This first of our CFS publications outlines the essential cardiac involvement of CFS.  We showed that 24 CFS consecutive patients had abnormal cardiac electrical conduction by 24-hr. ECG testing (Holter monitoring) compared to 106 non-fatigued control patients (p<0.03).  In 8 of the 24 patients, gross abnormal cardiac wall motion at exercise MUGA testing was seen.  Coronary artery disease was excluded by myocardial perfusion imaging in all CFS patients.

Continuing the CFS cardiac focus, 11 CFS patients were studied using the cardiac nuclear medicine MUGA test which measures muscle strength of the heart.  Abnormal cardiac wall motion at rest and stress, dilation of the left ventricle and segmental wall motion abnormalities were observed.  The cardiac abnormal dynamics worsen as CFS continues.

This is a controlled study of CFS cardiac involvement.  The prevalence of abnormal Holter monitoring in 67 CFS patients and 78 non-CFS patients matched for age, place and time and absence of other confounding medical diseases were compared.  Holter monitors in both CFS and control groups were read by two non-involved cardiologists without clinical knowledge about the patient or place in the study.  Dr. Lerner was not a reader of Holter monitors in this study.  The prevalence of T-wave abnormalities by Holter monitoring was greater in CFS than in non-CFS patients (p<0.01).  The presence of abnormal T-waves at Holter monitoring was “sensitive indicator of the presence of CFS.”  The “absence” of these abnormal T-waves made the diagnosis of CFS unlikely (statistical sensitivity 0.96).  Light and electron micrographic studies of right ventricular endomyocardial biopsies in these CFS patients showed cardiomyopathic changes.  We do not recommend further right ventricular cardiac biopsies in CFS patients since the hearts of CFS patients may be friable and may have an increased likelihood of post-biopsy bleeding. 

We originally hypothesize that CFS is a prolonged infectious mononucleosis syndrome in previously healthy (immunocompetent) persons.  We further speculate in this early study that prime candidates for the cause of CFS are two herpesviruses which cause infectious mononucleosis:  Epstein-Barr virus (EBV) and cytomegalovirus (HCMV).  We further suggest that studies seeking a single virus cause of CFS, even those studies searching for single virus EBV or single virus HCMV would conclude in a result of “no cause.”  Indeed, such negative studies have been done.  We suggest that (1997) there may be three causes of CFS: 1) single virus EBV CFS; 2) single virus HCMV CFS; and 3) EBV-HCMV co-infection CFS.  This hypothesis (1997) we now know is correct.

Dr. Lerner discusses the possible relationship between long-standing cardiomyopathy, heart muscle disease not associated with coronary artery disease, and CFS.  CFS is a cardiomyopathy of varying severity.

CFS patients in this study had significant IgG serum antibody titers to cytomegalovirus, but little to no evidence of EBV infection.  In this study 13 of 18 CFS patients were remarkably improved after 30 days of intravenous ganciclovir (p<0.05).  Single virus HCMV CFS in this pilot study was improved by antiviral treatment.  There were no side effects from this carefully monitored trial.  Results are similar using oral valganciclovir (valcyte). 

Twenty-five patients with CFS illness were treated for 6 months with pharmacokinetic doses of valacyclovir (valtrex) in a formulation to give continuous anti-EBVeffective blood levels throughout the day.  This is the first time such valacyclovir dosing was given.  The trial was approved by the U.S. FDA.  Patients were carefully monitored for safety by repeated appropriate blood tests.  There were no adverse side effects.  Sixteen patients with single virus EBV infection were benefited, but 9 clinically similar CFS patients with EBV-HCMB co-infection were not benefited.  Valacyclovir (valtrex) in the laboratory is effective versus EBV, but it is NOT effective (active) versus HCMV.  Therefore, the results strengthen the need for subset classification and appropriate subse-directed antiviral treatment for CFS illness.  This, to our knowledge, is the first successful report of valacyclovir treatment for EBV infection.  These results have now been repeated with similar benefit to CFS patients.

Eleven CFS patients with EBV-HCMV co-infections were treated according to their subset classification over an 18-month period with antiviral drug treatments.  All patients were monitored for safety every 4-6 weeks.  Valacyclovir for EBV infection and introvenous ganciclovir for HCMV infection were used.  There were no significant side effects in CFS patients.  All 11 CFS patients in this study significantly improved.

This is an enlightening study.  In many CFS patients in whom our work implies an EBV or HCMV single infection or EBV-HCMV co-infection cause for CFS illness, normal means for diagnosis by blood tests or virus isolation (including those using polymerase chain reactions) are negative.  In this study, we show a definitive new means of HCMV multiplication in HCMV subset of CFS patients.  The p52 and CM2 HCMV IgM antibodies were present in 16 CFS patients, and were not present in 77 control patients.  These data provide strong evidence for a virus etiology for CFS illness and provide strong evidence for antiviral treatment of CFS patients. 

We describe studies spanning over a decade which support the paradigm that CFS is a prolonged infectious mononucleosis due to Epstein-Barr virus, cytomegalovirus or the two viruses in co-infection.  This paradigm suggests that CFS patients’own immune defenses prevent complete virus formation, and that only parts of the virus’genetic material are expressed.  Cardiac involvement leads to rapid heart pumping at rest (tachycardia) and eventually cardiac muscle pump weakening.  Specific antiviral treatment has led to remarkable sustained improvement in CFS patients so that criteria for the diagnosis of CFS are no longer present.  Medical testing by Holter monitoring, MUGA, nuclear stress testing, cardiac biopsy, virus serologic tests and disappearance of symptoms of CFS support this paradigm.

A subset of CFS patients and specific diagnostic serum antibodies to cytomegalovirus HCMV) non-structural gene products p52 and CM2 (UL 44 and UL 57) indicate incomplete HCMV persistent multiplication.  The results suggest that specific antiviral HCMV treatment is beneficial.  A second Epstein-Barr Virus (EBV) distinct subset of CFS is defined.  Fifty-eight CFS patients and 68 non-CFS matched controls were studied.  Serum antibodies to EBV viral capsid antigen (VCA IgM and EBV Early Viral Antigen, diffuse (EA, D) as well as HCMV (V), IgM and IgG; VP (sucrose density purified V); p52 and CM2, IgM serum antibodies were assayed.  Serum EBV VCA IgM positive antibody titers were identified in 33 CFS patients (Group A subset EBV VCA IgM, 62.3,
neg < 20).  EBV VCA IgM titers remained positive in CFS patients for 24-42 months. 

This is a prospective consecutive case control study from 1987-1999 of cardiac dynamics measured by radionuclide, ventriculography in 98 CFS patients.  Controls were 191 patients with various malignancies who were evaluated in protocols requiring radionuclide ventriculography before initiation of cardiotoxic chemotherapeutic agents.  The prevalence of abnormal cardiac wall motion (ACWM) in CFS patients was 10 of 87 (11.5%).  With stress exercise, 21 CFS patients (24.1%) demonstrated ACWM.  Cardiac biopsies in 3 CFS patients with ACWM showed a cardiomyopathy.  ACWM in the controls at rest was present in 4 of 191 patients (2%) (p=0.0018).  A progressive cardiomyopathy associated with EBV and/or HCMV multiplication is present in CFS patients.

AIMS: The purpose of this study is to demonstrate that the use of recombinant early antigens for detection of antibodies to cytomegalovirus (HCMV) gene products CM2 (UL44, UL57) and p52 (UL44) is specific in the diagnosis and differentiation of active HCMV infection in a subset of patients with chronic fatigue syndrome (CFS) which is often missed by the current ELISA assay that uses crude viral lysate antigen. METHODS: At a single clinic from 1999 - 2001 a total of 4,774 serologic tests were performed in 1135 CFS patients using two immunoassays; Copalis immunoassay and ELISA immunoassay. The Copalis immunoassay utilized HCMV Early gene products of UL44 and UL57 recombinant antigens for detection of HCMV IgM antibody, and viral capsid antigen for detection of HCMV IgG antibody. The ELISA immunoassay utilized viral crude lysate as antigen for detection of both HCMV IgG and IgM. RESULTS: Of the total, 1135 CFS patients, 517 patients (45.6%) were positive for HCMV IgG by both HCMV IgG by both assays. Of these, twelve CFS patients (2.2%) were positive for HCMV(V) IgM serum antibody by HCMV ELISA assay, and 61 CFS patients (11.8%) were positive for IgM HCMV serum antibody by Copalis assays. The Copalis assay that uses HCMV early recombinant gene products CM2 (UL44, UL57) and p52 (UL44) in comparison with ELISA was 98% specific. CONCLUSIONS: Immunoassays that use Early Antigen recombinant HCMV CM2 and p52 are five times more sensitive than HCMV ELISA assay using viral lysate and are specific in the detection and differentiation of active HCMV infection in a subset of CFS patients.

BACKGROUND: We hypothesized that subset classification of Epstein-Barr virus (EBV) in chronic fatigue syndrome (CFS) is required. At first, a blinded-random placebo-controlled trial of valacyclovir in EBV CFS subset was performed (Group 1), and this EBV subset was followed for thirty-six months (Group 2). Patients were given valacyclovir at 14.3 mg/kg every 6 hours. The validated Energy Index (EI) point score assessing physical functional capacity, Holter monitor, multigated (radionuclide) MUGA rest/stress ventriculographic examination, EBV serum IgM viral capsid antibodies (VCA), and EBV early antigen diffuse (EA) were followed. After six-months, Group 1 CFS patients receiving valacyclovir experienced an increased mean least square EI point score +1.12 units (122 kcal/day), while the placebo cohort increased +0.42 EI units (65 kcal/day). EI point scores at Group 2 increased progressively. Sinus tachycardias decreased and abnormal cardiac wall motion improved. Serum antibody titers to EBV VCA IgM decreased. Patients resumed normal activities.