http://www.chronicillnet.org/reports/ci_report_6.html#anchor124582
This report groups 101 important publications (numbered) into nine sections:
Enterovirus sequences and persistent enterovirus infection ----- 27 - 42
Enterovirus sequences in heart tissues ----------------------------- 43 - 49
Featured reviews ------------------------------------------------------ 54 - 56
Contemporary reviews ----------------------------------------------- 57 - 60
Featured publications ------------------------------------------------- 61 - 67
Contemporary publications ------------------------------------------ 68 - 78
Selection of publications and editorial comments are by WH Murphy, PhD, Professor
Emeritus, Dept. of Microbiology and Immunology, University of Michigan School
of Medicine.
Bannister (1) notes that post-infectious syndromes have been recognized for
the last five decades and that they may follow either bacterial or viral infections.
His informative paper summarizes the evidence for and against a "post
viral fatigue syndrome". The term 'post-viral fatigue syndrome' is preferred
to 'chronic fatigue syndrome' because the latter has been confused with chronic
or reactivated Epstein-Barr virus (EBV) infection. The Centers for Disease
Control definition of the chronic fatigue syndrome (as "chronic disease
syndrome") is presented by Holmes et al. (2 below).
In keeping with its clinical characteristics, PVFS may be referred to as myalgic
encephalomyelitis (ME), thus reflecting involvement of muscle tissue and the
central nervous system. There is a consensus concerning the major signs and
symptoms, as noted in the general reviews (3-9) below. The onset
is sudden, with prodromal signs of a characteristic flu-like illness. PVFS
is characterized by a chronic debilitating fatigue lasting six or more months.
The fatigue is accompanied by fever, pharyngitis, myalgia, adenopathy, and
arthralgias, although these signs occur variably. Psychiatric illnesses, such
as depressive or anxiety disorders, occur in a significant number of patients
with PVFS (see 7 below). These characteristics serve to distinguish PVFS as
a clinical entity.
Pub.#:
1: Bannister, BA
1988
Post-infectious disease syndrome
Postgrad. Med. J. 64: 559-567
Comment: This excellent review provides an accurate historical prospective
of the PVFS. The disease, in its protean forms, has been recognized by physicians
as a distinct clinical disease since the late 1950s.
2: Holmes, GP, JE Kaplan, NM Gantz, AL Komaroff, LB Schonberger, SE
Straus, JF Jones, RE Dubois, C Cunningham-Rundles, S Pahwa, G Tosato, LS Zegans,
DT Purtilo, N Brown, and RT Schooley
1988
Chronic fatigue syndrome: a working case definition
Annals Int. Med. 108: 387-389
Comment: The article's abstract does not represent the substance of
this valuable contribution, i.e., the authors' established benchmarks for
an important "working case definition" for "the chronic fatigue
syndrome". The major criteria consist of two parameters:
(i) a definition of new-onset debilitating fatigue persisting for at least
six months; and (ii) an exclusion of a large number (720) of other signs and
symptoms. Minor criteria consist of two categories: (i) symptom criteria
and (ii) physical criteria. A diagnosis must fulfill both major criteria and
either (a) 6/11 symptom criteria and 2/3 physical criteria or (b) 8/11 symptom
criteria. Specific laboratory tests or clinical measurements are not required
to establish a diagnosis.
Pub.#:
3: Behan, PO and AM Bakheit
1991
Clinical spectrum of postviral fatigue syndrome
Brit. Med. Bull. 47: 793-808
Comment: This excellent review discusses the limitations of the CDC
and British Medical Council's definitions of the chronic fatigue syndrome.
The authors outline approaches to making a reliable clinical diagnosis of
PVFS and identify key criteria. Psychiatric disorders are evaluated; it is
pointed out, for example, that depression in PVFS has distinctive qualities.
The pathophysiology of PVFS is discussed, including abnormalities of the hypothalamus-pituitary
axis that relate to severe night sweats, changes in body weight and appetite,
fluid retention, fluctuations in body temperature, alterations in sleep pattern,
and depression.
4: Byrne, E
1991
The chronic fatigue syndrome: a reappraisal and unifying hypothesis
Clin. Exp. Neurol. 28: 128-138
Comment: This excellent review presents an important central concept,
i.e., the "chronic fatigue syndrome" has a multifactorial basis.
The concept is represented clearly by an appropriate Venn diagram. An additional
important contribution is that the author discusses fatigue and its causes
in a nonpejorative manner. The review considers the appropriateness of various
definitions of PVFS, putative viral causes, immunologic abnormalities, metabolic
findings, neurophysiological studies, and psychiatric abnormalities. The discussions
are clear, insightful, explicit, and informative.
5: Epstein, KR
1995
The chronically fatigued patient
Med. Clin. North Am. 79: 315-327
Comment: This article illustrates that diagnostic evaluation, as well
as the management of the patient presenting with chronic fatigue, can be done
in an orderly manner.
6: Komaroff, AL and G Goldenberg
1989
The chronic fatigue syndrome: definition, current studies, and lesson for
fibromyalgia research
J. Rheumatol.19 (Supple.): 23-27
Comment: This publication makes noteworthy contributions: (i) a good
working definition of PVFS is provided and principal symptoms are summarized;
(ii) PVFS and fibromyalgia are compared and contrasted; (iii) the frequency
of important symptoms is documented; (iv) cognitive difficulties are enumerated
and evaluated, (v) laboratory tests are listed and assessed, (vi) the putative
role(s) of etiologic viruses are discussed, and (vii) the main results from
a group of 350 patients with PVFS are presented in a very informative way.
For example, average age was 37 years; 70% of patients were women; debilitating
fatigue persisted for 2.9 years or longer; 25% of patients were bedridden
and unable to work; and only 33% could work part-time.
7: Krupp, LB, WB Mendelson, and R Friedman
1991
An overview of chronic fatigue syndrome
J. Clin. Psy. 52: 403-410
Comment: Krupp and his associates review "the chronic fatigue
syndrome" from the viewpoint of the clinical psychiatrist. The review
is comprehensive (86 papers), astute, objective, and insightful. For example,
the critical appraisal of immunologic studies of the PVFS is unusal in depth
and precision. Other contributions include the discussion of fatigue disorders
in various diseases, psychiatric aspects of fatigue, sleep disorders in PVFS,
and points of similarity between PVFS and fibromyalgia. Since PVFS and fibromyalgia
share many common features, "it is not surprising that both conditions
may coexist in the same individual." The section of the review on diagnosis
and treatment is a valuable contribution.
8: Moldofsky, H
1993
Fibromyalgia, sleep disorder and chronic fatigue syndrome
In Jenkins, R and JP Mowbray, eds. Chronic fatigue syndrome.
Ciba Foundation Symposium 173: 262-271
Comment: This publication, like Krupp et al. (7), compares the
similarities and differences between PVFS and fibromyalgia.
9: Spracklen, FHN
1988
The chronic fatigue syndrome (myalgic encephalomyelitis)---myth or mystery.
S. African Med. J. 74: 448-452
Comment: This contribution is robust, penetrating, insightful and refreshing.
The author brings out many cogent observations: The incidence of PVFS in the
UK approximates poliomyelitis prior to universal vaccination; myalgic encephalomyelitis
(ME) is a clinically important disease; a member of the British Parliament
introduced legislation aimed at confronting the disease; and environmental
stress may be an important factor in the occurrence of ME. Spracklen also
cites Dawsett's conclusion (Lancet ii:101, 1988) that the term "'chronic
fatigue syndrome' does nothing to indicate the unique epidemiological, geographical,
clinical and laboratory findings for ME. The use of the term would thus do
nothing to reduce the confusion surrounding the diagnosis, therapy, and prognosis
of the condition."
Epidemiologic studies are confounded primarily by two important factors: (i)
the failure of clinicians to recognize the PVFS as a clinical entity; and
(ii) the lack of laboratory tests that confirm a clinical diagnosis of the
disease. In a classic paper, Acheson (10) analyzed in detail (and with
remarkable perception) 14 of the well-recognized epidemics. The paper by Koo
(22) analyzes common defects in epidemiologic studies. The publication
by Matthews et al. (25) is an example of excellently designed and executed
epidemiological study. The contributions by Daugherty et al. (11) and
Hill et al. (12) are examples of excellent and highly informative epidemiologic
studies. The reports by Keighley and Bell (14) and Scott (16)
establish that the astute clinician can readily diagnose PVFS as it occurs
either endemically or in its epidemic form. The fact that PVFS is a challenge
to clinical diagnosis does not mean that it does not occur as a clinical entity
or has some obscure basis.
Pub.#:
10: Acheson, ED
1959
The clinical syndrome variously called benign myalgic encephalomyelitis,
Iceland disease and epidemic neuromyasthenia
Am. J. Med. 26: 569-595
Comment: This extraordinary review analyses 14 outbreaks of PVFS over
the years 1934-1959. Endemic and epidemic occurrences are considered separately.
Parameters are set forth that establish the PVFS as a distinct clinical entity.
The author discusses with exemplary accuracy: epidemiologic and clinical features;
laboratory findings; etiologic analyses; psychologic and psychiatric aspects;
and appropriateness of nomenclature and terminology. An excellent discussion
and summary are presented.
11: Daugherty, SA, BE Henry, DL Peterson, RL Swartz, S Bostien, and
RS Thomas
1991
Chronic fatigue syndrome in northern Nevada
Rev. Infect. Dis. 13 (Suppl): 39-44
Comment: This extremely well-controlled study, covering the period
1984-1988, involved ca 400 patients with clear-cut evidence for the
PVFS. Two groups of patients (ca 20 each) were studied in detail and
compared with age/sex-matched controls. The patients were not representative
of the general population: average age 43; ratio of females to males 3:1;
average income $75,000/yr. The neurologic and psychiatric evaluation of patients
was particularly well done. MRI scans disclosed in most patients tiny punctate
foci and multiple bilateral patchy areas in white matter tracts of the brain,
accompanied by abnormal signal intensities, i.e., objective evidence for organic
lesions in the brain. Personality disorders were analyzed relative to standard
psychological tests: MMPI, Beck Depression Inventory, and Rahe Life Events
Survey. The results showed that the protracted course of debilitating fatigue
and accompanying behavioral abnormalities (over 35.5 months) were not attributable
to elements of "hysterical" behavior.
12: Hill, RCJ, RWS Cheetham, and HL Wallace
1959
Epidemic myalgic encephalomyelopathy: the Durban outbreak
Lancet i: 689-693
Comment: This study of the summer outbreak of PVFS in the Addington
Hospital (a training center for nurses) is excellent in every respect. Figures
1 and 2 of the report illustrate the suddeness of onset and age-distribution
typical of the disease. The clinical phases of the disease are accurately
analyzed; prodromal, acute, convalescent, and chronic phases. Physical and
laboratory findings are presented clearly in appropriate tables. Psychiatric
disturbances are described and assessed accurately. Possible roles of environmental
toxins in the pathogenesis of the disease were considered and investigated.
An accurate summary of the possible causes of the signs and symptoms characteristic
of the disease is presented in a single short paragraph.
13: Jenkins, R
1991
Epidemiology: lessons from the past
Brit. Med. Bull. 47: 952-965
Comment: As a baseline, Jenkins analyzed the classic early epidemics
of PVFS and used this information to focus attention on the various factors
that may contribute to the pathogenesis of the disease. The author's analysis
of the psychiatric disorders that help distinguish the disease is very informative
and dispels the misconception that "hysteria" is a factor in the
origin of a diagnosis of PVFS. He notes, with some anguish, that in the UK
the Surveillance Centre for Communicable Diseases does not record cases diagnosed
as myalgic encephalomyelitis or PVFS. In an important contribution, Jenkins
recommends that any analysis of the pathogenesis of PVFS should consider and
evaluate its multifactorial basis.
14: Keighley, BD and EJ Bell
1983
Sporadic myalgic encephalomyelitis in a rural practice
.J. Royal College Gen. Pract. 33: 339-341
Comment: This publication establishes two important points: (i) PVFS
occurs endemically as sporadic cases. (ii) The astute clinician can diagnose
the disease on a clinical basis without undue difficulty. See also Scott (16).
15: McEvedy, CP and AW Beard
1970
Concept of benign myalgic encephalomyelitis
Brit. Med. J. 1: 11-15
Comment: This publication presents two basic notions: (i) During an
incipient or ongoing poliomyelitis epidemic, presenting patients may misinform
physicians (because of community hysteria) about symptoms simulating poliomyelitis.
(ii) Physicians in such communities, in response to the community hysteria,
may inadvertantly overdiagnose clinical syndromes simulating poliomyelitis.
16: Scott, BD, JHE Baines, BPP Judge, and DG Mayne
1990
Epidemic malaise
Brit. Med. J. i: 170
Comment: These authors point out that good diagnosticians can readily
identify benign myalgic encephalomyelitis in their patients, noting that hysteria
plays no role in the process. They strongly disagree with the notions of McEvedy
and Beard (15). This paper is one of many that disagree with the McEvedy-Beard
notion that PVFS is mainly hysterical in origin.
17: Sigurdsson, B, M Gudnadottir, and G Petursson
1958
Response to poliomyelitis vaccination
Lancet i: 370-371
Comment: The authors raise two interesting points: (i) why the antibody
response to Salk vaccine was poor in Egilsstadir but good in Thórshöln; and
(ii) whether an antecedent epidemic of Akureyri fever in Thórshöln enhanced
the antibody response to vaccine. These small but isolated communities are
excellent subjects for epidemiologic studies in which environmental factors
can be evaluated.
18: Wallace, PG
1991
Epidemiology: a critical review
Brit. Med. Bull. 47: 943-951
Comment: A central theme in this review is the accurate clinical diagnosis
of PVFS and how this is confounded by an inappropriate clinical definition
of the disease. Wallace discusses estimates of the frequency of its occurrence
among patients seen in general practice (280 / 10,000 subjects / year) and
in hospitalized patients (3 to 5 / 100,000). The Myalgic Encephalomyelitis
Association estimated ca 150,000 cases in the UK in their 1986 annual
report. Such frequencies far exceed those for clinical poliomyelitis in virus-infected
subjects prior to vaccination in temperate climates. The author notes the
many flaws that occur in epidemiologic studies of PVFS and how various biases
affect the analysis of data. The author is quite circumspect concerning the
soundness of our knowledge of the PVFS.
In clinical and seroepidemiological studies, a four-fold rise in serum antibody
titer between paired acute and convalescent sera is considered to be
necessary to establish an etiologic association between an infectious agent
and a specific disease entity. In many epidemiologic studies, such a requirement
is often difficult or impossible to meet. Koo (22) assessed a number
of other weaknesses in epidemiologic studies carried out to determine whether
EBV or HHV-6 infection was a major cause of the PVFS. The inherent problem
is that both EBV and HHV-6 infect most humans during the first two decades
of life. Thus, antibodies to their antigenic components are commonly found.
Fluctuation of antibody titers is common. Subclinical persistent infections
are known to be exacerbated by immunosuppressive experiences. From the publications
listed below (19, 21, 22, 25, 26 ), it is evident that neither EBV
nor HHV-6 are considered to be major causes of PVFS. The publication by Krueger
and Sander (24) presents an excellent review of HHV-6 and its putative
role(s) in various disease entities. The study by Bertram et al. (20)
failed to implicate human cytomegalovirus in PVFS.
Pub.#:
19: Bagg, J
1991
Human herpesvirus-6: the latest human herpes virus
J. Oral Pathol. Med. 20: 465-468
20: Bertram, G, N Dreiner, GR Krueger, A Ramon, DV Ablaski, SZ Salahuddin,
and N Balachandram
1991
Frequent double infection with Epstein-Barr virus and human herpesvirus-6
in patients with acute infectious mononucleosis
In Vivo 5: 271-279
Comment: Human cytomegalovirus (HCMV), like EBV and HHV-6, is a common
cause of subclinical infections that can be activated in various ways, particularly
in immunosuppressed subjects. This publication shows how difficult it is to
ascribe an etiologic role to any of these viruses in various syndromes. The
literature on PVFS tends to disregard HCMV as a putative etiologic agent of
the disease.
21: Gold, D, R Bowden, J Sixbey, R Riggs, WJ Katon, R Ashley, RM Obridgewitch,
and L Carey
1991
Chronic fatigue: a prospective clinical and virologic study
JAMA 265: 357-358
Comment: In a study comprising 26 patients with PVFS, these investigators
did not find evidence of ongoing EBV infection in the test population.
22: Koo, D
1989
Chronic fatigue syndrome. A critical appraisal of the role of Epstein-Barr
virus
West. J. Med. 150: 590-596
Comment: Koo assessed seroepidemiologic studies carried out to evaluate
whether EBV infection was a primary cause of PVFS. Koo makes a very valuable
contribution in his analysis of both systemic and nonsystemic errors in such
studies: (1) inaccurate clinical diagnoses; (2) poor selection of patients;
(3) absence or lack of suitable controls; (4) inconsistencies in laboratory
methodologies; etc. Koo does not accord significance to enterovirus infection
in the pathogenesis of PVFS. Koo concludes that seroepidemiologic studies
of EBV infection do not support a conclusion that EBV infection (acute, chronic
or otherwise) is a primary cause of PVFS.
23: Krueger, GR, DV Ablaski, SF Josephs, SZ Salahuddin, U Lembke, A
Ramon, and G Bertram
1991
Clinical indications and diagnostic techniques of human herpesvirus-6 (HHV-6)
infection
In Vivo 5: 287-295
24: Krueger, GR and C Sander
1989
What's new in human herpesvirus-6? Clinical immunopathology of the HHV-6
infection
Pathol. Res. Pract. 6: 915-929
25: Matthews, DA, TJ Lane, and P Manu
1991
Antibodies to Epstein-Barr virus in patients with chronic fatigue
Southern Med. J. 84: 832-839
Comments: This publication sets a standard for excellence in epidemiologic
studies of the "chronic fatigue syndrome," both in the methodologies
used and in the analysis of results. Patients with persistent chronic fatigue
were divided accurately into two groups: those that had chronic EBV infection
and those that did not. Subjects were age- and sex-matched for prospective
longitudinal studies. Detailed clinical and laboratory studies were done.
Eight detailed tables of data are presented: (i) EBV serologic data; (ii)
demographic and clinical characteristics; (iii) clinical features; (iv) symptomologies;
(v) physical findings; (vi) laboratory findings; (vii) psychiatric evaluations;
and (viii) attributable diagnoses. The data were carefully and critically
evaluated and compared without bias to published findings that also are critically
analyzed for both their strengths and weaknesses. Many important conclusions
were reached. One conclusion, e.g., is that EBV serologic patterns have little
clinical usefulness in evaluating patients with chronic fatigue. This conclusion
has substance since it is in accord with conclusions reached in most similar
investigations.
26: Sumaya, CV
1991
Serologic and virologic epidemiology of Epstein-Barr virus: relevance to chronic
fatigue syndrome
Rev. Infect. Dis. 13 (Suppl.): 19-25
Comment: Sumaya reviews the evidence indicating that EBV is not implicated
in the pathogenesis of the PVFS. The difficulties in implicating EBV in either
PVFS or multiple sclerosis are substantial, as noted in an analogous review
by Sumaya and his coworkers (see CIR#8, pub.# 59).
This portion of the report consists of two subsections: Enterovirus Sequences
and Persistent Enterovirus Infection (publication #s 27-42) and
Enterovirus Sequences in Heart Disease (#s 43-49). The latter
is included in order to document that enterovirus sequences (EVS) are commonly
found in myocardial tissues. Because the subject of viral myocarditis is of
major importance, it will be considered in detail in a subsequent report.
From the literature cited (27-42), it is evident that enteroviruses,
particularly Coxsackieviruses, appear to play an important role in the pathogenesis
of PVFS. The frequency of their occurrence in patients with PVFS was ca
35 to 67, as common (36, 37) as in controls. However, the actual frequency
is difficult to assess and undoubtedly underestimated. For example, since
the sampling of muscle tissues must be restricted (for practical reasons),
it is not known which muscle groups contain EVS with the greatest frequency,
and it is not known how stage or duration of disease affects frequency. There
also are precautionary notes: the detection of EVS in blood serum (32)
indicates virus complexed with antibody; and the occurrence of EVS in buffy
coat cells (36) cautions interpretations concerning detection of EBV
in muscle biopsies. Thus, the direct detection of enterovirus-like particles
in muscle biopsy by immune electron microscopy (28) is very important.
The literature cited also documents that enteroviruses (particularly Coxsackieviruses)
cause long-term persistent infections in which virus is detectable only by
very sensitive PCR assays. The literature cited (27, 34-38) also makes
it clear that the occurrence of elevated neutralizing antibodies, or IgM antibodies,
is not a pathogenomic indicator for recent Coxsackievirus infection.
Evidence also was cited (43-49) documenting that enteroviruses, particularly
members of the Coxsackievirus groups, persistently infect human cardiac tissues
with end-stage disease (48), being dilated cardiomyopathy (CMP). Since
CMP is the second most important cause of heart disease requiring cardiac
transplants (ischemic heart disease is first), it is evident that additional
information is sorely needed on the role of enterovirus infection as a predisposing
factor in CMP. (The finding (36) that EVS are not uncommonly found
in mammary or colon cancer tissues requires confirmation and further investigation.)
Enterovirus Sequences and Persistent Enterovirus Infection in PVFS
Pub.#:
27: Archard, LC, NE Bowles, PO Behan, EJ Bell, and D Doyle
1988
Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and
elevated creatine kinase
J. Royal Soc. Med. 81: 326-329
Comment: By use of reverse-transcribed probes of conserved Coxsackie-B2
sequences and quantitative slot hybridization tests, assays were done on muscle
biopsy specimens obtained from 96 patients that had diagnosed PVFS for as
long as 20 years. Of these, 20 were positive and 76 negative for Coxsackie-B2
sequences. Since sampling of tissue was relatively minimal, the results undoubtedly
underepresent the actual frequency of the occurrence of such sequences. Moreover,
results undoubtedly were influenced by the severity of disease at the time
when muscle biopsies were obtained. Other parameters of the PVFS were studied.
In the sample of 20 patients, levels of creatine kinase tended to be elevated,
i.e., evidence of muscle damage by single-fiber electromyographic (EMG) assays
of muscle failed to consistently show abnormalities. Many of the patients
had elevated levels of serum IgG to Coxsackie-B2, but IgM levels were not
consistently high. The authors suggest that PVFS is "a chronic metabolic
myopathy induced by persistent virus infection."
28: Behan, PO, WMH Behan, JW Gow, H Cavanaugh, and S Gillespie
1993
Enterovirus and postviral fatigue syndrome
In Jenkins, R. and J. Mowbray (eds.), Chronic fatigue syndrome.
Ciba Foundation Symposium, vol. 173, pp. 146-159. New York: J. Wiley &
Sons
Comment: The Behans and Gow report important new findings. Solid-phase
immunoelectron microscopy studies for the first time disclosed the presence
of enterovirus-like particles in muscle biopsy specimens obtained from patients
with the PVFS. An experimental model, with similarities to the PVFS, was established
by infecting mice with Coxsackievirus B1, so that the acute and persistent
phases of disease could be analyzed. Studies of the cytokine response during
the acute phase of infection disclosed increased intracerebral levels of cytokines
(evidently produced de novo in situ), including TNF-alpha. Increases of IL2,
IL4, IL5, IL6, and IFN-gamma were not detected. By the use of PCR cytokine
mapping, it was found that, in persistently infected mice, cytokines were
upregulated in the brains. The continuous secretion of IL6 was of interest
because of its putative role in causation of hypothalamic dysfunctions in
persistently infected mice. While the reported findings need to be confirmed
and extended, it is clear that they can provide important new insights into
the pathophysiology of the PVFS.
29: Bell, EJ, RA McCarthy, and MH Riding
1988
Cocksackie B viruses and myalgic encephalomyelitis
J. Royal Soc. Med. 81: 329-331
Comment: Two hundred ninety adults with diagnosed PVFS (1985-1986)
were tested for IgM antibodies to Cocksackie viruses B, types 1-5. Thirty
seven percent were positive compared to 9% of 500 adults free of PVFS. The
authors suggest that such results "provide further evidence that Cocksackieviruses
play a major role in ME, either directly or by triggering immunologic responses
which result in abnormal muscle metabolism.
30: Bowles, NE, TA Bayston, H-Y Lhang, D Doyle, RJM Lane, L Cunningham,
and LC Archard
1993
Persistence of enterovirus RNA in muscle biopsy samples suggests that some
cases of chronic fatigue syndrome result from a previous, inflammatory viral
myopathy
J. Med. 24: 145-160
Comment: These investigators used a Coxsackievirus B2 probe to detect
homologous sequences in five groups of subjects: (1) patients with adult dermatomyositis
(DM); (2) those with juvenile dermatomyositis (JDM); (3) patients with polymyositis
(PM); (4) those with PVFS; and (5) controls. It is not clear that subjects
were age- or sex-matched; controls were not fully described. The frequency
of the occurrence of viral sequences in groups 1-3 and patients with PVFS
were essentially identical. Where strand-specific probes were used for assays
on PVFS patients, equivalent amounts of genomic and template strands were
found, i.e., so-called symmetric RNA syntheses indicative of defective virus
replication. The authors make two very cogent suggestions: (1) symmetric viral
RNA syntheses result in the production of defective virus that is not eliminated
immunologically; and (2) cardiomyopathy in groups 1-3 may be a sequel to persistent
defective virus infection. The high frequency of viral sequences in the control
group of subjects has many important implications.
31: Cao, Y and DP Schnurr
1988
Persistent infection of YAC-1 cells by Coxsackievirus B3
J. Gen. Virol. 69: 59-65.
32: Clements, GB, F McGarry, C Nairn, and DN Galbraith
1995
Detection of enterovirus-specific RNA in serum: the relationship to chronic
fatigue
J. Med. Virol. 45: 156-161.
Comment: In this excellent study, three groups were tested: 118 patients
with PVFS; 110 hospitalized patients experiencing enterovirus infection that
was not PVFS; and 126 healthy subjects. For the most part, subjects were age-
and sex-matched. Enterovirus sequences ("nested PCR assays") were
found in 36/88 serum samples from the first group, in 22/82 of the second,
and in 3/126 of the third. The first group appeared to have higher amounts
of sequences. The authors make numerous significant observations. For example:
The skewed sex distribution among PVFS patients disappears in subjects with
the syndrome in excess of 2 years; that enterovirus infection in their population
had a rather stable incidence of ca 1-2% that was not seasonal; and
that, in a population of 106 subjects seen by general practitioners, there
was a frequency of PVFS of ca 0.1% (1154 cases).
33: Cunningham, L, NE Bowles, RJ Lane, V Dubowitz, and LC Archard
1990
Persistence of enteroviral RNA in chronic fatigue syndrome is associated
with the abnormal production of equal amounts of positive and negative strands
of enteroviral RNA
J. Gen. Virol. 71: 1399-1402.
Comment: Using Coxsackievirus B2 as a model, probes were used that
were specific for either genomic (+ stranded) or template (- stranded) viral
RNA. In productively infected cells in vitro, genomic viral RNA was
found at 100-fold excess compared to template RNA, i.e., so-called
asymmetric synthesis. In muscle biopsy specimens obtained from patients with
PVFS, both classes of RNA were found in equal amounts, i.e., such cells presumably
were infected with "defective" virus that had the capacity to establish
persistent infection. However, these important findings can be interpreted
in a number of other ways.
34: Cunningham, L, NE Bowles, and LC Archard
1991
Persistent virus infection of muscle in postviral fatigue syndrome
Brit. Med. Bull. 47: 852-871
Editorial comment: Cunningham and his associates determined whether
enterovirus sequences were present in muscle biopsy specimens obtained from
patients with PVFS. Two classes of probes were used: (i) so-called generic
probes that were enterovirus group-specific; and (ii) probes that made it
possible to determine whether virus RNA synthesis was asymmetrical (typical
of cytic infection) or symmetrical (typical of "defective" viral
RNA synthesis). Importantly, appropriate probes were used to test whether
specimens also were positive for EBV sequences. Seventeen patients were studied
that had fatigue for six or more months. Of these, five were mates and 13/17
were at midlife, i.e., 35-55 years of age. Then patients were tested for neutralizing
antibody to Coxsackievirus B3; five were negative. Eleven patients were tested
for IgM to Coxsackievirus B2, 3 and 5; of these, 10 were negative. Such results
indicate that antibodies to Coxsackieviruses are not good surrogate markers
for PVFS. When muscle biopsy specimens from 140 PVFS patients were tested
for enterovirus sequences, 34 were positive (24%). All of 152 controls were
negative. Seventy-six patient specimens were tested for EBV-specific sequences.
Only eight were positive, thus contraindicating a significant role for EBV
in the pathogenesis of the PVFS. All of the specimens positive for enterovirus
sequences provided evidence for symmetrical syntheses of enterovirus RNA.
The authors interpret this to mean that such results are evidence for persistent
defective virus infection. However, no "defective virus mutants"
were isolated and the term "mutant" was not used rigorously.
35: Dawson, J
1987
Royal free disease: perplexity continues
Brit. Med. J. 294: 327-328.
Comment: Outside of the US, a strong consensus exists that Coxsackievirus
infection appears to play a major role in the pathogenesis of PVFS. Commonly,
it was believed that IgM antibodies to Coxsackie viruses were a reliable indicator
of recent infection. Dawson comments that when IgM serologic studies were
done in PVFS patients and appropriate controls, the results indicated an equivalent
level of exposure in PVFS patients and controls. This led to the suggestion
by one of the investigators (Dr. H. A. Carmichael, vale of Leven Hospital)
that "another unknown factor acting against the background of a high
degree of exposure to Coxsackie B virus" might be involved.
36: Gow, JW and WMH Behan
1991
Amplification and identification of enteroviral sequences in the postviral
fatigue syndrome
Brit. Med. Bull. 47: 872-885
Comment: Many important points are brought out by Gow and Behan: (1)
The probes used to detect enterovirus sequences (EVS) detect most but not
all enteroviruses. (2) Antibody titers to enteroviruses in PVFS and control
patients did not differ significantly. (3) EVS were 6.7 times more frequent
in PVFS patients than in controls. (4) Elevated levels of creatine kinase
are not always found in PVFS patients. (5) Possibly HTLV-I or HTLV-II sequences
were detected in buffy coat specimens obtained from PVFS patients. Interestingly,
in the control group EVS were detected in 5/12 patients with mammary cancer
and in 1/3 with carcinoma of the colon. Similarly, the detection of EVS in
buffy coat specimens in both test and control groups has many interesting
implications. From their studies, the authors estimate an equivalent of 1
enterovirus virion / 2000 cells. The authors discuss how such a frequency
may impinge on the detection of EVS in biopsy specimens obtained from various
muscle groups. Possible seasonal impacts, or prior exposure to prophylactic
enterovirus vaccine, was not discussed.
37: Gow, JW, WMH Behan, GB Clements, C Woodall, M Riding, and PO Behan
1991
Enteroviral RNA sequences detected by polymerase chain reaction in muscle
of patients with postviral fatigue syndrome
Brit. J. Med. 302: 692-696
Comment: Antibody and enterovirus sequence assays were done in 60 patients
with PVFS and 41 controls. Overall, RNA sequences were detected in skeletal
muscle biopsy specimens of 53% of the PVFS group compared to 15% for controls.
Interestingly, and as noted by Tracy et al. (49 ), the occurrence of
such sequences did not correlate with elevated antibody levels to Coxsackie
viruses B1-B5.
38: Matteucci, D, M Pagliante, AM Giangregorio, MR Copobianchi, F Dianzani,
and M Bendinelli
1982
Group B Coxsackieviruses readily establish persistent infections in human
lymphoid cell lines
J. Virol. 56: 651-654.
Comment: Because Coxsackieviruses cause a variety of immunologic abnormalities,
the described model provides a methodology to analyze the interactions between
Coxsackievirus mutants possessing different pathogenic capabilities and subpopulations
of human lymphoid cells. The bibliography lists major papers on persistent
viral infection and on defective interfering viruses.
39: Righthand, VF and RV Blackburn
1989
Steady-state infection by ECHOvirus 6 associated with nonlytic viral RNA
and an unprocessed capsid polypeptide
J. Virol. 63: 5268-5275
Comment: The in vitro model of Echovirus 6 persistently-infected human
cells is an excellent paradigm for analyzing mechanisms of persistent defective
enterovirus infection. The introduction of the paper describes the extraordinary
features of the model. They include: noncytopathic infection; production of
virions in the same quantitative amounts as corresponding lytic virus; and
that persistent infection was not dependent on exogenous antiviral antibody
or interferon. The authors suggest that "the viral RNA is transferred
to daughter cells during division." The episomal transfer of enterovirus
RNA genomes is not a common phenomenon.
40: Strongwater, SL, K Dorovini-Zis, RD Ball, and TJ Schnitzer
1984
A murine model of polymyositis induced by Coxsackievirus B1 (Tucson strain)
Arthritis Rheum. 27: 433-442
Comment: This publication is representative of a very large literature
in which various Coxsackievirus types were used (mostly the B subgroup) to
establish persistent infections in mice and where "autoimmune" mechanisms
appear to be a major cause of cardiac myocarditis. In such studies, results
can be influenced markedly by the types of virus "mutant" used and
the strain of mice employed.
41: Woodall, CJ, MH Riding, DI Graham, and GB Clements
1994
Sequences specific for enteroviruses detected in spinal cord from patients
with motor neuronic disease
Brit. Med. J. 308: 1541-1543.
Comment: These authors report that their PCR assays detected enterovirus
sequences in 8/11 patients with motor neuron disease (MND) but not in six
age- and sex-matched controls. Poliovirus-infected monkeys used as positive
controls also were positive. The sequences detected in MND patients were homologous
to those of Coxsackie B5 and appeared to comprise two subgroups. The authors
conclude that there was low level persistent enterovirus infection in cord
tissues of MND patients that was not detectable by conventional virus isolation
techniques. They suggest a state of restricted enterovirus replication in
cord tissue analogous to the restricted replication of measles virus in subacute
sclerosing panencephalitis.
42: Zoll, GJ, WJG Melchers, H Kopecka, G Jambroes, HJA van der Poll,
and JMD Galama
1992
General primer-mediated polymerase chain reaction for detection of enteroviruses:
application for diagnostic routine and persistent infections
J Clin. Microbiol. 30: 160-165
Comment: The importance of the types of primers used to generate enterovirus
probes for PCR assays for EVS is explicitly considered in this valuable paper.
The authors report that their "generic enterovirus probes" did not
amplify Coxsackievirus A11, A17 or A24 sequences, or those of ECHO viruses
16, 22, and 23. Other investigators have also reported that such generic probes
may not amplify some Coxsackievirus A types. Moreover, based on PCR studies,
ECHO 9 is in fact a Coxsackievirus. Statements in the literature that "generic
enterovirus probes detect all enteroviruses" lack precision. Additionally,
there is little published data on how probes constructed to detect different
segments of enterovirus genomes detect corresponding sequences in various
test samples.
Enterovirus Sequences in Heart Tissues
Pub.#:
43: Archard, LC, NE Bowles, L Cunningham, CA Freeke, EG Olsen, ML Rose,
B Meany, HJ Why, and PJ Richardson
1991
Molecular probes for detection of persisting enterovirus infection of human
heart and their prognostic value
Eur. Heart J. 12 (Suppl.): 56-59.
Comment: This paper stresses the importance of antecedent or persistent
defective enterovirus infection in the pathogenesis of the inflammatory cardiomyopathies.
It is proposed that such infections progress to end-stage disease requiring
cardiac transplant. Better methods are needed to detect such viruses, since
standard virus isolation techniques and immunologic assays for relevant enterovirus
antigens are usually negative. The authors note that "persisting enterovisus
RNA in dilated cardiomyopathy is the strongest known predictor of poor prognosis."
44: Bowles, NE, PJ Richardson, EGJ Olsen, and LC Archard
1986
Detection of Coxsackie-B-virus-specific RNA sequences in biopsy samples
from patients with myocarditis and dilated cardiomyopathy
Lancet i:1120-1123
Comment: DNA complementary to 6.3-kb of the Coxsackie B-2 genome was
synthesized by reverse transcription. A 1.6-kb segment homologous to the conserved
3 ' region of the viral genome was used to detect Coxsackie B-2 sequences
(CB2) in myocardial samples obtained from patients with either active or healing
myocarditis or patients with dilated cardiomyopathy exhibiting inflammatory
changes. In tests on 17 patients, nine were positive. Only four patients putatively
free of Coxsackie virus infection were tested. All were negative. Several
interesting observations were made: CB2 sequences were detected "in a
large proportion of patients diagnosed as having active or healed myocarditis
or congestive cardiomyopathy ensuing from this disorder"; in positive
samples, virus RNA was present "at between 10 and 100 copies per cell
equivalent." The latter results suggest persistent infection even in
the convalescent patient. The authors make the important suggestion that the
failure to detect such viruses or their antigens by conventional assays might
have resulted from incorrect post-translational processing of viral capsid
precursor or immunologtic masking by antibody.
45: Jehn, VW and MK Fink
1980
Myositis, myoglobinemia, and myoglobinemia associated with enterovirus
ECHO 9 infection
Arch. Neurol. 37: 457-458
Comment: The findings summarized by Jehn and Fink serve the purpose
of suggesting that the pathogenesis of viral myocarditis may not be restricted
to the Coxsackievirus families.
46: Muir, P, AJ Tilzey, TAH English, F Nicholson, M Signy, and JE Banatvala
1989
Chronic relapsing pericarditis and dilated cardiomyopathy: serologic evidence
of persistent enterovirus infection
Lancet i: 804-807.
Comment: The authors' findings are consistent with the notion that
persistent enterovirus infection is associated with chronic pericarditis and
dilated cardiomyopathy, i.e, the data reported indicate that patients with
chronic relapsing pericarditis experience persistent antigenic stimulation,
predominately by Coxsackie B viruses. The authors suggest the possibility
that virus may persist at extracardiac sites. Occurrence of disease was noted
to be linked to some HLA allotypes, thus suggesting a genetic predisposition.
The authors comment that enteroviruses appear to be a common cause of some
chronic cardiac diseases. They note that after ischemic heart disease, dilated
cardiomyopathy is the most common reason for cardiac transplantation in the
UK. The authors also observe that improved diagnostic methods should lead
to a better understanding of the pathogenesis of virus-induced cardiac disease
and its prevention.
47: Schwaiger, A, F Umlauft, K Weyrer, C Larcher, J Lyons, V Mühlberger,
O Dietze, and K Grünewald
1993
Detection of enteroviral ribonucleic acid in myocardial biopsies from patients
with idiopathic dilated cardiomyopathy by polymerase chain reaction
Am. Heart J.126: 406-410
Comment: Nineteen patients with idiopathic dilated cardiomyopathy (CMP),
along with appropriate controls, were tested for enterovirus sequences in
heart muscle biopsy specimens. Two probes were used for PCR assays: one specific
for Coxsackie B3 (CV-B3) and the other for enteroviruses in general. None
of the controls yielded positive results. Since only 1/19 patients with heart
disease was positive for CV-B3 sequences, while 5/16 were otherwise positive,
the authors suggest that enteroviruses other than CV-B3 may be implicated
in CMP.
48: Tang, TT, GV Sedmark, KA Siegsmund, and SR McCreadie
1975
Chronic myopathy associated with Coxsackievirus type A9: a combined electron
microscopy and viral isolation study
N. Engl. J. Med. 292: 608-611.
Comment: This paper simply establishes that members of the Coxsackievirus
A group also can cause chronic myopathy.
49: Tracy, S, NM Chapman, BM McManus, MA Pallansch, MA Beck, and J
Carstens
1990
A molecular and serologic evaluation of enteroviral involvement in human
myocarditis
J. Molec. Cell. Cardiol. 22: 403-414.
Comment: This publication makes several important observations: (1)
No hybridization probe used as of the publication date detected a specific
enterovirus group to the exclusion of all others; and (2) when a "generic
enterovirus probe" was used to detect enterovirus sequences in human
myocardial specimens and the results then compared to IgM antibody titers,
the authors could not make a correlation between the two. There are many reasons
why this may have happened. In any case, the frequency of the occurrence of
enterovirus sequences in human muscle tissue, of vaccine origin or otherwise,
in the general population is unknown, and disease associations are not clearly
evident.
Only three publications were found, two of them preliminary and none peer-reviewed,
that provide laboratory evidence for a possible role of human retroviruses
in the etiology of PVFS. The problem is not in detecting such agents, but
in implicating detected agents in the syndrome, i.e., any hypotheses about
their etiologic role must be reconciled with pathogenesis, epidemiologic data,
and geographic distribution. There is an abundance of evidence documenting
that exogenous or endogenous retroviruses can be found in human cells or tissues
(see Urnovitz and Murphy, Clin. Microbiol. Rev. 9: 72-99: 1996).
But implicating them as etiologic agents of specific disease entities is a
difficult problem.
Pub.#:
50: DeFreitas, E, B Hilliard, PR Cheney, DS Bell, E Kiggundu, D Sankey,
Z Wroblewska, M Palladino, JP Woodward, and H Koprowski
1991
Retrovirus sequences related to human T-lymphocyte virus type II in patients
with chronic fatigue immune dysfunction syndrome
Proc. Natl. Acad. Sci. USA 88: 2922-2926
Comment: The studies reported by DeFreitas et al. were well-designed
and appear to have been well-executed. The subjects were: 12 adults with diagnosed
PVFS from the greater N. Carolina region and19 pediatric patients drawn from
a local epidemic of PVFS in upstate rural New York. Controls consisted of
20 subjects not exposed to PVFS patients. Fifty percent of the adults and
61% of the pediatric patients had antibodies to HTLV gag and env
products. Controls were all negative. When peripheral blood leukocytes from
PVFS patients were tested by PCR for gag and tax sequences of
HTLV-I, they were all negative. However, when subjects with PVFS were tested
for HTLV-II gag and env sequences, 83% of adults and 72% of
pediatric specimens were positive. Moreover, gag gene expression was
positive in 7/10 HTLV-II gag-positive specimens, as demonstrated by
gag-gene-directed RNA synthesis. The authors comment that they did
not believe that they had detected activated endogenous retrovirus sequences.
For unknown reasons, other investigators did not confirm the described results;
but this does not mean that they were not accurate. For example, Banki et
al., Proc. Natl. Sci. 89: 1939 (1982), reported that HERV HRES-1
encoded a protein possibly acting as an autoantigen for HTLV-1 gag-reactive
autoantibodies.
51: Folks, TM, W Heneine, A Khan, T Woods, L Chapman, and L Schonberger
1993
Investigation of retroviral involvement in chronic fatigue syndrome
In R Jenkins and J Mowbray, eds. Chronic fatigue syndrome. Ciba
Foundation Symposium 173: 160-166. New York: J. Wiley & Sons
Comment: Four groups of subjects were studied as part of the CDC surveillance
program for the chronic fatigue syndrome (CFS). Group I was diagnosed CFS.
Group II: patients with disease approximating CFS. Groups III and IV: patients
with predisposing diseases that could approximate CFS. Two sets of primer
/ probes were used, one for HTLV-II 5 ' gag sequences; the other for
tax sequences. PCR assays were done using the "whole blood lysate
method". None of 26 test or 28 control subjects were positive for the
probes used. Results also were negative where tests were done for other retrovirus
sequences: bovine leukemia virus; simian retrovirus types 1, 2 and 3; simian
T-cell leukemia virus; and "human spumavirus".
52: Holmes, MJ
1992
A retrovirus etiology for CFS
In BM Hyde et al., eds. The clinical and scientific basis of
myalgic encephalomyelitis chronic fatigue syndrome. Ottawa: Nightingale
Research Foundation
Comment: In this preliminary study, experiments were carried out on
six patients with diagnosed PVFS and six age- and sex-matched controls. Lymphocyte
cultures established from peripheral blood specimens were tested for reverse
transcriptase (RT) activity and examined by thin-section electron microscopy.
The RT activity of cells obtained from the PVFS patients was from 1.5 to 4
times as high as that found in control cells. The author noted that the mitogen
preparation used to sitmulate lymphocyte cultures contained a "powerful
inhibitor" of RT activity. Nevertheless, the author did not regard the
RT results to be "decisive". The six electron micrographs in the
publication convincingly show the presence of multiple budding C-type virus
particles with the structural characteristics of retroviruses.
53: Jubelt, B
1992
Motor neuron diseases and viruses: poliovirus, retrovirus and lymphomas
Curr. Opin. Neurol. Neurosurg. 5: 655-658
Comment: This excellent review illustrates the difficulties inherent
in adducing convincing evidence that either a known or previously undetected
human retrovirus may be implicated etiologically in a given clinical entity.
The examples used are antecendent poliovirus or HTLV-I or HTLV-II in the pathogenesis
of human motor neuron disease. To implicate a human retrovirus in the etiology
of the PVFS is a more difficult challenge.
The publications listed in this section comprise mainly two categories: general
reviews and publications on viruses as causes of immunologic abnormalities
in PVFS. Because of the putative importance of enterovirus infections in the
pathogenesis of PVFS, immunologic abnormalities attributable to Coxsackievirus
infections are emphasized. Surprisingly, rather limited information was found
in three key areas: genetics of susceptibility, allergic phenomena that may
predispose to PVFS, and the role(s) of the various cytokines on the pathogenesis
of PVFS. Comprehensive reviews addressing these subjects explicitly and in
detail were not found. The most extensive collection of reviews on immunologic
aspects of PVFS are published in BM Hyde et al., eds. The clinical and
scientific basis of myalgic encephalomyelitis chronic fatigue syndrome (Ontario,
Canada: Nightingale Research Foundation, 1992). The section devoted to immunologic
studies of PVFS consists of four chapters, for a total of 45 pages. Two additional
chapters deal with immune-based therapeutic approaches.
Featured Reviews
Pub.#:
54: Conaldi, PG, D Matteucci, SM Guidi, and M Bendinelli
1988
Interaction of group B Coxsackieviruses with immunocytes
In HP Schulteiss, ed. New concepts in viral heart disease: virology,
immunology, clinical management. New York: Springer-Verlag: 195-204
Comment: The authors' theme is that type B Coxsackieviruses alter immune
functions in vivo and cause a "profound involution of both central and
peripheral lymphoid organs." The striking depletion of lymphoid cells
in the thymus, spleen and lymph nodes occurred without direct cytopathic viral
effects, since virus replication in such cells was not detectable. Thus, the
important causes for such effects remain unknown. In Coxsackievirus-B3-infected
mice, the thymus is affected first. Effects are so substantial that the organ's
architectural features become obscured. Lymphocyte depletion in the spleen
and lymph nodes involves both the T- and B-cell areas. In humans, Coxsackievirus
infection reportedly caused a 20-50% reduction in the peripheral blood mononuclear
cell lymphocyte response to mitogens and was neither age- nor gender-related.
Coxsackieviruses readily cause persistent infections of human lymphoid cell
lines, or either B or T cell origin. Antibody frees cultures of persistent
infection.
55: Garzelli, C, F Basolo, D Matteucci, BS Prabhakar, and A Toniolo
1988
Picornavirus-induced immunosuppression
In S Specter et al., eds. Virus-induced immunosuppression. New
York: Plenum: 217-234
Comment: On the whole, this review indicates the importance of enterovirus
infection on the lymphoid system and the consequent immunologic abnormalities.
The authors point out that polioviruses replicate in blood monocytes and in
established human lymphoid cell lines, and that polioviruses can establish
persistent infections in cell lines of either B- or T-cell origin. Some of
the ECHO viruses alter the surface properties of human polymorphonuclear cells.
The basic features of the experimental model of Coxsackievirus-B3-infected
mice is described. In persistently infected mice, cell-mediated immunity in
vivo and the T-cell-dependent response in vitro are impaired. The authors
ascribe the immunodeficiencies observed in persistently-infected mice to two
main causes: damage to antigen-presenting cells and activation of suppressor
T-cells. The authors propose that a progressive loss of lymphocytes in infected
mice accompanies the development of autoreactivity which contributes to virus-induced
immunodeficiency. But the results summarized do not signify that losses of
lymphoid cells in the thymus, spleen or lymph nodes were a direct consequence
of virus cytopathology. Sixty-one well-selected references are listed in the
bibliography.
56: Gin, W, FT Christianson, and JB Peter
1989
Immune function and the chronic fatigue syndrome
Med. J. Australia 151: 117-118
Comment: The authors note that immunologic studies of PVFS are confounded
by variability which they attribute to three main factors: (i) The protean
nature of the disease; (ii) stage of disease when patients are studied; and
(iii) technologic differences among the immunologic tests applied. Overall,
results from 124 PVFS patients were summarized. The consistent results were
as follows: (1) a decreased absolute number of peripheral blood CD4 and CD8
cells; (2) a decreased lymphocyte response to mitogens; (3) a decreased response
in delayed hypersensitivity tests; (4) a decreased NK cell response; and (5)
sometimes a deficiency in the IgG1 immunoglobulin subclass. The authors comment
that the severity of the abnormalities are often striking. They also noted
an increased expression of the HLA-DR histocompatibility antigen in peripheral
blood monocytes, an event that, paradoxically, is suggestive of immune activation.
Contemporary Reviews
Pub.#:
57: Buchwald, D and AL Komaroff
1991
Review of laboratory findings for patients with chronic fatigue syndrome
Rev. Infect. Dis. 13 (Suppl): 12-18
Comment: This report summarizes a substantial and valuable effort designed
to analyze immunologic abnormalities in patients with PVFS. The authors identified
major confounding factors in such an analysis that inherently limit the accuracy
of their analysis: (i) patient heterogeneity, (ii) differences in test methods,
(iii) failure to standardize test parameters, (iv) differences in stage of
disease, and (v) lack of age- or sex-matched controls. The major immunologic
parameters reviewed in the analysis include: hematology, serum chemistry,
autoantibody levels, qualities and classes of immunoglobulins in serum, immune
complexes, cytokines, T-cell subsets and functional activities, phenotype
and functional activities of NK cells, phenotype and functional activities
of B cells, and predisposition to allergic reactivities. Thus, it is not clear
how the results relate to PVFS, since PVFS is a distinct clinical entity not
to be confused with chronic EBV infection. Nonetheless, this publication is
a valuable contribution, since it attempts to make sense of a large and inconsistent
literature. Sixty-one well-selected references are listed in the bibliography.
58: Prieto, J, J Camps-Bansell, and A Castilla
1993
Opiod-mediated monocyte dysfunction in the chronic fatigue syndrome
In BM Hyde et al., eds. The clinical and scientific basis for
myalgic encephalomyelitis chronic fatigue syndrome. Ottawa: Nightingale
Research Foundation: 575-584
Comment: This article focuses on the stress axis and how it interacts
with the immune system. The authors suggest that their findings indicate increased
opoid activity, such as the enkephalins, in patients with PVFS and that they
are associated with various immunologic abnormalities. Figure 1 diagrams the
stress axis; figure 6 diagrams type A and type B stress responses. This publication
summarizes many of the elements of psychoneuroimmunology. Eighty-three key
publications are cited.
59: Pross, HF
1993
Abnormalities of natural killer (NK) cell numbers and function in patients
with chronic fatigue immune dysfunction syndrome (CFIDS)
In BM Hyde et al., eds. The clinical and scientific basis for
myalgic encephalomyelitis chronic fatigue syndrome. Ottawa: Nightingale
Research Foundation: 566-572
Comment: The author provides an excellent and clear summary of the
immunologic abnormalities that may be found in patients with PVFS. He comments
that the lack of suitable diagnostic tests, as an aide in the diagnosis of
PVFS, contributes to the inconsistencies found in reports of immunologic studies
of the PVFS. The author also notes that the literature on NK studies is confounded
by the use of the 'NK' designation to mean either CD3+ or CD3- non-MHC lysis
of target cells (usually K562 cells) and equating the CD56 phenotype with
NK-mediated target cell lysis. Nonetheless, the author draws three main conclusions.
In patients with PVFS, (1) NK activity is significantly lower than controls;
(2) total CD56+ cells are increased; and (3) the proportion of CD3-CD56+ cells
is decreased. Forty nine well-selected publications are listed in the bibliography.
60: Rouse, BT and DW Horohov
1986
Immunosuppression in viral infections
Rev. Infec. Dis. 8: 850-873
Comment: This contribution is a major review on viral-induced immunosuppression.
Its abstract does not convey the substance of the article's contribution.
The article excells in clarity as well as in depth. The bibliography lists
222 references. Organization is excellent. The tables provide important explicit
information that is thoroughly referenced. Throughout, the authors clearly
present the basic conceptual foundations important to understanding how the
various mechanisms operative in viral-induced immunosuppression act in a functional
way.
Featured Publications
The papers listed below are selected to emphasize specific points. For example,
Behan et al. (61), Gupta et al. (64), and Lloyd et al. (65)
are reasonably consistent in reporting the immunologic abnormalities that
occur in patients with PVFS. Careful patient selection was the key point,
i.e., patients with active or chronic EBV infection were excluded for the
most part. The reports by Bendinelli et al (62) and Metteucci et al.
(67) document that enterovirus infections in mice cause severe immunologic
abnormalities and atrophy of lymphoid tissues not attributable to viral replication.
Coxsackie B viruses readily cause persistent noncytopathic infections of human
lymphoid cells in vitro (66). The report by Caligiuri (63) is
representative of many that consistently show depressed NK cell function in
PVFS patients. Lloyd et al. (65) convincingly document that IgG1 and
IgG3 levels, and delayed hypersensitivity reactivities, were depressed in
patients with PVFS (in 56/100 and 88/100 patients, respectively). Peterson
et al. (75) and Read et al. (77) report similar results. The
purported variability in immunologic abnormalities in patients with PVFS appears
to be overstated and may reflect, instead, inappropriate patient selection,
principally by investigators in the U.S.
Pub.#:
61: Behan, PO, WMH Behan, and EJ Bell
1985
The postviral fatigue syndrome - an analysis of the findings in 50 cases
J. Infect. 10: 211-222
Comment: In-depth studies were done on 50 patients at both acute and
chronic stages of disease. Extensive clinical laboratory tests were done,
including single-fiber electromyographic (EMG) and nuclear magnetic resonance
(NMR) studies of muscle. In a test group of 20 patients, scattered necrotic
muscle fibers were found without evidence of inflammatory infiltrates. The
NMR tests disclosed abnormal muscle metabolism that was characterized by excessive
intracellular acidosis. Acute disease was characterized by an absolute decrease
in T4 and T8 cells. In acute disease there was a significant decrease in T8
cells, while T4 cells were decreased in chronic disease. There was an impaired
lymphoproliferative response to phytohemagglutinin. Eighteen patients had
high serum antibody titers to smooth muscle. Serologic studies disclosed that
70% of patients had high titers to Coxsackie B viruses. On the whole, other
immunlogic abnormalities were not found. The authors suggest that PVFS results
from "the interaction of viral infection and immunologic processes which
produce damage to intracellular enzymes and result in abnormal muscle metabolism,
especially on exercise."
62: Bendinelli, M, D Matteucci, A Toniolo, AM Patone, and MP Pistillo
1982
Impairment of immunocompetent mouse spleen cell functions by infection
with Coxsackievirus B3
J. Infect. Dis. 146: 797-805
Comment: This important study analyzed the effects of the infection
of BALB/c inbred mice with Coxsackievirus B3. The antibody response to sheep
red blood cells was reduced, an effect not attributable to losses in B-cell
functions. Immune suppression was attributed to loss in macrophage functions,
presumably at the level of antigen presentation, and in combination with nonspecific
T-cell suppression. Marked atrophy of the spleen occurred in infected mice
and presumably affected B-cell and T-cell regions equally. There was no significant
evidence that virus multiplied or was cytopathic to splenocytes. The possible
suppression of monocyte function in humans as a result of poliovirus infection
was discussed, using the described experimental model as a paradigm. The bibliography
lists 36 references.
63: Caligiuri, M, C Murray, D Buchwald, H Levine, P Cheney, D Peterson,
AL Komaroff, and J Ritz
1987
Phenotypic and function deficiency of natural killer cells in patients
with chronic fatigue syndrome
J. Immunol. 139: 3306-3313
Comments: Although the results in the described study were resaonsably
consistent, the diagnoses of PVFS in the patients selected was somewhat discrepant.
Nonetheless, this paper is representative of many reporting the repression
of NK functions in patients with PVFS.
64: Gupta, S and B Vayuvegula
1991
A comprehensive immunological analysis in chronic fatigue syndrome
Scand. J. Immunol. 33: 319-327
Comments: The authors studied 20 CDC-defined patients with PVFS, along
with age- and sex-matched controls. The main findings suggest immunological
dysfunction in patients with CFS. In particular, studies of the adhesion molecule
LFA-1 and its ligand ICAM-1 revealed an increased proportion of CD4+ ICAM-1+
T-cells. Blood monocytes also showed increased densities of surface LFA and
ICAM. The antibody response to type 3 pneumococcal antigen was impaired in
PVFS, while the response to types 8, 12, and 14 evidently was not. Studies
of serum autoantibodies disclosed that 30% of patients with PVFS had elevated
titers only to ANA. On the whole, the authors provide a perceptive and well-balanced
assessment of their findings and how they relate to similar published findings.
It is gratifying to note that they discriminate PVFS as a clinical entity
and do not confuse it with chronic EBV infection.
65: Lloyd, AR, D Wakefield, CR Boughton, and JM Dwyer
1989
Immunologic abnormalities in the chronic fatigue syndrome
Med. J. Australia 151: 122-124
Comment: This study was carried out on a carefully defined group of
patients that had experienced long-standing disease (mean: 37 mos.). Controls
were matched carefully by age and sex. Absolute numbers of peripheral blood
T-cells were determined, not ratios. Delayed hypersensitivity (DTH) responses
were determined by the Multitest CMI System. Serum immunoglobulin subclasses
also were quantified. The authors report an absolute reduction in helper /
inducer T-cells (CD2, CD4) and suppressor T-cells (T8). Eighty-eight percent
of patients had reduced DTH activities. Fifty-six percent of PVFS patients
had reduced levels of either IgG1 or IgG3. The authors again propose that
PVFS is a consequence of persistent intracellular infection accompanied by
a disordered cell-mediated immune response that gives rise to a chronic cytokine-mediated
symptomology often called chronic fatigue syndrome.
66: Matteucci, D, M Paglianti, AM Giangregorio, MP Capobianchi, F Dianzani,
and M Bendinelli
1985
Group B Coxsackieviruses readily establish persistent infections in human
lymphoid cell lines
J. Virol. 56: 651-654
67: Matteucci, D, A Toniolo, PG Conaldi, F Basolo, Z Gori, and M Bendinelli
1985
Systemic lymphoid atrophy in Coxsackievirus B3-infected mice: effects of
virus and immunopotentiating agents
J. Infec. Dis. 151: 1100-1108
Comment: Generally, the authors establish that certain picornaviruses
may cause severe stress-independent lymphoid damage in the absence of viral
replication in situ. Three new insights are provided concerning the pathophysiology
of Coxsackievirus infections that may extend to other enteroviruses as well:
(1) Until circa 1985, the pathophysiology of Coxsackievirus infections
(particularly the B subgroup) was considered to be a direct consequence of
the highly lytic infection of cells by these agents. Subsequent studies, such
as those reported, revealed marked immunosuppressive effects of such viruses
that could not be attributed to their replication in immunocompetent cells.
(2) Coxsackievirus B3 caused severe anatomic and functional changes in lymphoid
tissues and organs without replicating in them. (3) Immunopotentiating agents
can exacerbate such pathologic changes. The authors suggest that their results
did not implicate adrenal mediated stress in the observed lymphoid atrophy.
The authors did not suggest that possible contamination of virus stocks by
lactic dehydrogenase virus might have contributed to some of the changes seen
in atrophied lymphoid tissues (cf. Snodgrass, MJ et al., 1972. J. Immunol.
108: 877).
Contemporary publications
Pub.#:
68: Huber, SA, LP Job, and JF Woodruff
1981
Sex-related differences in the pattern of Coxsackievirus B-3-induced immune
cell cytotoxicity against virus-infected myofibers
Infect. Immunol. 32: 68-73
Comment: The authors note that Coxsackievirus B3-elicited myocarditis
in adult mice is restricted to males. This raises the question of whether
the higher frequency of PVFS in females may be more sex-related than occupational
risk.
69: Irwin, M, TL Smith, and JC Gillin
1987
Low natural killer cytotoxicity in major depression
Life Sciences 41: 2127-2133
Comment: This is one of many papers in the area of psychoneuroimmunology
that show how psychological disorder can affect immunologic functions. A substantial
literature has accumulated in this field. Good assessment appoaches exist
and should be used (under psychiatric supervision) concerning mental symptomology
in patients with PVFS or Gulf War Syndrome; anecdotal information about mental
syndromes in relation to immunodeficiency are obviously not sufficient. See:
AL Buckman and AI Fins. 1993. Psychological and cognitive aspects of the
chronic fatigue syndrome. In PJ Goodnick and NG Klimas, eds. Chronic
fatigue and related immune deficiency syndromes. Progress in psychiatry.(Washington,
D.C.: American Psychiatric Press) 40: 67-94.
70: Klimas, NG, FR Salvato, R Morgan, and MA Fletcher
1990
Immunologic abnormalities in chronic fatigue syndrome
J. Clin. Microbiol. 28: 1403-1410
Comment: In an effort to characterize in a comprehensive manner the
status of laboratory markers associated with cellular immune function in patients
with CFS, the authors established a pattern of immune marker abnormalities
that is compatible with a chronic viral reactivation syndrome. This study
is distinctive by virtue of the detailed analysis of T-cell subsets; in particular,
CD4+ and CD45RA T-cells were depleted in the 30 patients studied. The authors
attribute the specific depression to the occurrence of "somewhat higher
percentages of CD29+ memory cells as a consequence of chronic virally-induced
antigenic stimulation." However, six alternative explanations also were
offered. The authors suggest that PVFS is a form of acquired immunodeficiency.
Fifty-four references are listed in the bibliography.
71: Linde, A, L Hammarström, and CIE Smith
1988
IgG subclass deficiency and chronic fatigue syndrome
Lancet i: 885-886
Comment: Six patients were tested that had symptoms "suggestive
of the chronic fatigue syndrome." The duration was more than one year.
Two of these had decreased amounts of IgG3. No laboratory data were reported.
The authors note that IgG3 deficiency has been correlated with chronic symptoms.
72: Lloyd, A, I Hickie, D Wakefield, C Baughtom, and J Dwyer
1990
A double-blind, placebo-controlled trial of intravenous immunoglobulin
therapy in patients with chronic fatigue syndrome
Am. J. Med. 89: 561-568
Comment: This study, like Peterson et al. (75), consisted of
well-selected patients, most of whom had chronic disease of ca four
years duration. The authors report that 10/23 (43%) of the PVFS group and
3/26 (12%) of the placebo group benefitted from immunoglobulin therapy. The
methodologies used by Lloyd et al. to evaluate patients appear to have been
considerably more rigorous than those employed by Peterson et al. Adverse
effects observed by Lloyd et al., as stipulated in the text, were not categorized
as "major". Some of the patients in both the treatment and placebo
groups had a relapse of symptoms several months after therapy was completed.
This finding has many interesting interpretations. The asserted resolution
by immunoglobulin therapy of abnormalities in cell-mediated immunity and delayed-hypersensitivity
skin-test reactivities are of particular interest.
73: Morrison, LJA, WHM Behan, and PO Behan
1991
Changes in natural killer cell phenotype in patients with post viral fatigue
syndrome
Clin. Exp. Immunol. 83: 441-446
Comment: The patients studied by the authors were distinct in that
they "all had severe fatigue that had been present for more than 1 year"
and included approximately equal numbers of each sex.
74: Murdoch, JC
1988
Cell mediated immunity in patients with myalgic encephalomyelitis syndrome
N. Z. Med. J. 101: 511-512
Comment: The "Multitest" assay technique was used to compare
delayed hypersensitivity reactions (DTH) of 33 well-defined PVFS patients
and matched controls. Test antigens were tetanus and diphtheria toxins, and
extracts from streptococci, tubercle bacilli, candida spp., Trichophyton spp.,
and "proteus" spp. Overall, the DTH response of PVFS patients was
suppressed, compared to controls. Some, however, were normal, relative to
diphtheria toxin, tubercle, candida, and proteus. Possibly the tetanus response
also was not different. Given the fact that 15% of the controls registered
as anaergic and that Multitest data are inconsistent among diverse population
groups, the reported results are difficult to assess.
75: Peterson, PK, J Shepard, M Macres, C Schenck, J Crosson, D Rechtman,
and N Lurie
1990
A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome
Am. J. Med. 89: 554-560
Comments: Several points are notable: The 28 selected patients were
carefully studied, mostly female, and had CFS for ca four years. Low
levels of IgG1 (42.9%) and IgG3 (64.3 %) were found in patients before therapy.
No therapeutic benefit from treatment was found. Major adverse experiences
were observed in 20% of both test and control groups. The reported results
appear to differ from those found in similar studies, as reported by Lloyd
et al. (see 72).
76: Prieto, J, ML Subira, A Castilla, and M Sorrano
1989
Naloxone-reversible monocyte dysfunction in patients with chronic fatigue
syndrome
Scand. J. Immunol. 30: 13-20
Comment: This publication, and similar papers by Prieto et al., report
that opiates and opioids known to be released during stress can suppress monocyte
functions. Monocyte dysfunctions, defined by the authors, that occurred in
patients with PVFS, were reversed by treating monocytes in vitro with Naloxone,
an opioid antagonist.
77: Read, R, G Spickett, J Harvey, AJ Edwards, and HE Larson
1988
IgG1 subclass deficiency in patients with chronic fatigue syndrome
Lancet i: 241-242
Comment: Two patients were studied that had PVFS 16-to-18 months, had
a low ratio of T4/T8 cells where studies were initiated, and had no evidence
for active or chronic EBV infection. The ages of the female and male patients
were 32 and 24, respectively. The initial assays revealed a low concentration
of IgG with a deficit in IgG1. Four months after initial studies, the T4/T8
cell ratios returned to normal levels in both patients, but one patient had
a persistent IgG1 deficit. The authors point out that IgG1 deficiencies are
rare in the general population and, when found, occur in subjects with common
variable hypogammaglobulinemia. They suggest that the IgG1 deficit observed
may reflect a failure in T-cell help or excess subclass-specific suppression,
i.e., the transitory nature of the defect in one patient argues against deletion
of IgG1-secreting B-cells.
78: Subira, ML, A Castilla, M-D Civeira, and J Prieto
1989
Deficient display of CD3 on lymphocytes of patients with chronic fatigue
syndrome
J. Infect. Dis. 160: 165
Comment: Twenty well-defined patients and matched controls were studied.
The duration of disease in the patient group ranged from eight months to 14
years, i.e., patients had chronic disease. The results indicated that PVFS
patients may have T lymphocytes (CD2 and CD5 positive) without immunoreactive
CD3.
Systematic
long-term studies of cytokine levels in patients with PVFS are largely lacking.
An important need is to determine serum and cerebrospinal fluid cytokine levels
over the course of disease (see 83), since there may be a cascade effect
at given times. The occurrence of signs and symptoms roughly analogous to
those found in patients with PVFS that occur in patients treated with cytokines
(81, 84, 87) imply an etiologic role of cytokines in the pathogenesis
of PVFS. As noted below, clearly aberrant levels of cytokines have not been
found consistently in patients with PVFS.
Pub.#:
79: Chao, CC, EN Janoff, SX Hu, K Thomas, M Gallagher, M Tsang, and
PK Peterson
1991
Altered cytokine release in peripheral blood mononuclear cell cultures
from patients with the chronic fatigue syndrome
Cytokine 3: 292-298
Comment: The authors measured the levels of cytokines in the serum
of patients with PVFS and also measured the release of cytokines from cultured
peripheral blood monocyte (PBMC) after stimulation with either lipopolysaccharide
(LPS) or phytohemagglutinin. Only serum levels of transforming growth factor-beta
(TGF-beta) were elevated. PBMC stimulated with LPS, when compared with controls,
released increased amounts of IL-1, IL-6 and TNF-alpha. Paradoxically, the
amount of TGF-beta was decreased.
80: Cheney, PR, SE Dorman, and DS Bell
1989
Interleukin-2 and the chronic fatigue syndrome
Ann. Internal Med. 110: 321
Comment: Plasma levels of interleukin-2 (IL-2) were determined in 104
patients with accurately diagnosed PVFS and 22 sex- and age-matched controls.
The mean plasma levels in the PVFS patients were ca 55.8 U/ml and 1.4
U/ml for controls. The observed difference was statistically significant,
but failed to correlate with severity or duration of disease. "A greater
frequency of very high values (7/50 U/ml) was seen in patients younger than
20 years of age who were purposefully omitted from this adult study."
81: Denicoff, KD, DR Rubinow, MZ Papa, C Simpson, CA Seipp, MT Lotze,
AE Chang, D Rosenstein, and SA Rosenberg
1987
The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated
killer cells
Ann. Internal Med. 107: 293-300
Comment: Table 8 in this paper lists the clinically significant neuropsychiatric
abnormalities that occurred in patients treated with IL-2. Forty-four patients
with metastatic cancer were studied. The signs and symptoms listed in Table
8 are similar to those described by McDonald and Mann (84) and also
show a commonality with those found in patients with PVFS.
82: Lever, AML, DM Lewis, BA Bannister, M Fry, and N Berry
1988
Interferon production in the postviral fatigue syndrome
Lancet ii: 101
Comment: Eight children with PVFS of three-to-five months duration
were studied along with four age-matched controls. Peripheral blood mononuclear
cells were assayed for alpha interferon production. The authors report that
children with PVFS produced significantly more interferon than controls.
83: Lloyd, AR, D Wakefield and I Hickie
1993
Immunity and pathophysiology of chronic fatigue syndrome
In R Jenkins and JF Mowbray, eds. Chronic fatigue syndrome.
Ciba Foundation Symposium 173: 176-187. New York: J Wiley &
Sons
Comment: In the section of the review allocated to effects of cytokines
on the pathogenesis of PVFS, the authors noted that there were only elevations
in the serum levels of transforming factor beta and IL-1. Lloyd et al. comment
that their studies disclosed only a marginal increase in interferon-alpha.
The authors make a valuable assessment of the varous problems associated with
evaluating cytokine levels in PVFS patients. For example, only single samples
are usually tested, despite the recognized fact that cascades of cytokines
occur during the course of an immune response, and it is probable that they
are neither quantitatively or qualitatively equivalent at different points
of time.
84: McDonald, EM, AH Mann, and HC Thomas
1987
Interferons as mediators of psychiatric morbidity
Lancet ii: 1175-1177
Comment: This study is quoted widely in the literature as documentation
for psychiatric syndromes elicited by IFN-alpha used therapeutically. In fact,
the publication reports an array of additional interesting and important findings.
But the paper focuses on an association between treatment of patients with
IFN-alpha and psychiatric morbidity. The patients studied were males, 18-58
years of age, most were homosexual, some had HIV-1 infection, and many had
antecedent psychiatric problems (34% of the therapy group and 46% of the controls).
IFN-alpha was used to treat the hepatitis-B carrier state. In the therapy
group, 17/27 "became psychiatric cases". This was most frequent
in the HIV-1 subgroup. The "psychiatric symptoms seem[ed] to be non-psychotic,
the most commonly reported being fatigue, impaired concentration, anxiety
and depression." The authors comment that the most commonly reported
adverse reactions to INF-alpha are fatigue, drowsiness, disorientation, slowness
and withdrawal---all suggestive of impaired cerebral function, organic in
nature, and confirmable by electroencephalography. Clearly, some of the signs
and symptoms characteristic of PVFS may be attributable to cytokines.
85: McDonald, E and A Mann
1991
Interferon in viral illness and myalgic encephalomyelitis
In R Jenkins and J Mowbray, eds. Post-viral fatigue syndrome
(myalgic encephalomyelitis). New York: J Wiley & Sons
Comment: In a clear and straightforward way, the authors briefly review
the role(s) of interferon (IFN) in viral diseases and discuss the possible
role(s) of IFNs in the pathogenesis of PVFS. The results of IFN studies on
112 patients with PVFS are summarized. Increased levels of IFN in the sera
of such patients were not found. In a limited study involving eight children
(see 82), it was reported that their peripheral blood monocytes produced
more IFN than those of controls. The authors did not report on studies of
IFN in the cerebrospinal fluid of patients with PVFS. The review includes
40 citations.
86: Patarca, R, MA Fletcher, and NG Klimas
1993
Immunologic correlates of chronic fatigue syndrome
In PJ Goodnick and NG Klimas, eds. Chronic fatigue and related
immune deficiency syndromes. Progress in Psychiatry 40:1-21. Washington,
D.C.: American Psychiatric Press
Comment: In their summary, the authors comment that patients with PVFS
have "two basic problems with immune function: (1) chronic immune activation
[in which there are elevations of circulating cytokines] and (2) poor cellular
function with low NK cell cytotoxicity, poor lymphocyte response to mitogens,
and frequent immunoglobulin deficiencies, most often with IgG1 and IgG3."
In the authors' report of their studies, they state that the serum levels
of cytokines in the patients studied were: 18% had elevated levels of IL-2;
IL-4 levels were normal; 12% had elevated levels of soluble receptor for IL-2;
12% had elevated levels of neopterin; and 20% had elevated levels of IFN-alpha.
The authors could not detect IFN-gamma. Overall, the review is clear and precise.
No laboratory data are presented, and the patient and control groups are not
documented. The bibliography includes 109 citations.
87: Smedley, H, M Katrak, K Sikora, and T Wheeler
1983
Neurological effects of recombinant human interferon
Brit. Med. J. 286: 262-264
Comment: The 10 women in the described study group were 42-69 years
of age, and 7/10 had mastectomies. The described, limited clinical trial employed
"highly purified human leukocyte A interferon (IFN) produced by recombinant
DNA technology." The major adverse effects were profound lethergy in
6/10 patients; 5/10 developed frank confusion, loss of concentration and expressive
dysphasia. Baseline electroencephalograms allowed detection of abnormal tracings
four weeks after treatment. The authors point out that interferon does not
cross the blood-brain barrier and cannot be detected in cerebrospinal fluid,
even when there are high blood concentrations in patients receiving IFN therapy.
88: Straus, SE, JK Dale, JB Peter, and CA Dinarello
1989
Circulating lymphokine levels in the chronic fatigue syndrome
J. Infec. Dis. 160: 1085
Comment: In this study, 18 women and seven men with documented PVFS
and 25 age- and sex-matched controls were studied. Serum and plasma levels
of alpha, beta-1, gamma, IL-2, and TNF were determined. The authors could
not demonstrate consistently elevated levels of any of these lymphokines in
PVFS patients.
The pathophysiology of PVFS is complex. There are three main problems: (1)
None of the signs or symptoms typical of the syndrome are distinct enough
to provide a clear-cut indication of cause. (2) Neither histopathologic, biochemical,
nor ultrastructural analyses of biopsy specimens have provided a definition
of a central pathologic process. (3) Although the pathophysiology of the disease
is clearly multifactorial, none of the individual interactive elements is
sufficiently aberrant to be ascribed a primary role in the pathogenesis of
the syndrome. If it is agreed that no single disease marker is pathognomonic,
the requirement is to develop and apply patterns of recognition that are diagnostic.
Such a strategy requires a departure from conventional diagnostic approaches
in clinical laboratory medicine. Computer-based techniques abound that could
be applied to such an analysis. Largely, these have not been employed.
This section of the report focuses mainly on two aspects of the pathophysiology
of PVFS: (i) myalgia and its possible causes (89, 91, 93, 95-98, 100 )
and (ii) putative control CNS involvement affecting the so-called hypothalamic-pituitary-adrenal
axis (90, 92, 94, 99 ). Detailed discussions of the pathophysiology
of PVFS are presented in the excellent mongraph: R Jenkins and J Mowbray,
eds. Post-viral fatigue syndrome (myalgic encephalomyelitis), New York:
J Wiley & Sons, 1991. The chapters on pathologic changes in skeletal muscle
(TJ Peters and VR Preedy) and on neurophysiological findings (GA Jamal) are
very good.
Pub.#:
89: Arnold, DL, GK Radda, PJ Bore, P Styles, and DJ Taylor
1984
Excessive intracellular acidosis of skeletal muscle on exercise in a patient
with a post-viral exhaustion / fatigue syndrome. A 31P nuclear magnetic resonance
study
Lancet ii: 1367-1369
Comment: The metabolic abnormality described by the authors resulted
from the study of one patient by NMR. The patient's PVFS occurred as a sequale
to varicella virus infection that caused clinically apparent chickenpox at
age 26, which is infrequent.
90: Bakheit, AM, PO Behan, TG Dinan, CE Gray, and V O'Keane
1992
Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in
patients with postviral fatigue syndrome
Brit. Med. J. 304: 1010-1012
91: Behan, PO, WMH Behan, and EJ Bell
1985
The postviral fatigue syndrome - an analysis of the findings in 50 cases
J. Infect. 10: 211-222
Comment: The authors report that muscle biopsies disclosed abnormal
results in 20/20 patients studied. In 15/20, widely scattered necrotic muscle
fibers were identified without an accompanying inflammatory infiltrate. All
20 patients had moderately increased size and numbers of Type II fibers. Mitochondria
were increased conspicuously at the periphery of fibers. Conventional electromyography
disclosed primary muscle lesions in 30/40 patients. NMR studies revealed abnormal
muscle metabolism in 6/6 patients studied. The authors state that, during
exercise, there was early intracellular acidosis in muscle suggestive of a
disorder of regulation. The described results are interesting to compare with
those reviewed by Edwards et al. (95). This publication is also 61
above (with a different focus of comments).
92: Bell, DS
1994
Chronic fatigue syndrome update
Postgrad. Med. 96: 73-81
Comments: This review is clear and refreshing. The central theme is
that there may well be a causal relationship between CNS dysfunction and much
of the symptomology that characterizes PVFS. Bell summarizes the studies of
Bakheit et al. (90) on pituitary and hypothalamic abnormalities, and
the preliminary work of Demitrack et al. (94) on neurotransmitter abnormalities,
in support of this central notion. In a sense, it may be considered a refined
statement of early hypotheses concerning the pathophysiology of PVFS.
93: Byrne, E and I Trounce
1987
Chronic fatigue and myalgia syndrome: mitochondrial and glycolytic studies
in skeletal muscle
J. Neurol. Neurosurg. Psych. 50: 743-746
Comment: The findings reported by Byrne and Trounce failed to disclose
"a major defect in muscle intermediary energy pathways" in the PVFS.
Since NMR studies were not done, the results do not necessarily contradict
those of Arnold et al. (89). Since electron microscopy studies were
not done, the results reported do not necessarily contradict those found by
Gow and Behan (37), who reported "obvious evidence of mitochondrial
damage" in 45/60 cases they studied.
94: Demitrack, MA, PW Gold, JK Dale, DD Krahn, MA Kling, and SE Straus
1992
Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic
fatigue syndrome: preliminary findings
Biol. Psychiatry 32: 1065-1077
Comment: Demitrack believes that abnormalities in the hypothalamus-pituitary-adrenal
axis may play a key role in the pathophysiology of PVFS. His excellent paper
on the subject should be consulted: Neuroendocrine research strategies
in chronic fatigue syndrome. In PJ Goodnick and NG Klimas, eds.
Chronic fatigue and related immune deficiency syndromes. Progress in Psychiatry
40: 45-66. Washington, D. C.: American Psychiatric Press, 1993.
95: Edwards, RHT, H Gibson, JE Claque, and T Helliwell
1993
Muscle histopathology and physiology in chronic fatigue syndrome
In R Jenkins and JF Mowbray, eds. Chronic fatigue syndrome.
Ciba Foundation Symposium 173: 102-131. New York: J Wiley &
Sons
Comment: The detailed and careful studies summarized by the authors
did not indicate that fatigue in PVFS was a result of myopathy. In the described
study, "fatigue" was defined to mean the failure to sustain force
or power. Fatigue was classified neurophysiologically according to site of
origin (central or peripheral). The response to objective electrophysiological
assessment was classified as high or low frequency fatigue. For example, the
central category correlates with failure of neural drive, i.e., the failure
to sustain maximal recruitment of neural motor units or firing frequency.
High frequency fatigue signifies impaired neuromuscular transmission or conduction
of action potential. Low frequency fatigue was characterized by impaired excitation-contraction
coupling. In other words, fatigue is physiologically definable and not some
vague abstraction.
96: Friman, G, JE Wright, NG Illback, WR Beisel, JD White, DS Sharp,
EL Stephen, WL Daniels, and JA Vogel
1985
Does fever or myalgia indicate reduced physical performance capacity in
viral infections?
Acta Med. Scand. 217: 353-361
Comment: In this very interesting (albeit limited) study, the authors
propose that, in brief viral infections, impaired muscle performance correlates
with subjective symptoms such as myalgia, while decreased cardiac output correlates
with febrile reaction.
97: Jamal, GA and S Hansen
1985
Electrophysiological studies in the post-viral fatigue syndrome
J. Neurol. Neurosurg. Psych. 48: 691-694
Comment: The authors report important findings: Ca 75% of 40
patients with PVFS had single-fiber electromyograph abnormalities, i.e., evidence
of abnormality in the peripheral component of a motor unit. Such a result
suggests disturbed muscle-fiber conduction, i.e., the "high frequency
fatigue" discussed by Edwards et al. (95).
98: McCluskey, DR
1993
Pharmacological approaches to the therapy of chronic fatigue syndrome
In R Jenkins and JF Mowbray, eds. Chronic fatigue syndrome.
Ciba Foundation Symposium 173: 280-297. New York: J Wiley &
Sons
Comment: The work capacity of patients with PVFS was compared with
normal healthy subjects and a group of patients with irritable bowel syndrome,
using a modified Bruce stress test. Overall, PVFS patients had reduced aerobic
work capacity, higher heart rates, and higher whole-blood lactic acid levels.
Subjective observations were interesting: PVFS patients had a grossly abnormal
perception of their physical exertion and their premorbid level of physical
fitness.
99: Montague, TJ, TJ Marrie, GA Klassen, DJ Bewick, and BM Horàcek
1989
Cardiac function at rest and with exercise in the chronic fatigue syndrome
Chest 95: 779-784
Comment: The authors conclude from their studies that patients with
PVFS "have normal resting cardiac function but a markedly abbreviated
exercise capacity characterized by slow acceleration of heart rate and fatigue
exercising muscles long before peak heart rate is achieved." These are
important findings. However, examination of patient documentation (Table 1)
disclosed that, of the 40 patient test group, 13 had fatigue of less than
five months duration, thus contracting the valid test group to 27. Of these,
24 were between 20-57 years of age (mean=28). In this group, 15 were females
and nine were males. In the other age category, patients were 58, 59, and
70 years of age, respectively. The 70 year old patient was female. It was
not clear how such distributions affected results. Nonetheless, the authors
make the interesting suggestion that their data are compatible with latent
viral effects on cardiac pacemaker cells or their autonomic control, an observation
of clinical relevance.
100: Schiller, HH, MS Schwartz, and G Friman
1977
Disturbed neuromuscular transmission in viral infection
N. Engl. J. Med. 296: 884
Comment: The important findings summarized here are rarely cited in
the literature. Single-fiber electromyography (SFEMG) was used to investigate
causes of myalgia in type A influenza virus infection. Virus particles are
known to be detectable in motor endplate regions. In a study of 14 patients,
disturbances in neuromuscular transmission were found that appeared to be
related to the viral associated myalgia.
101: Wakefield, D and A Lloyd
1987
Pathophysiology of myalgic encephalitis
Lancet ii: 918-919