ArticleCauses and Treatment of CFS and Fibro (long)

Discussion in 'Fibromyalgia Main Forum' started by mrstyedawg, Jun 21, 2006.

  1. mrstyedawg

    mrstyedawg Member

    Diagnosis and Integrative Treatment of Intracellular Bacterial Infections in Chronic Fatigue and Fibromyalgia Syndromes, Gulf War Illness, Rheumatoid Arthritis and other Chronic Illnesses



    Garth L. Nicolson,* PhD, Marwan Y. Nasralla,*+ PhD, A. Robert Franco, MD, Nancy L. Nicolson,* PhD, Robert Erwin,* MD, Richard Ngwenya, MD, and Paul A. Berns,* MD



    *The Institute for Molecular Medicine, Huntington Beach, CA 92649 USA,
    +International Molecular Diagnostics, Inc., Huntington Beach, CA 92649 USA
    Arthritis Center of Riverside, Riverside, CA 92501 USA,
    James Mobb Immune Enhancement, Harare, Zimbabwe



    Address correspondence to: Prof. Garth L. Nicolson, The Institute for Molecular Medicine, 15162 Triton Lane, Huntington Beach, CA 92649. Tel: 714-903-2901; Fax: 714-379-2082; Website: www.immed.org; Email: gnicolson@immed.org.



    ABSTRACT
    Bacterial and viral infections are associated with many chronic illnesses as causative agents, cofactors or more likely as opportunistic infections in immune suppressed individuals. The prevalence of invasive pathogenic Mycoplasma species infections (and possibly other bacterial infections, such as Chlamydia, Borrelia, etc.) in patients with Chronic Fatigue Syndrome, Fibromyalgia Syndrome, Gulf War Illness, Rheumatoid Arthritis and other chronic illnesses was significantly higher than in healthy controls. When we examined chronic illness patients for multiple Mycoplasma species infections, we found that almost all patients had multiple intracellular infections, suggesting that multiple bacterial infections commonly occur in certain chronic illness patients. These patients generally respond to particular antibiotics if administered long-term, but an important part of their recovery involves nutritional supplementation with appropriate vitamins, minerals, immune enhancement and other supplements. Nutraceuticals appear to be necessary for recovery and maintenance of a strong immune system. In addition, patients should be removed from potentially immune-depressing drugs, such as some antidepressants, to allow recovery of their immune systems. Other chronic infections (viral), may also be involved in various chronic fatigue illnesses with or without mycoplasmal and other bacterial infections, and these multiple infections could be important in causing patient morbidity and resulting difficulties in treating these illnesses.





    INTRODUCTION



    Most if not all debilitating chronic illnesses are characterized by the presence of chronic fatigue (1), the most commonly reported medical complaint of all patients seeking medical care (2). The fatigue syndromes, such as Chronic Fatigue Syndrome (CFS or Myalgic Encephalomyelitis [ME]), Fibromyalgia Syndrome (FMS) and Gulf War Illnesses (GWI), share many complex, multi-organ signs and symptoms (3-6), including immune system abnormalities (7), but are distinguishable as separate syndromes that have muscle and overall fatigue as major signs. These syndromes usually have overlapping signs and symptoms, including muscle pain, chronic fatigue, headaches, memory loss, nausea, gastrointestinal problems, joint pain, vision problems, breathing problems, depression, low grade fevers, skin disorders, tissue swelling, chemical sensitivities, among others (5, 6, 8). Because of the complex nature of these illnesses, many patients are often diagnosed with multiple syndromes, and their potential to recover from their chronic illness is usually poor at best.

    Chronic illness patients usually have cognitive problems, such as short-term memory loss, depression, difficulty concentrating and psychological problems that can result in practitioners diagnosing chronic illness patients with somatoform disorders rather than organic problems (6, 8). Thus due to the lack of definitive laboratory or clinical tests that could identify the cause(s) of chronic illnesses, such disorders are thought to be caused for the most part by psychological stressors. In fact, emotional stress is often an important factor in somatoform disorders, and stress itself can have many effects on the hormonal and immune systems that could be detrimental in virtually any chronic illness (9). But we feel strongly that stress alone is unlikely to cause most of the chronic illnesses discussed here, the most classic being GWI (6, 8), where battlefield stress was promoted as the cause of the illness (10). GWI patients are often diagnosed with Post Traumatic Stress Disorder (PTSD), but the evidence that stress or PTSD is the source of GWI is based on the assumption that veterans must have suffered from stress by virtue of the stressful environment in which they found themselves during the Gulf War (10). The notion that stress is the major factor in GWI or indeed in other chronic illnesses, we feel, is not supported by most evidence that suggests that these illnesses were caused by toxic exposures (10, 11).

    There is growing awareness that the chronic fatigue illnesses, such as CFS/ME, FMS, GWI and certain autoimmune illnesses, such as Rheumatoid Arthritis (RA), among others, can have an infectious nature that is either responsible (causative) for the illness, a cofactor for the illness (required but not the only causative factor) or more likely appears as an opportunistic infection(s) responsible for aggravating or causing patient morbidity (8, 11, 12). There are several reasons for this notion, including the nonrandom or clustered appearance of the illnesses, often in immediate family members, the course and signs/symptoms of the illnesses and their responses to therapies based on treatments directed at infectious agents and enhancement of immune responses. Most chronic fatigue illnesses are difficult to treat and do not have effective therapies, and these patients rarely recover from their illnesses (11), causing in some cases catastrophic economic problems. Here we will discuss methods for diagnosing chronic infections in patients with CFS/ME, FMS, GWI, RA and other chronic illnesses and offer some suggestions for appropriate treatments directed at some of the chronic infections that play important roles in these illnesses.

    SIMILAR SIGNS AND SYMPTOMS OF CHRONIC ILLNESSES



    Most chronic illnesses have complex but relatively nonspecific signs and symptoms that are not characteristic for a particular disease. However, other chronic illnesses, such as RA, are well established in their diagnostic profiles (13, 14). One difference between some of the most common chronic illnesses appears to be in the severity of particular signs and symptoms. For example, in CFS/ME essentially all patients complain of chronic fatigue and joint pain, stiffness and soreness, whereas in FMS essentially all patients complain of muscle and overall pain, soreness and weakness. But when secondary signs and symptoms of these chronic illnesses are compared, they look very similar (6, 8). For the most part, the signs/symptom profiles of CFS/ME, FMS, GWI illnesses are similar (Fig. 1). Thus the chronic illnesses under discussion here have overlapping signs and symptoms, suggesting that these illnesses may be related (8). In addition, CFS/ME, FMS and GWI patients often show increased sensitivities to various environmental irritants and chemicals and enhanced allergic responses, suggesting that their immune systems are, at least in part, dysfunctional. This is supported by laboratory studies on the natural immune and other immunological abnormalities in chronic illness patients (7).

    The overlapping signs and symptoms of many chronic illness patients are easily documented. For example, the patient signs/symptoms data presented in Figure 1 were obtained using patient Illness Survey Forms to determine common signs and symptoms at the time when blood was drawn from patients for analysis. In this figure the intensity of approximately 120 patient signs and symptoms prior to and after onset of illness were recorded on a 10-point rank scale (0-10, extreme). The data were then arranged into 29 different signs and symptoms groups and were considered positive if the average value after onset of illness was two or more points higher than prior to the onset of illness. The CFS/ME and FMS patients had complex signs and symptoms that were similar to those reported for GWI, and the presence of rheumatic signs and symptoms in each of these disorders indicates that there are also some similarities to RA (13-15) (Fig. 1). Some differences were noted, however, when patients with chronic illnesses without evidence of intracellular bacterial infections were compared to the above groups (Fig. 1). The data suggest that patients with intracellular bacterial infections have more complex clinical signs/symptoms.

    In our signs/symptom analyses it was not unusual to find immediate family members who displayed similar chronic signs and symptoms. For example, we found that the spouses and children of GWI patients often slowly developed chronic illnesses with signs and symptoms similar to GWI, but only some time after the return home of veterans who developed GWI (8, 10, 11). That these civilian patients contracted their illnesses from chronically ill family members with GWI was a likely explanation (8) that was supported by the finding of similar chronic infections in these families (8, 11).



    CHRONIC INFECTIONS AND MORBIDITY IN CFS/ME, FMS AND GWI



    Although chronic illnesses have been known in the medical literature for years, most patients with CFS/ME, FMS, GWI and in some cases RA have had few treatment options. This is probably due to the fact that the underlying causes of most chronic illnesses are unknown and treatments have been mainly palliative or supportive. Even if the causes or triggering events in chronic illnesses are not understood, these illnesses may show similarities in their progression; that is, they could have different initial causes or triggers but similar secondary events that result in progression (8, 11). We have proposed that the secondary event(s) could be opportunistic viral and/or bacterial infections that cause significant morbidity and illness progression (10-12). With time these secondary events may evolve or progress to be important or even dominant factor(s) in determining overall signs/symptoms and treatment strategies.

    Since indirect evidence suggests the infectious nature in at least certain subsets of chronic illness patients (8, 11, 12), we have been examining chronic illness patients for pathogens that could explain, at least in part, their complex signs and symptoms. One type of infection that could fulfill the criteria of association with a wide range of chronic illness signs and symptoms are certain microorganisms of the class Mollicutes (8, 11, 12). This is a class of small bacteria, lacking cell walls and genetics for lipid and other macromolecule synthesis pathways. It is primarily composed of Mycoplasmas, and although most species are nonpathogenic, some pathogenic Mycoplasma species are capable of invading several types of human cells and tissues and are associated with a wide variety of human diseases (11, 15-19).

    Are pathogenic Mycoplasma species and other intracellular bacteria (Chlamydia, Borrelia, etc.) associated with chronic illnesses such as CFS/ME, FMS, GWI and RA? We (6, 8, 11, 15, 17-19, 24) and others (20-23) have examined chronic illness patients for the presence of mycoplasmal blood infections and have found a strong association with the presence of chronic illnesses. In our studies the clinical diagnosis of these disorders was obtained from referring physicians according to the patients’ major signs and symptoms. Blood was collected, shipped over night at 4°C and processed immediately for Nucleoprotein Gene Tracking (NPGT) after isolation of blood leukocyte nuclei (17, 18) or Polymerase Chain Reaction (PCR) after purification of blood leukocyte DNA using a Chelex procedure (6, 8, 15, 19). These procedures are very sensitive and specific and can detect down to a few copies of intracellular bacteria in a blood sample. The sensitivity and specificity of the methods were determined by examining serial dilutions of purified DNA of M. fermentans, M. pneumoniae, M. penetrans and M. hominis in blood samples. Amounts as low as 1-10 fg of purified microorganism DNA were routinely detectable. Using PCR the amplification with the appropriate primers produced the expected fragment size in all tested species, which was confirmed by hybridization with an inner probe or DNA sequencing to confirm the sequence of the PCR product.

    We used the NPGT and the PCR procedures to examine chronic illness patients for Mycoplasma species and Chlamydia species infections. For example, using NPGT to analyze the blood leukocytes of GWI patients we found that 91/200 (~45%) were positive for mycoplasmal infections. In contrast, in nondeployed, healthy adults the incidence of mycoplasmal infections was 4/62 (~6%) (17, 18). Similarly, others have more recently used PCR to examine GWI patients and found that 55% were positive for Mycoplasma species and 36% were found to have M. fermentans infections (23). The slight difference in percentage of positive patients is probably due to the differences in sensitivities of these two methods. Using PCR procedures 52-63% of CFS/ME and FMS patients (n~1,000) had mycoplasmal infections (6, 19-24), whereas only 6-15% of controls (n~450) tested positive.

    An important observation was that patients with chronic illnesses that test positive for mycoplasmal infections usually have multiple infections. When we examined mycoplasma-positive CFS/ME and FMS patients (~60% of such patients are usually mycoplasma-positive) for the presence of M. fermentans, M. pneumoniae, M. penetrans, M. hominis infections, multiple infections were found in the majority of approximately 100 patients (19). CFS/ME/FMS patients had two (>30%) or three (>20%) species of mycoplasmal infections, but only when one of the species was M. fermentans or M. pneumoniae (19). We also found higher score values for increases in the severity of signs and symptoms after onset of illness in CFS/ME/FMS patients with multiple infections. Also, CFS/FMS patients with multiple mycoplasmal infections generally had a longer history of illness, suggesting that patients may have contracted additional infections during their illness (19). Most of these patients also show evidence of various viral and Chlamydia species infections. Thus it is likely that most CFS/ME and FMS patients have multiple bacterial and viral infections.

    CONVENTIONAL TREATMENT OF CHRONIC BACTERIAL INFECTIONS



    Once chronic intracellular bacterial infections, such as Mycoplasma species infections, have been identified in the blood of subsets of CFS/ME, FMS, GWI, RA and other chronic illness patients, they can be treated using conventional and alternative approaches. Appropriate treatment with antibiotics should result in patient improvement and even recovery, and this has been found in most but not all chronic illness patients (8, 11, 17, 18, 52-54) (Table 1). The recovery is usually slow and gradual after an initial period of Herxheimer and other adverse reactions that make patients temporarily more symptomatic. This period can last for several weeks. The recommended treatments for mycoplasmal blood infections are usually long-term antibiotic therapy, usually multiple 6-week cycles of doxycycline (200-300 mg/day), ciprofloxacin (1,500 mg/day), azithromycin (250-500 mg/day) or clarithromycin (750-1,000 mg/day), among others (53). Multiple 6-week cycles are required, because few patients recover after only a few cycles of antibiotics. This is probably due to the intracellular locations of mycoplasmas like M. fermentans and M. penetrans or other bacteria, such as Chlamydia species, the slow-growing nature of these infections, their inherent insensitivity to most antibiotics and the persistence of the infections in metabolically inactive forms. For most patients, treatment must be continuous for at least 6 months, followed by additional 6-week cycles of antibiotics, if necessary. Some treat these infections by administration of antibiotics every other day, and some recommend daily dosing. Due to poor gastrointestinal absorption in certain patients or the acuteness of signs and symptoms, intravenous therapy has been used for a few weeks, followed by oral antibiotics. Most patients cannot tolerate intravenous antibiotics for more than a few weeks or complications can then occur, so follow-on therapy with oral antibiotics is necessary.

    Can antibiotic therapy be successful in treating intracellular bacterial infections often found in chronic illness patients? Yes, but antibiotics should not be used solely or exclusively to treat intracellular bacterial infections. They have proven successful for many if not most patients; however, many patients eventually fail on antibiotic therapy alone. For example, of 87 GWI patients that tested positive for mycoplasmal infections, all patients relapsed after the first 6-week cycle of antibiotic therapy, but after up to 6 cycles of therapy 69/87 previously mycoplasma-positive patients recovered and returned to active duty (17, 18). Since few patients recovered within 6 months of antibiotic therapy, as discussed above, this is now the minimal recommendation of antibiotic treatment (54). These were relatively young patients (most <25 years of age) that were healthy before their illness, and this could have played a role in their higher response rates compared to civilians with chronic illnesses which tend to be on the average older and not as healthy. The clinical responses that were seen in patients were not due to placebo effects, because administration of some antibiotics, such as penicillins, resulted in patients becoming more not less symptomatic, and they were not due to immunosuppressive effects that can occur with some of the recommended antibiotics. Interestingly, CFS/ME, FMS and GWI patients that slowly recovered after several cycles of antibiotics were generally less environmentally sensitive, suggesting that their immune systems were slowly returning to pre-illness states. If such patients had illnesses that were caused by psychological or psychiatric problems or solely by chemical or viral exposures, they should not have responded to the recommended antibiotics and slowly recovered. In addition, if such treatments were just reducing autoimmune responses, then patients should have immediately relapsed after the treatments were discontinued and they should not have responded to antibiotics that do not suppress immune systems.

    Although the majority of GWI patients in these unblinded, initial studies responded to antibiotic therapy, the studies have been justifiably criticized for not being controlled, blinded clinical trials. In the case of GWI, large double-blinded, placebo-controlled studies have recently been initiated using doxycycline. In the case of RA, however, double-blinded, placebo-controlled antibiotic trials using minocycline have been successfully conducted. These trials show that the treatment of RA patients with minocycline is clinically effective and results in recovery of approximately one-half of an unselected group (not tested for chronic infections) of patients (Table 1) (35, 55). The reason for the incomplete responses among RA patients was probably due to the fact that only a portion of the patients under study probably had intracellular bacterial pathogens as their main clinical problem. Viruses and other pathogens may also play an important role in these patients, and minocycline would not be expected to have any effect on this type of infection.

    Another less conventional approach to the treatment of chronic illness patients with intracellular bacterial infections is oxygen therapy. Hyperbaric oxygen, intravenous ozone and hydrogen peroxide have been used to treat anaerobic infections similar to the infections discussed here. Most patients with anaerobic infections respond to such therapy with at least temporary alleviation of signs and symptoms, but additional evidence is needed before one can conclude that such therapy results in sustained suppression of anaerobic infections, such as those caused by Mycoplasma and Chlamydia species. Since these therapies are mainly cytostatic not cytotoxic, they must be sustained for some period of time. However, the use of long-term protocols that include oxygen therapy is likely to prove useful, and it is certainly beneficial in patients who cannot tolerate antibiotics due to chemical sensitivities or other reasons. In some patients, alternating antibiotic and oxygen therapies may be useful, but this has not been done in a controlled study.

    CONVENTIONAL TREATMENT OF CHRONIC BACTERIAL INFECTIONS



    Once chronic intracellular bacterial infections, such as Mycoplasma species infections, have been identified in the blood of subsets of CFS/ME, FMS, GWI, RA and other chronic illness patients, they can be treated using conventional and alternative approaches. Appropriate treatment with antibiotics should result in patient improvement and even recovery, and this has been found in most but not all chronic illness patients (8, 11, 17, 18, 52-54) (Table 1). The recovery is usually slow and gradual after an initial period of Herxheimer and other adverse reactions that make patients temporarily more symptomatic. This period can last for several weeks. The recommended treatments for mycoplasmal blood infections are usually long-term antibiotic therapy, usually multiple 6-week cycles of doxycycline (200-300 mg/day), ciprofloxacin (1,500 mg/day), azithromycin (250-500 mg/day) or clarithromycin (750-1,000 mg/day), among others (53). Multiple 6-week cycles are required, because few patients recover after only a few cycles of antibiotics. This is probably due to the intracellular locations of mycoplasmas like M. fermentans and M. penetrans or other bacteria, such as Chlamydia species, the slow-growing nature of these infections, their inherent insensitivity to most antibiotics and the persistence of the infections in metabolically inactive forms. For most patients, treatment must be continuous for at least 6 months, followed by additional 6-week cycles of antibiotics, if necessary. Some treat these infections by administration of antibiotics every other day, and some recommend daily dosing. Due to poor gastrointestinal absorption in certain patients or the acuteness of signs and symptoms, intravenous therapy has been used for a few weeks, followed by oral antibiotics. Most patients cannot tolerate intravenous antibiotics for more than a few weeks or complications can then occur, so follow-on therapy with oral antibiotics is necessary.

    Can antibiotic therapy be successful in treating intracellular bacterial infections often found in chronic illness patients? Yes, but antibiotics should not be used solely or exclusively to treat intracellular bacterial infections. They have proven successful for many if not most patients; however, many patients eventually fail on antibiotic therapy alone. For example, of 87 GWI patients that tested positive for mycoplasmal infections, all patients relapsed after the first 6-week cycle of antibiotic therapy, but after up to 6 cycles of therapy 69/87 previously mycoplasma-positive patients recovered and returned to active duty (17, 18). Since few patients recovered within 6 months of antibiotic therapy, as discussed above, this is now the minimal recommendation of antibiotic treatment (54). These were relatively young patients (most <25 years of age) that were healthy before their illness, and this could have played a role in their higher response rates compared to civilians with chronic illnesses which tend to be on the average older and not as healthy. The clinical responses that were seen in patients were not due to placebo effects, because administration of some antibiotics, such as penicillins, resulted in patients becoming more not less symptomatic, and they were not due to immunosuppressive effects that can occur with some of the recommended antibiotics. Interestingly, CFS/ME, FMS and GWI patients that slowly recovered after several cycles of antibiotics were generally less environmentally sensitive, suggesting that their immune systems were slowly returning to pre-illness states. If such patients had illnesses that were caused by psychological or psychiatric problems or solely by chemical or viral exposures, they should not have responded to the recommended antibiotics and slowly recovered. In addition, if such treatments were just reducing autoimmune responses, then patients should have immediately relapsed after the treatments were discontinued and they should not have responded to antibiotics that do not suppress immune systems.

    Although the majority of GWI patients in these unblinded, initial studies responded to antibiotic therapy, the studies have been justifiably criticized for not being controlled, blinded clinical trials. In the case of GWI, large double-blinded, placebo-controlled studies have recently been initiated using doxycycline. In the case of RA, however, double-blinded, placebo-controlled antibiotic trials using minocycline have been successfully conducted. These trials show that the treatment of RA patients with minocycline is clinically effective and results in recovery of approximately one-half of an unselected group (not tested for chronic infections) of patients (Table 1) (35, 55). The reason for the incomplete responses among RA patients was probably due to the fact that only a portion of the patients under study probably had intracellular bacterial pathogens as their main clinical problem. Viruses and other pathogens may also play an important role in these patients, and minocycline would not be expected to have any effect on this type of infection.

    Another less conventional approach to the treatment of chronic illness patients with intracellular bacterial infections is oxygen therapy. Hyperbaric oxygen, intravenous ozone and hydrogen peroxide have been used to treat anaerobic infections similar to the infections discussed here. Most patients with anaerobic infections respond to such therapy with at least temporary alleviation of signs and symptoms, but additional evidence is needed before one can conclude that such therapy results in sustained suppression of anaerobic infections, such as those caused by Mycoplasma and Chlamydia species. Since these therapies are mainly cytostatic not cytotoxic, they must be sustained for some period of time. However, the use of long-term protocols that include oxygen therapy is likely to prove useful, and it is certainly beneficial in patients who cannot tolerate antibiotics due to chemical sensitivities or other reasons. In some patients, alternating antibiotic and oxygen therapies may be useful, but this has not been done in a controlled study.










  2. musikmaker

    musikmaker New Member

    Thanks for posting this. It is a good article. I am going to print it.
  3. Tantallon

    Tantallon New Member

    Really good info here, am going to read this again tonight. Thanks for posting it.

    Sue

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