Cell Associated Therapy for Chronic Fatigue Syndrome: Is this the Next Frontier? Paul R. Cheney MD, PhD BACKGROUND: Chronic Fatigue Syndrome (CFS) is a disorder of unknown cause characterized by significant functional disability associated with fatigue, pain and neuropsychological complaints. For over twenty years since the first clear clinical presentation of CFS in the United States by Straus(1) and Jones(2) and the first epidemic of CFS was reported in Lake Tahoe(3), the therapeutic domain for CFS has been dominated by pharmaceutical, nutriceutical, herbaceutical, or alternative medical interventions. After these twenty-plus years, there is no consensus on what optimal therapy looks like and many reasons to believe that this situation will continue as it has for years to come. With the advent of stem cell therapy in chronic illness, we are entering a new era in medicine where the old therapeutic ideas are being challenged if not rejected, in favor of newer ideas about therapies that are more appropriate for the treatment of complex chronic illness. Low molecular weight, cell signaling peptides or factors (CSF's) from human bone cell cultures have been used as implants to successfully heal non-union bone fractures at UCLA as far back as 1982(4). More recently, implanted human fetal brain tissue(5) as well as cultured human stem cell transplants(6) have been used to successfully (at least initially) treat younger (though interestingly not older) patients with Parkinson's disease. Other studies have shown that donor embryonic cells need not be human to work(7). It has additionally been shown that injected low molecular weight cell signaling factors alone can induce functional recovery from Parkinson's-like syndromes induced by drugs in monkeys(8). Finally, human bone marrow derived CSF therapy via intra-coronary IV infusion for acute myocardial infarction was shown to produce a significant improvement (67%) in myocardial left ventricular performance as compared to untreated patients who only had a marginal improvement (7%) over a six month time period(9). In Europe, cell associated therapies known as "live cell" products have been used as injections for over seventy years in health spas as rejuvenation therapy and by physicians for the treatment of chronic disease(10). Pope Pius XII received live cell injections on his deathbed by the leading Swiss proponent at that time, Dr. Paul Niehans, and lived another four years(11). There is over a half century long history of their safe use in humans. In the U.S., this type of therapy was first legitimized in 1981 with the publication of a 59% remission rate of an immunosuppressive disease of childhood in the New England Journal of Medicine using intramuscular injections of thymus extract from 5-day-old calves(12). In the case of CFS, the first successful use of CSF's was reported by Steinbach in 1994 with the use of an injected low molecular weight extract of porcine Liver (KutapressinÒ )(13). We completed a six month pilot study of nine patients in 2000 using oral, frozen extracts from porcine sourced, multiple organ extracts with mixed though promising results. This present study explores further the potential for cell associated therapy using low molecular weight peptides derived from mammalian tissue extracts in CFS. METHODS: Eighteen patients from a national referral practice, meeting the 1994 case definition for CFS, were enrolled in a prospective, one year therapeutic protocol using porcine cell signaling factors derived from heart and liver tissue homogenates. In the 18 patient study cohort, the average age was 42.6 (range 15-63) with 10 females (55.5%) and 8 males (44.4%). The average length of illness was 15 years (3-21 range). At the start of the study, the average Karnofsky Performance Scale (KPS) score was 60 (40-70) and only two patients were employed (part-time) out of 18. The rest were disabled. The study length was one year consisting of two parts, each six months long. The primary endpoint was KPS as determined by physician interview at study conclusion. Primary studies with pre- and post-interrogations included echocardiography, both with and without oxygen, impedance cardiography, urine organic acid analysis and 24-hour hormone analysis. Secondary testing included a set of routine blood test panels. In the initial six month trial period, the primary therapy was a transdermal, porcine liver extract applied to the skin along with low dose hGH at 0.2 mg SQ per week. This therapy had previously been used in our pilot study of 2000 except that a different porcine liver extract was given as an oral frozen extract. For the final six months, the patients received an oral, frozen porcine extract consisting of 50% porcine adolescent heart extract and 50% porcine mesenchymal or fetal extract. Patients were evaluated at six months for KPS and echocardiography and impedance cardiography as well as at study endpoint. As support therapy, a standard group of therapies, mostly anti-oxidant nutriceuticals and pharmaceuticals for sleep, used by this clinic for ten years or more was also part of the study protocol but was not a significant shift from the patients' normal therapeutic routine, pre-study. All the patients had been on most of these therapies for a year or more pre-therapy and therefore represented a baseline therapy. Additional therapies were allowed on a case-by-case basis for symptom management but patients were asked to limit the addition of any new therapies during the study period. RESULTS: Sixteen of eighteen patients completed the study. Two patients failed to complete the study due to intolerances and are not part of the final analysis but remain on parts of the protocol due to some favorable aspects of the therapy for them. Both these patients had a strong history of environmental illness and previous intolerances to many other agents. There were no severe reactions reported. Through the first six months of therapy, there was no significant improvement in functional measures (KPS) but some notable changes were seen in both echocardiography (drop in IVRT, p < 0.00006) and in impedance cardiography (rise in stroke volume, p < 0.00004). However, during the next six months, notable improvement was reported by some patients attributable, by most participants, to the heart/mesenchyme porcine extract. Final endpoint KPS scores, compared to pre-study KPS scores, showed a significant improvement of an average of 10 KPS points (p < 0.006). Furthermore, almost all the improvement was reported in the oxygen tolerant subgroup compared to the non-responders who were mostly oxygen toxic. Because the discovery of near universal oxygen toxicity in CFS came after the start of the study, we were only able to establish in two patients, who were late getting started, that they converted from oxygen toxic to oxygen responsive while on therapy and both were responders. CONCLUSION: Therapy with low molecular weight peptides from cell associated, mammalian tissue homogenates appear to offer a significant benefit in CFS, especially where it counts the most, namely function. A 10-point rise in KPS score will change lives and the response over baseline function was shown to be highly significant (p < 0.0005). The use of several tissue extracts as opposed to only one appears to be more effective though this cannot be known with certainty from this study. Both tissue extracts (liver and heart/mesenchyme) appeared to be bioactive but especially the heart. Intolerance was observed in 2 of 18 or 11% and was observed in the most environmentally challenged (EI) of the 18 who were treated. Both patients had a history of intolerance to other therapies and the subsequent finding of porcine liver toxicity in a subsequent study, especially in EI patients, may help explain their failure to respond well and their intolerance to this protocol. It is likely, therefore, that future, mixed CSF protocols based on this and other studies will have even better outcomes, including EI patients. ***************************************************** 1. 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