Chronic Fatigue Syndrome (CFS), Fibromyalgia Syndrome (FMS) and Gulf War Illnesses (GWI) are characterized by their complex, multi-organ chronic signs and symptoms, including neurological, muscular-skeletal, rheumatic, mucocutaneous, gastrointestinal, sinopulmonary, and constitutional, among others. Also included in this complex clinical picture are increased sensitivities to various environmental agents and enhanced allergic responses. Often such patients have cognitive problems and are seen by psychologists or psychiatrists who usually decide in the absence of contrary laboratory findings that the condition is a somatoform disorder. However, there is another, quite different possibility--these patients may suffer from chronic infections that can penetrate the CNS and PNS as well as other tissues and organs and cause the complex signs and symptoms seen in CSF, FMS and GWI, 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, 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. These organisms, 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 [1].

Interestingly, as these illnesses progresses, there are a number of accompanying problems, including in some patients MS-like, ALS-like, Lupus-like and arthritis-like signs and symptoms, and the presence of usually rare autoimmune responses is consistent with mycoplasmal infections that penetrate into nerve cells, synovial cells, etc. As mycoplasmas escape from cellular compartments, they can leave with pieces of cell membranes containing important antigens that can trigger immune responses.

Although most mycoplasmas are not considered important human pathogens, some species, such as M. fermentans, M. penetrans, M. pneumoniae, M. genitalium, and M. hominis, among others, have been American Academy of Environmental Medicine Newsletter, p.2 closely associated with various human diseases [1].

In a majority of CFS and FMS patients examined we and others, principally Dr. Daryl See of the University of California College of Medicine, Irvine, are finding strong evidence for mycoplasmal blood infections that can explain their chronic conditions. In our studies on GWI, a CFS/FMS-like condition [2], we have found mycoplasmal infections in approximately one-half of patients, principally one species, M. fermentans [3, 4]. Moreover, in approximately one-half of the civilians with CFS, FMS or arthritis we are finding a variety of pathogenic mycoplasmas, 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 [5], 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.

The identification of mycoplasmal infections in the leukocyte blood fractions of a rather large subset of CFS, FMS and arthritis 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 [6]. 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 (500 mg/d).

Multiple cycles are required, because few patients recover after only a few cycles [4], possibly because of the intracellular locations of mycoplasmas like M. fermentans and M. penetrans, and the slow-growing nature of these microorganisms. 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, CFS, FMS, 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 only chemical exposures as the reason for their illness, they should not respond to the recommended antibiotics and recover.

Before systemic mycoplasmal infections can be considered important in causing disease, certain criteria must be fulfilled [7]: (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 [3, 4]. (2) More of the mycoplasma must be recoverable from diseased patients than from those without disease.

This has been found [3, 4]. (3) An antibody response should be found American Academy of Environmental Medicine Newsletter, p.3 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. [8-10] M. fermentans hides inside cells and does not illicit 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 [3, 4]. (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 [3, 4]. (6) The mycoplasma must cause a similar disease in susceptible animals. The best description comes from Lo et al. [8], 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 [8]. (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.

Are chronic, systemic mycoplasmal infections the answer to CFS, FMS, GWI and other disorders? Of course not! This is likely to be an appropriate explanation for a rather large subset of CFS, FMS, GWI and some arthritis patients, but certainly not every patient will have the same chronic infections. Some patients may have chemical exposures or other environmental problems as the underlying reason for their chronic signs and symptoms. In these patients antibiotics should have no effect whatsoever.

The identification of specific infectious agents in the blood of chronically ill patients may allow many patients with CFS, FMS, GWI or arthritis to obtain more specific diagnoses and effective treatments for their illnesses. Blood samples can be sent to the Institute for Molecular Medicine for mycoplasma and other testing.

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References Cited

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

2. Nicolson, G.L. and Nicolson, N.L. Chronic fatigue illness and Operation Desert Storm. J. Occup. Environ. Med. 1996; 38: 14-16. American Academy of Environmental Medicine Newsletter, p.4

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

4. 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. 1997; in press.

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

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

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

8. 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.

9. 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). Mod. Pathol. 1991; 6: 750-754 .

10. 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 .