regarding ME and CFS as well as implicated pathogens. This is but, one
page and resource. A tip of the hat to XMRV Global Action.
Herpes Viruses - Experts and Research
Stanford School of Medicine/Infectious Diseases/Chronic Fatigue
A. Martin Lerner, MD
president of the Treatment Center for CFS
Lerner is an internist and infectious disease specialist. Before
beginning his practice, Lerner had background in Infectious Diseases,
particularly viral diseases, and was aware of virus-induced heart
disease. Soon after beginning his practice in 1982, Lerner noticed
that the symptoms of CFS resembled a prolonged infectious
mononucleosis. Infectious mononucleosis may be caused by one of three
herpes viruses: the Epstein-Barr virus (EBV), Human Herpesvirus 6
(HHV-6) or the Human Cytomegalovirus (HCMV). These three
mononucleosis syndromes are self-limited; that is, patients recover.
Lerner began to question… Could the Chronic Fatigue Syndrome be a
prolonged mononucleosis syndrome? Everyone with heart conditions is
fatigued. Could the Chronic Fatigue Syndrome also involve the heart?
He began to look at patients with CFS for evidence of involvement of
the heart, and the three mononucleosis viruses (EBV, HHV-6, and HCMV).
The findings have been remarkable.
Abnormal Holter Monitoring
Holter monitoring records electrical activity in the heart, producing
an electrocardiogram. The T-wave of the electrocardiogram shows the
repolarization (electrical recovery) of the left ventricle after every
heartbeat in preparation for the next heartbeat. The normal T-wave is
upright. With increased heart rates and exercise, abnormal T-waves
Abnormal T-wave flattening and inversions are found in patients who
meet the US Center for Disease Control's diagnostic criteria for CFS.
This finding has been tested statistically, and at least 90% of
patients with CFS have abnormal electrocardiograms. This abnormal
electrical activity in the heart is thus a biomarker for CFS. If a
fatigued patient lacks abnormal T waves, CFS is less likely to be the
cause of the patient's fatigue.1, 2, 3
Abnormal Contraction of the Heart
Patients with CFS who have been ill for months may have abnormal
cardiac dynamics. This means that the rhythmic, symmetrical,
harmonious closure of the left ventricle is asymmetric. This
indicates that there is some weakening of the left ventricular muscle.
(Patients with coronary artery disease may also have abnormal left
ventricular dynamics.) Of patients who have had CFS for one year or
more, approximately one in four has abnormal asymmetric cardiac
dynamics. Fortunately, treatment with anti-viral medication can
reverse this heart muscle weakness. 4,5,6,7
Heart Biopsies Show Cardiomyopathy
Biopsies of the heart from CFS patients indicate a cardiomyopathy.3
Active Epstein-Barr virus (EBV), active cytomegalovirus (HCMV), active
Human Herpesvirus 6 (HHV-6), or a combination of these viruses is a
common finding in patients with CFS. In 1997, Lerner hypothesized CFS
is caused by 3 herpesviruses: EBV, HCMV and/or HHV-6. These three
viruses establish "latent" infection in B-lymphocytes,
monocyte-macrophage precursors, or T-lymphocytes respectively. Virus
reactivation, and both abortive (40-90 gene products) and complete
(200 gene products) virus multiplication occur. Therefore CFS
patients have been described as having continuing primary (initial
onset) or reactivated (reactivation of a previous virus)
Lerner has been fortunate to attract a very talented group of
physicians interested in studying CFS with him. Full list of
Jose G. Montoya, MD,
associate professor of medicine in the Division of Infectious Diseases
Montoya is associate professor of medicine in the division of
infectious diseases at Stanford University Medical Center. His
expertise is in infections of immunocompromised hosts and in the
laboratory diagnosis of toxoplasmosis.
His expertise in these two areas led him to postulate that CFS
patients with elevated titers against HHV-6 and EBV may be amenable to
long-term (e.g. ≥ 6 months) antiviral therapy. He proposes that the
humoral immune response to intracellular pathogens that persist for
the life of the host should be "low" and at a "steady" state as
suggested by Amanna et al.11
Thus, elevated titers for EBV and HHV-6 (e.g. EBV early antigen (EA) ≥
160 and/or HHV-6 ≥ 320) in CFS patients suggests the possibility that
these viruses have been reactivated and could be behind the complex
and unexplained symptoms observed in these patients.
He also postulated that in order to "control" this state of high viral
activation that the use of broad spectrum antivirals for a long period
of time would be necessary despite that previous reports had suggested
that antiviral therapy had not been successful. In the 1980's Straus
et al. reported that five weeks of acyclovir (1 week intravenously
plus 4 weeks orally) had no clinical benefit to CFS patients infected
However, Montoya began treating CFS patients with elevated titers
against EBV and HHV-6 and noted that approximately 60 to 70% of the
patients had a significant clinical response. For these patients he
has primarily used valganciclovir for 6 or more months. The results
of a randomized, double blind, placebo controlled trial are being
analyzed at this time and a final manuscript to be submitted for
publication is expected shortly.
Other subgroups of CFS patients have been identified and treated by
Montoya and the Stanford CFS team. CFS patients in whom elevated
antibody titers against Herpes Simplex Virus-1, Herpes Simplex
Virus-2, Q fever, Mycoplasma pneumonia, Chlamydia pneumoniae, and
Varicella Zoster Virus or any combination of those, have been
identified and treated accordingly appear to have significantly
However, it is important to emphasize that in some patients, antibody
titers against all the proposed pathogens have been found to be
negative or low. Many of these patients, as well as approximately 30
to 40% of the patients with elevated titers, have not responded to
long-term antimicrobial therapy.
Another subgroup of CFS patients that has been identified at Stanford
is that of patients with very high (≥ 106) PCR copy numbers for HHV-6.
Several of these patients have been found to have HHV-6 integrated
into their chromosome, which is considered an extremely rare
occurrence among herpes viruses. These patients also have responded
clinically to antiviral therapy but they have required higher does and
PLEASE READ THIS IMPORTANT DISCLAIMER REGARDING THIS PORTION OF THE WEBSITE:
The information and opinions contained in this portion of the website
are intended for educational and research purposes only. It is not
intended for the medical management of patients and does not
necessarily reflect the views of Stanford University or Stanford
Hospital and Clinics.
Only a physician familiar with a patient's individual medical history
can make medical judgments and give that patient specific medical
1 Lerner AM, Lawrie C, Dworkin HJ. Repetitively negative changing
T-waves at 24-h electrocardiographic monitors in patients with the
chronic fatigue syndrome (left ventricular dysfunction in a cohort).
Chest. 1993; 104:1417-1421.
2 Lerner AM, Goldstein J, Chang CH et al. Cardiac involvement in
patients with chronic fatigue syndrome as documented with Holter and
biopsy data in Birmingham, MI 1991-1993. Infectious Diseases in
Clinical Practice 1997;6:327-33.
3 Lerner AM, Zervos M, Dworkin JH, Chang CH, O'Neill W. A unified
theory of the cause of chronic fatigue syndrome. Infectious Diseases
Clinical Practice 1997; 6:239-243.
4 Dworkin HJ, Lawrie C, Bohdiewicz P and Lerner AM Abnormal left
ventricular myocardial dynamics in eleven patients with the chronic
fatigue syndrome. Clinical Nuclear Medicine 1994;19:675-677.
5 Lerner AM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald JT, Beqaj S,
Deeter RG, Goldstein J., Gottipolu P and O'Neill W. Prevalence of
abnormal cardiac wall motion in the cardiomyopathy associated with
incomplete multiplication of Epstein-Barr Virus and/or cytomegalovirus
in patients with chronic fatigue syndrome. In Vivo. 2004;18:417-424.
6 Lerner AM, Beqaj SH and Deeter RG et al. A six-month trial of
valacyclovir in the Epstein-Barr virus subset of chronic fatigue
syndrome: improvement in left ventrical function. Drugs of Today.
7 Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir
treatment in Epstein-Barr virus subset chronic fatigue syndrome:
thirty-six months follow-up. In Vivo. 2007 Sep-Oct;21(5):707-13.
8 Lerner AM, Beqaj SH, Deeter RG and Fitzgerald JT. IgM serum
antibodies to human cytomegalovirus nonstructural gene products p52
and CM2 (UL44 and UL57) are uniquely present in a subset of patients
with chronic fatigue syndrome. In Vivo. 2002;16:153-160.
9 Lerner AM, Beqaj S, Deeter RG, and Fitzgerald JT. IgM serum
antibodies to Epstein-Barr Virus are uniquely present in a subset of
patients with the chronic fatigue syndrome. In Vivo.2004;18:101-106.
10 S H Beqaj, A M Lerner, J T Fitzgerald Immunoassay with
cytomegalovirus early antigens from gene products p52 and CM2 (UL44
and UL57) detects active infection in patients with chronic fatigue
syndromeJ Clin Pathol 2008;61:623-626.
11 Amanna IJ, Carlson NE, Slifka MK. Duration of humoral immunity to
common viral and vaccine antigens. N Engl J Med 2007 Nov
12 Straus SE et al. "Acyclovir treatment of the chronic fatigue
syndrome. Lack of efficacy in a placebo-controlled trial." N Engl J
Med. 1988 Dec 29;319(26):1692-8.