ME/CFS: The Challenge of Chronic Iilness:  A Role for Complex Infections and Channelopathy, Proceedings of the Intern. ME/CFS Conference, T. K. Roberts, ed., Lloyd Scott Publishers, Sydney, Australia, 1999

THE ROLE OF CHRONIC INFECTIONS IN THE MAINTENANCE 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 

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 illnesses, 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.  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. hominis, M. penetrans) in ~60% and ~70% of patients, respectively.1,11  In over 200 GWI patients we found mycoplasmal infections (primarily M. 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 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., in press

 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

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 St. H, Huntington Beach, CA 92647 USA, Tel: +1-714-596-6636; Fax: +1-714-596-3791; Email: gnicolson@immed.org; Website: 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.