THE ROLE OF CHRONIC INFECTIONS IN THE MAINTAINANCE AND

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THE ROLE OF CHRONIC INFECTIONS IN THE MAINTAINANCE AND Powered By Docstoc
					                     International ME/CFS Conference, Sydney, Australia 1998

     THE ROLE OF CHRONIC INFECTIONS IN THE MAINTAINANCE AND
PROGRESSION OF CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME,
 RHEUMATOID ARTHRITIS, IMMUNE DEFICIENCY SYNDROMES AND GULF WAR
                             ILLNESS
Prof. Garth L. Nicolson, Marwan Y. Nasralla, Joerg Haier, Robert Irwin, Nancy L. Nicolson and Richard
Ngwenya

The Institute for Molecular Medicine, Huntington Beach, California, USA and the James Mobb Immune Enhancement
Clinics, Harare, Zimbabwe (IMM Website: www.immed.org)

Abstract
Chronic infections (bacterial, viral, fungal) are associated with a variety of acute and chronic illnesses that
have fatigue as a major clinical sign. In addition to illnesses that have pain and fatigue as the major clinical
signs, such as Chronic Fatigue Syndrome (CFS), Fibromyalgia Syndrome (FMS) and Gulf War Illness
(GWI), other illness, such as respiratory diseases, rheumatoid diseases, immunosuppressive diseases,
genitourinary diseases, cardiac diseases, gastrointestinal diseases, skin diseases and autoimmune diseases,
also show chronic systemic infections at high incidence. These chronic infections could be causative in some
patients’ illnesses but are more likely to be cofactors or opportunistic in most patients, and they are often
expressed as multiple infections, especially in patients whose illnesses has progressed in terms of severity
and numbers of chronic signs and symptoms. As an example of this we have examined chronic systemic
mycoplasmal infections in patients with CFS, FMS or GWI. There was a significant difference in the blood
mycoplasmal infections symptomatic CFS (~60%), FMS (~70%) and GWI (~50%) patients (n>200) than in
normal controls (6-9%) (P<0.001). This difference was also present when specific species of mycoplasmas
were determined (M. fermentans, M. pneumoniae, M. hominis, M. penetrans). With the exception of GWI,
most patients had multiple mycoplasmal infections. The number of species of mycoplasmas found in white
blood cell samples generally correlated with the length and the severity of the illness. These infections can
be treated with multiple cycles of particular antibiotics (doxycycline, minocycline, ciprofloxacin,
sparfloxicin, azithromycin or clarithromycin) but patients also need nutritional support, dietary supplements
and immune enhancers, especially after the antibiotics are withdrawn. We propose that multiple chronic
infections are important in causing patient morbidity and are involved in the progression of many chronic
diseases. If left untreated, chronic infections may prevent patients from recovering from their chronic
illnesses.

Introduction
Evidence is accumulating that chronic bacterial, viral and fungal infections play an important role in many
chronic diseases. Irrespective of whether these infections are the cause of the disease or are involved in
disease progression as cofactors or even as opportunistic infections, most patients will not recover from their
chronic illnesses if these infections are left untreated or immune systems are not boosted to the point that the
infections are suppressed.1,2 Since there is nonrandom incidence of many chronic illnesses (for example, it is
sometimes found in immediate family members) and the illnesses often respond to therapies based on
infectious agents, many chronic illnesses probably have chronic infections as important components that
need to be considered in any therapy regimen.1,2
         Most chronic illnesses do not yet have effective therapies that can reliably cure most patients of their
illnesses. However, patients can be treated for clinical problems that cause most of their morbidity or
sickness, and they can return to relatively normal lives. Since most chronically ill patients do not usually
recover from their illnesses, new approaches to successfully treating these conditions are important for both
medical and economic reasons.2

Overlapping Signs and Symptoms in Chronic Illnesses
Most chronic illnesses are multisystem or multiorgan diseases with complex, nonspecific, slowly
progressing signs and symptoms. Their origins are for the most part unknown, although there are ample
proposals for the roles of chemical exposures, viruses, bacteria, allergens and others in the onset of illness.


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It is often considered impossible to treat chronic illnesses without a precise cause for the illness, but we do
not consider this essential in treatment of these disorders.1,2 The question of origin is further complicated
because often patients’ signs and symptoms overlap, and in some cases they are almost identical.3 For
example, in Chronic Fatigue Syndrome (CFS), Fibromyalgia Syndrome (FMS) and Gulf War Illness (GWI)
the most commonly found signs and symptoms are chronic fatigue, muscle pain and soreness, joint pain,
headaches, short term memory loss, depression, nausea, cognitive problems, breathing problems,
gastrointestinal problems, lymph node pain and soreness, and a variety of other signs and symptoms. The
major difference between these illnesses is that FMS patients have muscle pain and soreness as their most
common complaint, while CFS patients have chronic fatigue and joint pain and soreness as their most
common complaints. When comparing GWI with CFS, it is apparent that these are very similar if not
identical.3
          Fatigue is generally the most common complaint made by all patients and is reported by 20% of
patients seeking medical care.4,5 Obviously the presence of fatigue can indicate any number of different
medical conditions,6 so the diagnosis of illnesses such as CFS depends on a number of other signs and
symptoms and remains basically an illness defined by exclusion rather than inclusion of specific diagnostic
criteria. When we used Illness Survey Forms to document the signs and symptoms and their severity in CFS,
FMS and GWI patients, we found that there was essentially no difference in patient signs (Figure 1).2 Our
data were arranged into 38 categories from 114 different signs and symptoms, and the intensity of patient
signs and symptoms prior to and after onset of illness were scored (0, absent; 10, extreme) and were
considered positive if the values after onset of illness were two or more points higher than prior to onset of
illness. We also noted that there were similarities in CFS, FMS and GWI with Rheumatoid Arthritis (RA).7
Interestingly, we have found similar signs and symptoms in immediate family members, suggesting that
these illnesses can, in some cases, be transmitted. When we find signs and symptoms that are similar in
family members, these individuals must be monitored closely for onset or progression of illness.

CFS is not a Strictly Psychiatric Condition
Since the signs and symptoms of many chronic illnesses, especially CFS, FMS and GWI, are nonspecific
and involve cognitive loss, depression and other mental problems, physicians often decide in the absence of
other definitive laboratory and clinical data that these patients suffer from somatoform disorders caused by
psychiatric or psychological problems.6 Many CFS, FMS and GWI patients have cognitive, neurological and
psychiatric problems, but that does not mean that these disorders are strictly psychiatric or psychological in
origin.
         Stress is often given as an explanation for chronic illnesses, such as in GWI where Post Traumatic
Stress Disorder (PTSD) was proposed to be the cause.6 However, most patients do not feel that their illness
is caused by stress, and this does not explain the spread of illnesses like GWI to immediate family
members.2 Of course, stress can exacerbate chronic illnesses and suppress immune systems, suggesting that
it has an important role in chronic illness. But this does not mean that stress causes the illness and that the
illness must be treated solely as a psychiatric or psychological disorder. Unfortunately, this has resulted in
patients being treated only for their individual psychological symptoms (for example, with the use of
antidepressants) and not being afforded the possibility of other therapies that could have significant benefit
in reducing their overall morbidity.

Chronic Infections in CFS, FMS, GWI and RA
Chronic infections can cause most or essentially all of the signs and symptoms found in chronic illness
patients.2 These infections can be caused by viruses, fungi or bacteria. We have focused our efforts initially
on mycoplasmas, small bacterial microorganisms lacking cell walls, that are capable of invading several
types of organs, tissues and cells. Mycoplasmal infections are associated with a wide variety of human
diseases as causative agents, cofactors or opportunistic infections. 8
         When we examined CFS, FMS and GWI patients for the presence of mycoplasmal infections in
their blood leukocytes, we found significant infections in each of these disorders.1,9,10 Blood was collected,
cooled, shipped overnight at 4 degrees C and processed immediately for forensic PCR after isolation and
purification of DNA using a Chelex procedure.1,7 In over 200 CFS and FMS patients we found
mycoplasmal infections (M. fermentans, M. pneumoniae, M. homonis, M. penetrans) in ~60% and ~70% of
patients, respectively.1,11 In over 200 GWI patients we found mycoplasmal infections (primarily M.



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fermentans) in about one-half of cases.9,10 The differences between patient and control groups (6-9%
positive) were significant (P<0.001).1,9-11

CFS and FMS patients often have multiple mycoplasmal infections, suggesting that they also have other
chronic infections as well. When we examined CFS and FMS patients for multiple mycoplasmal infections,
we found that most had multiple infections, either as double (over 30% of patients) or triple or more (over
20% of patients) infections (Figure 2), but only when one of the species was M. fermentans or M.
pneumoniae. We also found higher score values for severity of signs and symptoms in patients with
multiple mycoplasmal infections. Also, patients that had been sick longer were more likely to have multiple
infections.11 This suggests that patients accumulate chronic infections during the course of their illness, and
these infections may contribute to the progression of their illness.
         In the course of our studies we also found that the conditions of blood storage and the type of
anticoagulant used were very important.1 If blood was held at room temperature, most samples lost activity
within 1-2 days, indicating that the methods used for drawing, transporting and processing blood are very
important.

Mycoplasmal Infections in Other Illnesses
We have examined the incidence of mycoplasmal infections in other chronic illnesses. For example, in RA
and other rheumatoid diseases, the presence of various infectious agents has been proposed for some time.
Aerobic and anaerobic intestinal bacteria, viruses and mycoplasmas have all been proposed as important
agents in RA.12 In fact, mycoplasmas have been proposed to play a role in the initiation and progression of
RA,13 and various mycoplasmas have been found in the joint tissues of patients with rheumatological
diseases.14 When we examined RA patients for the presence of mycoplasmal infections, we found that one-
half were infected with various species of mycoplasmas.7 The most common species found was M.
fermentans, followed by M. pneumoniae, M. hominis and M. penetrans. Similar to CFS and FMS patients,
we found that RA patients often had multiple species of mycoplasmas in their blood.7
        Mycoplasmas and other infectious agents have been found in a variety of upper respiratory diseases,
such as Asthma, Chronic Pneumonia and other diseases.15 They are also found in a variety of heart
pathologies (endocarditis, myocarditis, pericarditis and others)16 along with Clamydia17 and other infections.
        Chronic infections like mycoplasmal infections have been proposed to be important cofactors in the
progression of HIV-AIDS, and they are probably an important source of morbidity in these patients.18 For
example, M. fermentans can cause renal and CNS complications in AIDS patients, and M. pirum and M.
hominis infections have been associated with disease progression.19,20
        Mycoplasmal infections are also associated with autoimmune diseases. We found that
M. fermentans infections were usually found GWI patients with signs and symptoms of Multiple Sclerosis
(MS), Amyotrophic Lateral Sclerosis (ALS), Lupus Erythromatosis (Lupus), Grave’s Diseases (thyroiditis)
and other autoimmune disorders. Chronic cell-invasive infections like mycoplasmas can penetrate into nerve
cells and other cells, and when they escape these cells they can incorporate into their structures normal
membrane antigens that could trigger host autoimmune responses.
        Other chronic illnesses, such as gastrointestinal diseases like Inflammatory Bowel Disease, skin
diseases, hepatitis, and infections of the eye, ear, throat, urinary tract, among others, can also be associated
with mycoplasmal infections. Once these infections are identified, they should be treated.

Mycoplasmal Infections: Treatment Suggestions
Any blood bacterial infection that is likely to be a source of patient morbidity should be treated. The
treatment of choice is antibiotics, but there also are other important considerations.1,21,22 Since the
pathogenic mycoplasmas are usually intracellular, not especially sensitive to antibiotics and divide very
slowly, long-term antibiotics are rquired.22 We now recommend that patients be placed on antibiotics
(doxycycline or minocycline, 200-300 mg/day; ciprofloxacin, 1,500 mg/day or sparfloxacin, 400 mg/day;
azithromycin, 500 mg/day; clarithromycin, 750-1,000 mg/day) for at least 6 months before using the 6-week
on, 2-week off regimen.21,22 This is because few patients recover after only a few 6-week cycles, and it does
not make sense to have patients repeatedly relapsing during therapy. CFS, FMS and GWI patients slowly
recover on the antibiotics, and their environmental sensitivities slowly return to preillness states, suggesting
that their immune systems are slowly recovering. If such patients had psychiatric causes of their illness,
they should not respond to the antibiotics listed above. The responses are not placebo responses, because


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some antibiotics, such as pencillins, result in patients becoming more not less symptomatic. Also, the
responses are not due to antibiotic-induced immunosuppression, because patients’ immune systems slowly
recover, and antibiotics that have minimal antisuppressive effects also work. In addition, patients can relapse
during the treatment, but as time goes on, these relapses become milder and milder until antibiotics are no
longer required. Eventually most patients recover, and when retested are negative for their mycoplasmal
infections.9,10
         There are a number of nutritional deficiencies in chronically ill patients that must be corrected
during the course of treatment.22 For example, patients with CFS, FMS, GWI, RA, etc., have nutritional,
vitamin and mineral deficiencies that must be corrected. Supplementation with vitamins B complex, C and
E, CoQ10, as well as beta-carotene, bioflavoids and minerals such as magnesium, selenium, zinc,
manganese and chromium are useful. Since antibiotics result in depletion of normal gut flora,
supplementation with Lactobacillus acidophilus and other beneficial flora is needed. Often these patients
have damaged gut tissue, which can result in passage of gut bacteria into the system (see other contributions
in this volume). There are also a number of natural immune enhancers that are useful in boosting the
immune system, and protein and amino acid supplementation should be considered. Often these patients
have poor gut absorption, and they need various supplements to restore natural immunity and system
balance. Since each patient is unique in these requirements, specific suggestions for application to all
patients are generally not useful. Finally, some patients have chemical and other exposures that need to be
considered. For example, the use of moderate exercise and dry saunas to remove contaminating chemicals is
recommended during the course of therapy.

Conclusions
A variety of chronic illnesses appear to have systemic chronic infections as a major source of patient
morbidity. These infections appear to be multiple and involve a variety of chronic pathogenic agents
(viruses, bacteria, mycoplasmas, fungi). Each patient will undoubtedly have different mixtures of chronic
infectious agents that could result in unique signs and symptoms, although these will tend to be overlapping
in nature. Chronic infections do not have to be causative in these illnesses to be important; they could be
cofactors or opportunistic infections that result in significant patient morbidity. The identification of
specific chronic infections in these patients should allow for more effective treatments of these illnesses.

References
1.    Nicolson GL. Nasralla M, Haier J, Nicolson NL. (1998) Diagnosis and treatment of chronic mycoplasmal
      infections in fibromyalgia and chronic fatigue syndromes: Relationship to gulf war illness. Biomed. Ther. 16: 266-
      271
2.    Nicolson GL, Nasralla MY, Haier J, Irwin R, Nicolson NL, Ngwenya R. (1999) Mycoplasmal Infections in
      Chronic Illnesses: Fibromyalgia and Chronic Fatigue Syndromes, Gulf War Illness, HIV-AIDS and Rheumatoid
      Arthritis. Med. Sent. 4: 172-176.
3.    Nicolson GL, Nicolson NL. Chronic Fatigue Illness and Operation Desert Storm. J Occup Environ Med 1995;
      38:14-17
4.    Morrison JD. (1980) Fatigue as a presenting complaint in family practice. J. Fam. Pract. 10: 795-801
5.    Kroenke K, Wood DR, Mangelsdorff AD, Meier NJ, Powell JB. (1988) Chronic fatigue in primary care.
      Prevalence, patient charecteristics, and outcome. JAMA 260: 929-934
6.    NIH Technology Assessment Workshop Panel. (1994) The Persian Gulf Experience and Health. JAMA 272: 391-
      396
7.    Haier J, Nasralla M, Franco AR, Nicolson GL. (1999) Detection of Mycoplasmal Infections in Blood of Patients
      with Rheumatoid Arthritis. Br. J. Rheumatol., in press
8.    Baseman JB, Tully JG. (1997) Mycoplasmas: Sophisticated, Reemerging, and Burdened by Their Notoriety.
      Emerg. Infect. Dis. 3: 21-32
9.    Nicolson GL, Nicolson NL. (1996) Diagnosis and treatment of mycoplasmal infections in Persian Gulf War
      Illness-CFIDS patients. Int. J. Occup. Med. Tox. 5: 69-78
10.   Nicolson GL, Nicolson NL, Nasralla M. (1998) Mycoplasma infections and Chronic Fatigue Illness (Gulf War
      Illness) associated with deployment to Operation Desert storm. Intern. J. Med. 1: 80-92
11.   Nasralla M, Haier J, Nicolson GL. (1999) Multiple Mycoplasmal Infections detected in Blood of Chronic Fatigue
      Syndrome and Fibromyalgia Syndrome Patients. Eur. J. Clin. Microbiol. Infect. Dis. 18: 859-865.
12.   Midtvedt T. (1987) Intestinal bacteria and rheumatic disease. Scan. J. Rheumatol. Suppl. 64: 49-54
13.   Schaeverbeke T, Vernhes JP, Lequen L, Bannwarth B, Bebear C, Dehais J. (1997) Mycoplasmas and arthritis.
      Rev. Rheum. Engl. Ed. 64: 120-128



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14. Simecka JW, Ross SE, Cassell GH, Davis JK. (1993) Interactions of mycoplasmas with B cells: antibody
    production and nonspecific effects. Clin. Infect. Dis. 17 (Suppl. 1): S176-82
15. Balassanian N, Robbins FC. (1967) Mycoplasma pneumoniae infection in families. N. Engl. J. Med. 277: 719
16. Hofner G, Hofbeck M, Koch A, Schmiedl N, Singer H. (1997) Intrapericardial hemorrhage as a manifestation of
    mycoplasma pneumoniae infection Zeitschr. Kardiol. 86: 423-426
17. Davidson M, Kuo CC, Middaugh JP, Campbell LA, Wang SP, Newman WP 3rd, Finley JC, Grayston JT. (1998)
    Confirmed previous infection with Chlamydia pneumoniae (TWAR) and its presence in early coronary
    atherosclerosis. Circulation 98: 628-633
18. Blanchard, A. and Montagnier, L. (1994) AIDS-associated mycoplasmas. Ann. Rev. Microbiol. 48, 687-712
19. Bauer FA, Wear DJ, Angritt P, Lo S-C. (1991) Mycoplasma fermentans (incognitus strain) infection in the
    kidneys of patients with aquired immunodeficiency syndrome and associated nephropathy: a light microscopic,
    immunohistochemical, and ultrastructural study. Hum. Pathol. 22: 63-69
20. Savio ML; Caruso A; Allegri R; Fallacara F; Pollara CP; Foresti I; Comberti E; Gargiulo F; Dima F; Cadeo GP.
    (1996) Detection of Mycoplasma genitalium from urethral swabs of human immunodeficiency virus-infected
    patients. New Microbiologica, 19: 203-209
21. Nicolson GL, Nicolson NL. (1995) Doxycycline treatment and Desert storm. JAMA 273: 618-619
22. Nicolson GL. (1998) Considerations when undergoing treatment for chronic infections found in Chronic Fatigue
    Syndrome, Fibromyalgia Syndrome and Gulf War Illnesses. (Part 1). Antibiotics Recommended when indicated
    for treatment of Gulf War Illness/CFIDS/FMS. (Part 2). Intern. J. Med. 1: 115-117, 123-128

Contact: Prof. Garth L. Nicolson, The Institute for Molecular Medicine, 16371 Gothard Street H, Huntington Beach,
CA 92647 USA; Email: gnicolson@immed.org; Website: http://www.immed.org/

Figure Legends
Figure 1. Incidence of increase in severity of signs and symptoms in 203 patients with CFS/FMS compared to GWI
after the onset of illness. Severity of signs and symptoms was assessed using a Patient Illness Survey Form that
included 114 signs and symptoms. The intensity of signs and symptoms were scored by patients on a 10-point scale (0,
none; 10, extreme) prior to and after onset of illness. Scores were determined in each category (3-9 questions) as the
sum of differences between values prior to and after onset of illness divided by the number of questions in the category.
Changes in socre values of 2 or more points were considered relevant.

Figure 2. Incidence of multiple mycoplasmal infections in 93 CFS/FMS patients. Patients were examined for M.
fermentans, M. pneumoniae, M. penetrans or M. hominis blood infections by Forensic PCR.




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Fi gure 2




                                 0%   20%     40 %   60%     80%
            Mycoplasma                                     >65%
            any infection(s)
            Mycoplasma
            single infection          >15%

            Mycoplasma
            multiple infection                       >50%

            Mycoplasma
            one infection             >15%

            Mycoplasma
            two infections                    >30%

            Mycoplasma
            three+ infections          >20%




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