993), EEG abnormalities
(Donati, Fagioli, Komaroff, & Duffy, 1994), abnormalities in
cerebral white matter (Natelson, Cohen, Brassloff, & Lee,
1993), decreases in blood ”ow in certain areas of the brain
(Schwartz et al., 1994), autonomic nervous system dysfunc-
tion (Freeman & Komaroff, 1997), frequent HHV-6 reactiva-
tion (Ablashi et al., 2000), and multiple mycoplasmal
infections (Nicolson et al., 1999). However, such laboratory
“ndings are inconsistent, which may be a function of com-
bining distinctive groups of patients into a large heteroge-
neous group rather than analyzing them within subtypes. One
reason for medical skepticism concerning CFS is that many
studies examining cellular immune response abnormalities in
people with CFS have not been consistently reproduced
(Krupp, Mendelson, & Friedman, 1991).
In reality, rarely is there a perfect biological test for an ill-
ness. With CFS, there does appear to be mounting evidence of
brain and immune system abnormalities (Komaroff, 2000a).
It is possible that low levels of circulating cortisol suggest a
condition of mild adrenal insuf“ciency. In individuals with
CFS, this condition could stimulate immune activation,
which could contribute to brain dysfunction (Komaroff,
2000b). Although no virus has been identi“ed as the cause of
CFS, the immune pattern seems to be “ghting a virus, as
evidenced by the RNase-L pathway. Increasing evidence also
points to neurological “ndings including hyperintense signals
on MRI scans, reductions in cerebral blood ”ow on SPECT
scans (Lange, Wang, DeLuca, & Natelson, 1998), and auto-
nomic dysfunction (primarily orthostatic intolerance and neu-
rally mediated hypotension; Schondorf & Freeman, 1999).
The onset of CFS is often linked with the recent presence
of an infection. CFS has been reported following acute
mononucleosis (a viral infection), Lyme disease (a bacterial
infection), and Q fever (an infection with a different type
of infectious agent; Komaroff, 2000b). Activation by macro-
phages due to a virus or bacteria produces a release of inter-
leukin 1, which causes an alteration in the electrical activity
of the brain; it also causes a number of behavioral changes
(e.g., decreases in activity and social interaction, somno-
lence) designed to reduce unnecessary energy expenditure, so
that available energy stores can be used to “ght the infection
(Maier, Watkins, & Fleshner, 1994). These cytokines might
induce a state of chronic activation, which leads to a deple-
tion of the stress hormone axis, and to other neuropsychiatric
and neuroendocrine features associated with CFS (Saphier,
1994).
Some individuals might be at higher risk of developing
this chronic activation due to genetic vulnerabilities, or to
constitutional or psychological factors. Individuals with CFS
might have hyperactive premorbid lifestyles, and this high
•action-pronenessŽ might be a predisposing factor for devel-
oping CFS (Van Houdenhove, Onghena, Neerinckx, &
Hellin, 1995). Individuals who are chronically stressed have
a persistent lack of cortisol, and this might also contribute to
CFS (Heim, Ehlert, & Hellhammer, 2000). In addition, stress
might be a conditioned stimulus that leads to an impaired im-
mune response (Cohen, Moynihan, & Ader, 1994). In addi-
tion, environmental factors might play a role in the etiology
of CFS: People with CFS have signi“cantly higher levels of
chlorinated hydrocarbons than do control subjects (Dunstan
et al., 1995).