ME/CFS in the Department of Medicine

Herpes Viruses

Featured Experts

A Martin Lerner, MD

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 occur.

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

Viruses

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) infections.3,8,9,10

Collaborators

Lerner has been fortunate to attract a very talented group of physicians interested in studying CFS with him. Full list of collaborators

Jose Montoya, MD

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 with EBV.12

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 improved.

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 longer courses.

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 advice.


CITATIONS:

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. 2002; 38:549-561.

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 8;357(19):1903-15

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.

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