- 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
- 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 . 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 closely
associated with various human diseases .
- 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 , 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 , 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
- 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 . 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 (500-750 mg/d). Multiple cycles are required, because few patients
recover after only a few cycles , 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 : (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 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. , 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 .
(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. (Website for
further information: www.immed.org).
- Garth L. Nicolson, Ph.D. The Institute
for Molecular Medicine (Tel: 714-903-2900) 15162 Triton Lane, Huntington
Beach, CA 92649-1401 and Professor of Internal Medicine, The University
of Texas Medical School at Houston
- 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.
- 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;
- 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.