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Reasons to suspect viruses in CFS Komaroff’s Review article on HHV-6 & CFS
HHV-6 is an infection that can persist in the brain tissue long after the primary infection and after evidence of the virus has long disappeared from the plasma in the circulating blood. Therefore, direct evidence of chronic infection is not easily attainable by standard laboratory tests, even though it has long been suspected as playing a role in chronic fatigue syndrome (CFS), in conjunction with Epstein Barr Virus (EBV) the virus that causes mononucleosis. Ironically, one of the best tests for active infection may turn out to be not the new PCR tests, but rather the widely available and relatively inexpensive HHV-6 IgG antibody IFA test, using a high cutoff. While an HHV-6 IgG titer of say 1:640 might be perfectly normal for a 4 year old, or a teenager just over a bout of mononucleosis, it is not common in a 45 year old, and could be a sign of active infection. (IgM titers are rarely positive except after the primary infection. One study of CFS patients found that elevated antibody titers do correlate with active infection by culture. (See Testing for HHV-6) Ultimately, it may be impossible to find direct evidence of the virus, and the only way to prove if an association exists is to treat for virus to see if the patients get better. This is exactly what infectious disease specialist Jose Montoya, MD from Stanford University did with 12 patients he treated for long standing fatigue and elevated antibody titers to HHV-6 and EBV. He established a high cutoff and then treated these patients with a strong antiviral; an astounding 75% improved dramatically. Some of these patients had been sick for over 10 years. He is now planning a placebo-controlled trial.(See Stanford press release) Most physicians are reluctant to use a strong antiviral without certainty that the virus is active. Antibody levels can remain elevated for years after the primary infection and in some cases, merely indicate a healthy response to a past infection. Montoya reasoned, however that since 97% of us have had our primary infection with HHV-6 by the age of two, highly elevated antibody levels in an adult could mean active disease. His results so far suggest that his theory may be correct. Antibody levels to both HHV-6 and EBV dropped with treatment. (Montoya 2006). His initiative is invaluable because treatment results will provide clarity where diagnostic studies have failed to provide an answer. Efforts to establish an association between HHV-6 and CFS have been complicated by the fact that several studies have been published using tests that don’t differentiate between active and latent infection. These studies showed no association between HHV-6 and or CFS, contradicting the positive studies and creating confusion. When a measures were used that can detect active infection such as IgG “early antigen” antibodies (which are present only during active infection), there have been dramatic disease associations suggesting an important role for HHV-6 in these conditions. Only longitudinal studies using correct testing methodology will provide conclusive answers In all, there have been 27 published studies on the association of CFS and HHV-6.The results vary according to whether or not the study used an assay that could differentiate between active and latent virus:
Assays that can detect active vs. latent infection (albeit imperfectly) include: PCR DNA tests on serum or plasma, IgM early antigen IgG or IgM antibodies, primary cell culture and lymphocyte response. (Buchwald, 1992; Josephs, 1991; Zorzenon, 1996; Patnaik,1995; Wagner, 1996; Ablashi, 2000. Assays that cannot differentiate between active and latent infection include PCR DNA tests on whole blood and IgG antibody levels without a high theshold. Also viral isolation is too insensitive to be useful. (Secchiero, 1995; Reeves, 2000; Koelle, 2000). As Anthony Komaroff of Harvard points out, the number of patients in the studies that have found an association between CFS and active HHV-6 infection (717) is much larger than the number in studies that have failed to find an association (48). (Komaroff, 2006). When the most sensitive testing method was used, a test that measures antibodies to "early antigen" (EA) protein that is produced only during active infection, the evidence is strong for a role for HHV-6 in CFS:
CDC epidemiologist Dr. William Reeves conducted the study that did the most to dampen enthusiasm for research into the role of HHV-6 in CFS in 2000. He looked at latent virus in the cells by PCR and found no difference between 26 patients and 52 controls. This assay could not differentiate active virus in a patient from latent virus in a healthy control. Sadly, the CDC never did another study on HHV-6 in CFS with a more sophisticated approach. Now that there are new diagnostic methods (including quantitative PCR, messenger RNA and early antigen antigenemia assays) new studies are urgently required. The “early antigen” antibody test is not available commercially, but the HHV-6 Foundation has been working diligently for the past two years to try to get this assay into production. Nested PCR is available in one laboratory. (See Testing) Reasons to Suspect Viruses in CFS Viruses have long been suspected as a cause of Chronic Fatigue Syndrome or CFS, but research studies have been mixed, in part because we lack the tools to detect the virus once it has retreated away from the blood and into other tissues. The sudden onset of CFS in some patients with an “infectious-like” illness, the nature of some of the symptoms, and the state of chronic immune activation suggest that chronic fatiguing illnesses can be triggered and perpetuated by a virus. CFS symptoms have been described in a variety of acute infections (Leventhal , 1991; Rosen, 1982; Cluff, 1959; Salit, 1985.). Many investigators have reported enteroviral in CFS (Cunningham, 1990; Gow 1991, 1996; Bowles 1993; Clements 1995; Richardson, 1995; Richardson, 1995; Soteriou, 1996). Also, a number of studies have suggested that parvovirus can produce CFS (Kerr 2001, 2002; Matano, 2003). A recent observational study has confirmed the existence of a post-infectious fatigue syndrome that has been described often subsequent to acute mononucleosis. Hickie and colleagues identified all cases of acute infection with Epstein-Barr virus, Ross River virus, and Coxiella burnetii in one township in rural Australia (Hickie 2006). The study involved 253 patients and found that post-infectious fatigue syndrome was present in 12% of the patients six months after their acute infection. Several studies have shown that antiviral pathways are activated in CFS patients (Suhadolnik 1997, Gow 2001). Gene expression profiling has found an up-regulation of mitochondrial translation initiation factor EIF4G1, which is consistent with persistent viral infection (Kerr 2005). CFS has been associated with reduced NK cell activity (Siegel 2006), Klimas 1990) , reduced TH1 cell activity and activated TH2, findings consistent with long-term viral infections. (Patarca 2001) Viral infections reduce blood fatty acid levels, which are reduced in patients with CFS. If the body’s ability to synthesize essential fatty acids is impaired by chronic virus, cell membrane function could be affected which would explain many symptoms of CFS (Puri 2006). Finally, antiviral treatments (Ampligen, isoprinosine, beta interferon, valacyclvir, valganciclovir) have been found effective in small studies (Strayer, 1994, Newport Pharmaceuticals; Lerner 2001, Lerner 2006,; See, 1996; Montoya 2006).
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