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New Treatments for Chronic Infections Found in Fibromyalgia Syndrome, Chronic Fatigue Syndrome, Rheumatoid Arthritis and Gulf War Illnesses

Prof. Garth L. Nicolson
Chief Scientific Officer
(Professor of Internal Medicine)
The Institute for Molecular Medicine
15162 Triton Lane, Huntington Beach, CA 92649-1401 U.S.A.

Fibromyalgia Syndrome (FMS), Chronic Fatigue Syndrome (CFS) and Gulf War Syndrome, or as we prefer to call it Gulf War Illnesses (GWI), are characterized by their complex, multi-organ chronic signs and symptoms, including muscle pain, chronic fatigue, headaches, memory loss, nausea, gastrointestinal problems, joint pain, lymph node pain, among others. A particular problem in these patients is the appearance of the clinical problems (rheumatoid signs and symptoms) seen in Rheumatoid Arthritis (RA) patients. The signs and symptoms of FMS overlap with CFS, and often they can be diagnosed as CFS, but the distinguishing feature of FMS is the presence of chronic widespread pain and tenderness. Often included in this complex clinical picture are increased sensitivities to various environmental agents and enhanced allergic responses. There are other troubling problems in these patients, such increased problems with heart function, increases in spontaneous abortions and other chronic signs and symptoms.

The signs and symptoms of FMS and CFS are similar to those found in GWI, and this suggests that GWI is not a separate syndrome, it is a FMS/CFS-like disorder [1]. Over 100,000 veterans of the Persian Gulf War in 1991 now have GWI, and according to one government study, it has spread to immediate family members [2]. Although incomplete, this report was undertaken in 1994 by investigators of a U.S. Senate committee, and they found after contacting approximately 1,200 GWI families that 77% of spouses and a majority of children born after the war had the signs and symptoms of GWI [2]. Notwithstanding official U. S. Department of Defense and British Ministry of Defence denials, this indicates that at least a subset of GWI patients have a transmittable illness that is being passed to spouses and children [3]. We have been particularly interested in the illness passing to children, and when children present, the most significant problem is "failure to thrive," a pediatric condition marked by failure to gain weight and develop properly. It is also accompanied by chronic fatigue, skin rashes, hair loss, diarrhea and gastrointestinal problems in these children.

The Issue of Stress and Cognitive Problems

FMS, CFS and GWI patients usually have cognitive problems, such as short term memory loss, as well as problems concentrating, depression and irritability. Psychologists or psychiatrists who examine FMS, GWI and CFS patients often find psychological or psychiatric problems in these patients and decide in the absence of contrary laboratory findings that these conditions are somatoform disorders. That is, these illnesses are caused by psychological or psychiatric problems, not medical problems. Important among the potential origins of psychological or psychiatric problems is stress, and stress is often mentioned as an important factor or the important factor in these disorders. For example, in GWI patients Post Traumatic Stress Disorder (PTSD) is a common diagnosis given to GWI patients in veterans and military hospitals in the U. S. and Great Britain [4].

The sole evidence that physicians have offered as proof that stress or PTSD is the source of most GWI sickness is the assumption that most veterans must have suffered from stress by virtue of the stressful environment in which they found themselves during the war [4]. Most testimony to the U. S. House of Representatives committee studying the origins of GWI refutes the notion that stress is the major cause of GWI [4], and the General Accounting Office (GAO), the investigational arm of the U. S. Congress, after studying government and civilian data on the subject concluded that while stress can induce some physical illness, the link between stress and GWI has not been established [5]. Of course, stress can exacerbate chronic illness but most military personnel that we interviewed indicated to us that the Gulf War was not a particularly stressful war, and they strongly doubted that stress was the origin of their illnesses [6]. Again, in the absence of physical or laboratory tests that can identify possible origins of FMS, CFS or GWI, many physicians accept that stress is the cause of these illnesses.

Chronic Infections as a Problem in Chronic Illnesses

There is another, quite different possibility that can explane the complex signs and symptoms found in FMS, CFS, RA and GWI. At least some of these patients may suffer from system-wide or systemic chronic infections that can penetrate various tissues and organs, including the central and peripheral nervous systems [7]. Such infections can cause the complex signs and symptoms seen in CSF, FMS, GWI and in some RA patients, including immune dysfunction that may underlie some of the environmental responses as well as increased titers to various endogenous viruses that are commonly found to be expressed in these patients.

Few infectious agents can produce the complex chronic signs and symptoms found in CFS, FMS and GWI patients (and some RA patients), but one type of airborne infection that has received renewed interest of late as an important element in these disorders is represented by the class Mollicutes [7]. These microorganisms, principally mycoplasmas and other rather primitive bacteria, although not well known agents, are now considered important emerging pathogens in causing chronic diseases and may be important cofactors in some illnesses, including AIDS and other immunosuppressive diseases [7].

Interestingly, as GWI progresses, there are a number of accompanying problems, including in some patients MS-like (Multiple Sclerosis), ALS-like (Amyotrophic Lateral Sclerosis), Lupus-like and RA-like signs and symptoms, and the presence of usually rare autoimmune responses is consistent with mycoplasmal infections that penetrate into nerve cells, synovial cells and other cell types. Some of these signs and symptoms have also been seen in a subset of FMS, RA and CFS patients. As intracellular mycoplasmas escape from cellular compartments, they incorporate into their own structures pieces of host cell membranes containing important antigens that can trigger autoimmune responses. Thus patients with such infections may be responding to mycoplasma antigens as well as their own antigens, producing unusual autoimmune signs and symptoms.

Mycoplasmas as Important Infections in Chronic Illnesses

Although most mycoplasmas are not considered important human pathogens, some species, such as M. fermentans, M. penetrans, M. pneumoniae, M. genitalium, M. pirum and M. hominis, among others, have been closely associated with various human diseases [7]. This does not necessarily mean that these diseases are entirely caused by mycoplasmal infections but this type of infection is important in causing much of the morbidity or illness seen in patients with chronic illnesses.

Do FMS, CFS, RA or GWI patients show evidence of mycoplasmal infections? In a majority of FMS, CFS, RA and GWI patients examined we and others, principally Dr. Daryl See of the University of California College of Medicine, Irvine, CA, are finding strong evidence for mycoplasmal blood infections that can explain much if not most of their chronic signs and symptoms. In our studies on GWI, a CFS/FMS-like condition [1], we have found mycoplasmal infections in about one-half of approximately 400 patients, and these patients were found to have principally one infectious species, M. fermentans [8, 9]. Moreover, in over one-half of the 500 civilians with CFS, FMS or RA that we have examined we are finding a variety of pathogenic mycoplasma species, such as those listed above, in the leukocyte fractions of blood samples. The tests that we use to identify mycoplasmal infections, polymerase chain reaction and nucleoprotein gene tracking [10], are very sensitive and highly specific. These tests are a dramatic improvement over the relatively insensitive serum antibody tests that are routinely used to assay for systemic mycoplasmal infections. In fact, we have received a Department of Defense contract to train scientists and physicians to conduct these tests, and in the second week of January 1988 a group, including staff from the Armed Forces Institute of Pathology and Walter Reed Army Medical Center, the University of Texas Medical School at San Antonio and the University of California, Irvine School of Medicine, will be arriving at the Institute for Molecular Medicine for advanced training in mycoplasma detection in blood and other body fluids.

New Treatments for Chronic Infections Found in FMS, CFS, RA and GWI

The identification of mycoplasmal infections in the leukocyte blood fractions of a rather large subset of CFS, FMS and RA patients suggests that mycoplasmas, and probably other chronic infections as well, may be an important source of morbidity in these patients. If such infections are important in these disorders, then appropriate treatment with antibiotics should result in improvement and even recovery. This is exactly what has been found [11]. The recommended treatments for mycoplasmal blood infections require long-term antibiotic therapy, usually multiple 6-week cycles of doxycycline (200-300 mg/d), ciprofloxacin or Cipro (1,500 mg/d), azithromycin or Zithromax (500 mg/d) and clarithromycin or Biaxin (750-1,000 mg/d). Multiple cycles are required, because few patients recover after only a few cycles [9], possibly because of the intracellular locations of mycoplasmas like M. fermentans and M. penetrans, and the slow-growing nature of these microorganisms. These responses are not due to placebo effects, because administration of some antibiotics, such as penicillins, resulted in patients becoming more not less symptomatic.

Treatment recommendations for mycoplasmal infections are similar to those used to treat Lyme Disease, caused by other slow-growing intracellular bacteria that are difficult to identify and treat. Interestingly, FMS, CFS, RA and GWI patients that recover after several cycles of antibiotics are generally less environmentally sensitive, suggesting that their immune systems may be returning to pre-illness states. If such patients had illnesses that were caused by psychological or psychiatric problems or by environmental or chemical exposures, they should not respond to the recommended antibiotics and recover their health.

Criteria for Determining that Mycoplasmas Cause Chronic Diseases

Before systemic mycoplasmal infections can be considered important in causing disease, certain criteria must be fulfilled [12]:
(1) The incidence rate among diseased patients must be higher than in those without disease. This has been found for M. fermentans. Although this mycoplasma has been found in asymptomatic adults, the incidence is low, usually a few percent compared to almost one-half of Gulf War Illness patients [8, 9].
(2) More of the mycoplasma must be recoverable from diseased patients than from those without disease. This has been found [8, 9].
(3) An antibody response should be found at higher frequency in diseased patients than in those without disease. This has been found but usually not until the disease has progressed. According to Lo et al. [13-15] M. fermentans hides inside cells and does not elicit a strong immune response until near death.
(4) A clinical response should be accompanied by elimination of the mycoplasma. This is exactly what has been seen [8, 9].
(5) Clinical responses should be differential depending on the type of antibiotic. This is what has been found. Only antibiotics that are effective against the pathogenic mycoplasmas result in recovery, and some antibiotics, such as penicillins, can worsen the condition [8, 9].
(6) The mycoplasma must cause a similar disease in susceptible animals. The best description comes from Lo et al. [13], where injection of M. fermentans into monkeys resulted in development of a fulminant disease that leads to death. These animals display many chronic signs and symptoms [13].
(7) The mycoplasma must cause a similar disease when administered to volunteers. This has not been done, because of ethical considerations.
(8) A specific anti-mycoplasma antibody reagent or immunization protects against disease. This has not yet been done to my knowledge. Therefore, six out of eight of the above criteria have been fulfilled, at least for M. fermentans, strongly suggesting that certain mycoplasmas can cause human disease.

Mycoplasmal Infections: Only Part of the Problem in Chronic Illnesses

Are chronic, systemic mycoplasmal infections the answer to FMS, CFS, RA, GWI and other disorders? Of course not! This is likely to be an appropriate explanation for a rather large subset of FMS, CFS, RA, GWI and many RA patients, but certainly not every patient will have the same types of chronic infections. Some patients may have chemical exposures or other environmental problems as the underlying reason for their chronic signs and symptoms. In others somatoform disorders or illnesses caused by psychological or psychiatric problems may indeed be important. However, in these patients antibiotics should have no effect whatsoever, and they should not recover on antibiotic therapies.

The identification of specific infectious agents in the blood of chronically ill patients may allow many patients with FMS, CFS, RA, or GWI to obtain more specific diagnoses and effective treatments for their illnesses. The Institute for Molecular Medicine can test patients for evidence of mycoplasmal infections of the types that cause human disease. Blood samples can be sent to the Institute for Molecular Medicine for mycoplasma and other testing. (Website for further information: www.immed.org).

Contact:
Prof. Garth L. Nicolson
The Institute for Molecular Medicine
15162 Triton Lane
Huntington Beach, CA 92649-1401
Tel: 714-903-2900
Fax: 714-379-2082

References

1. Nicolson, G.L. and Nicolson, N.L. Chronic fatigue illness and Operation Desert Storm. J. Occup. Environ. Med. 1996; 38: 14-16.

2. U. S. Congress, Senate Committee on Banking, Housing and Urban Affairs, U. S. chemical and biological warfare-related dual use exports to Iraq and their possible impact on the health consequences of the Persian Gulf War , 103rd Congress, 2nd Session, Report May 25, 1994.

3. Nicolson, G.L. and Nicolson, N.L. The eight myths of Operation Desert Storm and Gulf War Syndrome. Medicine Conflict & Survival 1997; 13: 140-146.

4. U. S. Congress, House Committee on Government Reform and Oversight, Gulf War veterans : DOD continue to resist strong evidence linking toxic causes to chronic health effects, 105th Congress, 1st Session, Report 105-388, 1997.

5. U. S. General Accounting Office, Gulf War Illnesses: improved monitoring of clinical progress and reexamination of research emphasis are needed. Report GAO/SNIAD-97-163, 1997.

6. Nicolson, G.L. and Nicolson, N.L. Chronic Fatigue Illnesses Associated with Service in Operation Desert Storm. Were Biological Weapons Used Against our Forces in the Gulf War? Townsend Lett. Doctors 1996; 156: 42-48.

7. Baseman, J.B. and Tully, J.G. Mycoplasmas: Sophisticated, reemerging, and burdened by their notoriety. Emerg. Infect. Diseases 1997; 3: 21-32.

8. Nicolson, G.L. and Nicolson, N.L. Diagnosis and treatment of mycoplasmal infections in Persian Gulf War Illness-CFIDS patients. Intern. J. Occup. Med. Immunol. Tox. 1996; 5: 69-78.

9. Nicolson, G.L., Nicolson, N.L. and Nasralla, M. Mycoplasmal infections and Chronic Fatigue Illness (Gulf War Illness) associated with deployment to Operation Desert Storm. Intern. J. Med. 1998; 1: 80-92.

10. Nicolson, N.L. and Nicolson, G.L. The isolation, purification and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes. Methods Molecular Genet. 1994; 5: 281-298.

11. Nicolson, G.L. and Nicolson, N.L. Doxycycline treatment and Desert Storm. JAMA 1995; 273: 618-619.

12. Taylor-Robinson, D. Infections due to species of mycoplasma and ureplasma: an update. Clin. Infect. Diseases 1996; 23: 671-682.

13. Lo, S.-C., Wear, D.J., Shih, W.-K., Wang, R.Y.-H., Newton, P.B., Rodriguez, J.F. Fatal systemic infections of nonhuman primates by Mycoplasma fermentans (incognitus strain). Clin. Infect. Diseases 1993; 17(Suppl 1): S283-288.

14. Lo, S.-C., Buchholz, C.L., Wear, D.J., Hohm, R.C., Marty, A.M. Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain). Modern Pathol. 1991; 6: 750-754 .

15. Lo, S.-C., Dawson, M.S., Newton, P.B., Sonoda, A.A., Shih, W.-K., Engler, W.F., Wang, R.Y.-H., Wear, D.J. Association of the virus-like infectious agent originally reported in patients with AIDS with acute fatal disease in previously healthy non-AIDS patients. Amer. J. Trop. Med. Hyg. 1989; 41: 364-376

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