Chronic Co-Infections in Fibromyalgia Syndrome, Chronic Fatigue Syndrome and Other Chronic Illnesses

Prof. Garth L. Nicolson
The Institute for Molecular Medicine (Website www.immed.org)
1631 Gothard Street H, Huntington Beach, CA 92647 USA

Fibromyalgia Syndrome (FMS), Chronic Fatigue Syndrome/Myalgic Encepthalomyelitis (CFS/ME) and Gulf War Illnesses (GWI) present with similar chronic signs and symptoms.  One characteristic difference is that FMS patients present with widespread pain, but this is sometimes seen in CFS/ME and GWI.  This is why we originally proposed that GWI is a CFS/ME or in some patients a FMS like-illness [1].  Other chronic illnesses, such as Rheumatoid Arthritis (RA), Inflammatory Bowel Disease, among others, also show many of the same signs and symptoms, suggesting that there may be some overlap in the underlying causes of these chronic conditions or at least in the factors that could result in sickness (morbidity) or illness progression [2].

Infections Cause Morbidity in Many Chronic Illness Patients

Although the causes of chronic illnesses are for the most part unknown, the complex signs and symptoms that evolve in many, perhaps even a majority of patients, may be due, in part, to systemic chronic infections (bacteria, viruses, fungi).  Such infections can follow acute or chronic chemical or other insults (viral, environmental, trauma, etc.) that have the potential to suppress the immune system and cause endocrine dysfunction, and this may be the link between chronic illnesses [2].  Chronic illnesses probably evolve over time as a multi-step process that may require multiple toxic exposures, including infections that can be causative for illness in some patients, cofactors for illness (not cause the illness but important to morbidity), or they can be opportunistic in immune-compromised patients.  Chronic infections that are usually held in check by our immune systems can take hold if they can avoid immune surveillance and penetrate and hide in various tissues and organs, including cells of the Central and Peripheral Nervous Systems.  When such infections occur, they can cause many of the complex signs and symptoms seen in CFS/ME, FMS, RA and GWI, including widespread pain and immune dysfunction [2].  This is especially apparent when peripheral nerves are infected, such as in FMS patients, causing changes in sensitivities and pain thresholds.  Changes in environmental responses as well as increased titers to various endogenous viruses that are commonly found to be expressed in these patients and may be a natural consequence of immune dysfunction. 

Chronic infections may also be important cofactors in some illnesses, including HIV-AIDS and other immunodeficiency disorders,  skin diseases, metabolic diseases and some neurodegenerative and autoimmune diseases [3].  It is proposed that autoimmune signs and symptoms are caused when intracellular pathogens, such as mycoplasmas and other bacteria, escape from cellular compartments.   Microorganisms like mycoplasmas can incorporate into their own structures pieces of host cell membranes that contain important host membrane antigens that can trigger autoimmune responses, and they can also mimic host cell antigen structures.  Thus patients with such infections may respond immunologically to microorganism antigens as well as their own membrane antigens, producing unusual autoimmune signs and symptoms. 

Bacterial Infections in Chronic Illnesses

Bacterial (Mycoplasma, Chlamydia, Borrelia, Brucella, etc.) infections have been commonly found in CFS/ME, FMS, RA and GWI patients [2, 3], and these infections are thought to be important factors in the illnesses that require physicians’ attention.  Although chronic illness patients like other patients are exposed to various bacterial pathogens, only certain bacterial species have the capacity to cause the signs and symptoms found in chronic illnesses.  

As an example, one type of airborne microorganism that has received renewed interest of late as an important cause, cofactor or opportunistic infection in these disorders is represented by various primitive classes of bacteria [2].  These microorganisms, principally Mycoplasmas and other primitive bacteria (Chlamydia, Coxiella, Brucella, Borrelia, etc.), although not as well known as other agents in causing disease, are now considered important emerging pathogens in various chronic diseases where a majority of patients show evidence of these infections in their blood.   In our recent study on CFS/ME and FMS patients, most patients had multiple bacterial infections, especially if they had been sick for many years or had severe signs and symptoms [4].  These infections invade the vascular system and cause coagulation problems, and they can cause or increase the risk of coronary diseases, such as endocarditis and myocarditis.

We also found that some CFS/ME patients have Brucella or Chlamydia infections.  Although few urban CFS/ME patients have Brucella infections, these are more commonly found in rural CFS/ME patients.  Chlamydia pneumoniae infections were found in approximately 7% of CFS/ME patients and one control subject out of 100 that also did not have other bacterial or viral infections [5].  This finding is similar but somewhat lower than previously reported for CFS patients [6].  We also found that Brucella sp. infections were relatively common, especially in rural regions, and were found in approximately 10% of CFS/ME patients [7]. 

Viral Infections in Chronic Illnesses

Another type of infection that appears to play an important role in various chronic illnesses is viral in origin.  Different types of viruses have been found in CFS/ME, FMS and various autoimmune diseases.  One of the most common viral infections found in CFS/ME patients is Human Herpes Virus-6 or HHV-6 [8, 9].  Antibodies against HHV-6 are routinely found in CFS patients, and most of these patients have the HHV-6A variant [10].   HHV-6 appears to play a role as a major contributing factor in several chronic illnesses [8, 9].  Although several studies have associated HHV-6 with CFS [10-14], there are also reports that could not find an association with CFS/ME [15, 16]. When we studied CFS/ME patients we found that approximately 31% had HHV-6 infections [5].  Others have found even higher percentages of CFS/ME patients with HHV-6 infections [10-13]. In control subjects without evidence of signs or symptoms we found HHV-6 infections in 9 of 100 subjects.  None of these HHV-6-positive control subjects had other infections [5].

In addition to HHV-6, cytomegalovirus or CMV has been found in various chronic illness patients.  

Multiple Co- nfections in Chronic Illnesses

Previously we found multiple co-infections of various mycoplasma species in a majority of North American [4] and European [17] CFS/ME patients.  This occurred when one of the mycoplasma species was either M. fermentans or M. hominis.  When we examined the incidence of active HHV-6 infections in mycoplasma-positive and –negative CFS/ME patients, we found that there was no preference for HHV-6 infections in mycoplasma-infected patients.  For example, we found that the incidence of HHV-6 in mycoplasma-positive patients was 30.7%, whereas in mycoplasma-negative patients HHV-6 infections were found in 30.2% of patients.  There was also no preference for particular Mycoplasma species in HHV-6 co-infections  [5].  
When we examined the incidence of C. pneumoniae infections in mycoplasma-positive and –negative patients, we found that there was no preference for multiple infections, nor was there a preference for particular Mycoplasma species in C. pneumoniae+mycoplasma co-infections.  In 104 mycoplasma-positive patients C. pneumoniae infections were found in 8 patients (7.7%), whereas in 98 mycoplasma-negative patients C. pneumoniae infections were found in 7 patients (7.3%).  Similarly, in 61 HHV-6-positive patients C. pneumoniae infections were found in 5 patients (8.2%), whereas in 139 HHV-6-negative patients C. pneumoniae infections were found in 10 patients (7.2%) [5].

An unexpected finding in our study was that Mycoplasma species, Chlamydia pneumoniae and HHV-6 infections were not clustered together in CFS patients.  When we examined the incidence of Chlamydia pneumoniae or HHV-6 in mycoplasma-positive or –negative CFS patients, we found no differences, indicating that clustering of these infections is not more likely in certain CFS patients.  Although patients that had multiple infections had on the average more severe signs and symptoms, we did not find differences between the types of infections and signs and symptoms.  The signs and symptoms of CFS are relatively non-specific; therefore, the possibility of unique patient subsets with different patterns of signs/symptoms based on the types of infections present is probably unlikely and consistent with the results that we obtained

Family Study Shows that Some GWI Patients Have a Contagious Illness

As found in previous studies [18, 19], veterans of the Gulf War with chronic illnesses (Gulf War Illnesses or GWI) display multiple signs and symptoms.  Upon examination, the signs and symptoms of GWI were indistinguishable from civilian patients in the same immediate family diagnosed with Chronic Fatigue Syndrome or CFS, expect for symptomatic children aged 3-12 who were also diagnosed with autism [20].  Similar to previous studies on GWI patients [18, 19], we found that 45 of 110 patients or ~42% had mycoplasmal infections , and almost all of these (37 out of 45 or ~82%) were single infections (one species of mycoplasma) [8].   M. fermentans was found in ~85% of these single infection cases.  When the few multiple species infection cases were examined, most were found to have combinations of M. fermentans plus either M. pneumoniae, M. hominis or M. genitalium.  In contrast, in healthy control subjects only 6 of 70 subjects (8.5%) were positive for mycoplasmal infections, and all of these were single species infections of various types [20].  Comparing GWI patients and non-symptomatic control subjects, there was a significant difference in the incidence of mycoplasmal infections (P<0.001).  However, significant differences in infection incidence or species of mycoplasmal infection between male and female GWI patients or control subjects were not seen in these patient groups [20]. 
In families of Gulf War veterans with GWI there was evidence of transmission of the illness to immediate family members.  In our study the families were not randomly chosen; they were families in which one or more veteran members were found to be positive for a mycoplasmal infection and one or more family members reported illnesses.  We found that 57 out of 107 (53.2%) of these members from families with one or more Gulf War veteran diagnosed with GWI and with a positive test for a mycoplasmal infection showed symptoms of CFS (and autism or attention deficit hyperactivity  disorder in their children).  Among CFS-symptomatic family members, most (40 out of 57 or 70.2%) had mycoplasmal infections compared to the few non-symptomatic family members who had similar mycoplasmal infections (6 out of 50 or 12%) [20].  When the incidence of mycoplasmal infection(s) was compared within families, the CFS-symptomatic family members were significantly more likely to have mycoplasmal infections compared to non-symptomatic family members (P<0.001).  Symptomatic children (mostly diagnosed with autism and other chronic disorders) in these families were also infected with mycoplasmas at high incidence, but this was not seen in aged-matched control subjects (data not shown).  Although some non-symptomatic family members did have mycoplasmal infections (6 out of 50 or 12%), this was not significantly different from the incidence of mycoplasmal infections in control subjects (6 out of 70 or 8.5%).  Some of these control subjects may be carriers and some may eventually present with CFS or other illnesses related to mycoplasmal infections.
The mycoplasma infection types were also similar between GWI patients and their CFS-symptomatic family members.  In 45 mycoplasma-positive CFS-symptomatic family members, most (31 out of 40 or 77.5%) had single species infections, similar to the mycoplasma-positive Gulf War veterans (37 out of 45 or 82%).   Most mycoplasma-positive GWI patients as well as mycoplasma-positive family members with CFS or children diagnosed with Autism had M. fermentans.  We did not find differences in the incidence of infection or type of infections between males and females, children versus adults or spouses versus other family members.  However, similar to previous reports, the time of onset of CFS illness after the Gulf War tended to be shorter in spouses than other family members, but these differences did not achieve significance [20].

Possible Source of Microorganisms found in Chronic Illness Patients

Most microorganisms like mycoplasmas are not considered as important human pathogens when they are found at superficial sites, such as the oral cavity or gut, but some species, such as M. fermentans, M. penetrans, M. pneumoniae, M. genitalium, M. pirum  and M. hominis, among others, have the capacity to penetrate into the blood circulation and colonize various tissues, and these cell-penetrating microorganisms have been closely associated with various human diseases [2, 3].  Do such infectious agents actually cause CFS/ME, FMS, GWI or RA?  Probably not on their own, but microorganisms like Mycoplasma, Chlamydia, Brucella, Coxiella and other bacteria and some viruses, in particular HHV-6 and CMV, appear to be important in causing chronic illness progression and patient morbidity, exacerbating the major signs and symptoms seen in patients with chronic illnesses.  Our recent results have shown that the combination of multiple bacterial and viral infections can be particularly difficult for patients to overcome, and when multiple infections occur, they are inevitably associated with more severe signs and symptoms [5].

How do patients contract the bacterial and viral infections found in FMS, CFS/ME, RA and GWI?   The answer to this is not known, but many patients may already have these infections in dormant or latent forms, and their triggering of illness may be associated with a decline in the ability of the immune system to hold them in check.  In some cases it is associated with an acute illness or acute infection or acute trauma, such as an accident.  In other patients, infections may occur by a variety of routes, including airborne transmission, fluid exchange (such as blood transfusions or sexual intercourse), or in contaminated vaccines.   Only rarely are vaccines contaminated, and most vaccinations would not be expected to cause illness, but in some commercial vaccines contamination has been documented.   For example, some of the more common contaminants of commercial vaccines are mycoplasmas [21].

In the case of GWI, the multiple vaccines that the Armed Forces received upon deployment to the Persian Gulf have recently been associated with GWI.  Unwin and colleagues [22] studied British Gulf War veterans with GWI and found an association with the multiple vaccines that they received during deployment.  In the United States there has been a rash of GWI signs and symptoms in Armed Forces personnel who recently received the anthrax vaccine.  In some cases this has resulted in chronic illnesses in as many as 7-10% of personnel receiving the vaccine [23].  The chronic signs and symptoms associated with anthrax vaccination are very similar to those found in GWI patients, suggesting that at least some of the chronic illnesses suffered by veterans of the 1991 Gulf War may have been caused by vaccines in combination with other exposures [23].  The anthrax vaccine, in particular, should not be used in Armed Forces personnel because of valid questions concerning its safety and efficacy.

Antibiotic and Antiviral Treatments for Chronic Illnesses

When microorganism infections are identified in blood fractions of subsets of patients with CFS/ME, FMS, GWI or RA, these patients can be treated as medical not psychological or psychiatric patients, just like any other patients with blood bacterial infections.  This does not mean that psychological or psychiatric problems are not important in some chronic illness patients.  But if such infections are important in these disorders, then appropriate treatments with antibiotics, antivirals or other medications that suppress chronic infections should result in improvement and even recovery.  This is exactly what has been found [24].

Long-term treatment with antibiotics is required for the types of bacterial infections found in CFS/ME, FMS, GWI and other chronic illnesses.  Few patients recover after only a few cycles of therapy [18, 19, 24], possibly because of the intracellular locations of the infections and the slow-growing nature of most of these microorganisms.  We now recommend that patients who have been diagnosed with blood infections receive continuous antibiotics for at least 6 months before using 6-week cycles of treatment.  Although patients starting such therapy usually have Herxheimer reactions and feel initially worse due to die-off or release of toxic materials from damaged microorganisms, they eventually stabilize and then slowly begin to recover.  Unfortunately, the treatment requires long-term therapy and recovery is usually very slow.  Patients that have been sick for many years are unlikely to recover within a year of therapy.  

The clinical responses with antibiotics that are seen are not due to placebo effects, because administration of some antibiotics, such as penicillins, resulted in patients becoming more not less symptomatic.  In addition, they are not due to immunosuppressive effects of some of the antibiotics, because other antibiotics that do not cause immune suppression are also effective but only if they suppress the chronic infections.  Some patients recover to a certain point and then fail to continue to respond to the recommended antibiotics, suggesting that other problems, such as viral infections, environmental exposures and other toxic events also play an important role in these illnesses, and may even play a predominant role in some patients.  

Since many patients also have viral (HHV-6, CMV, etc.) infections, these must also be treated.  For severe infections, there are some antivirals that can help, but most patients do well on immune enhancement and nutritional supplements (see www.immed.org for further information).

A variety of over-the-counter products also appear to be useful, and I noticed that many of these are already advertised in your newsletter, such as plant natural products and remedies.

Complex Role of Toxic Exposures in Chronic Illnesses

Do chronic infections explain illnesses like CFS/ME FMS, RA or GWI?  It is unlikely that there are only one or even a few explanations for complex chronic illnesses.  Rather, these illnesses are probably due to a combination of multiple toxic exposures, chemical and biological, in combination with genetic susceptibility (immune systems and/or detoxification systems) that determines whether a person becomes chronically ill.  These considerations probably also play an important role in determining who will recover to various extents on different types of therapy.  In addition, recovery can be complicated by patients’ over-dependence on drugs, such as certain antidepressants or other drugs that can suppress portions of the immune system.

The treatments of chronic illnesses that are due to toxic exposures from chemical or radiological agents are quite different from the treatment of chronic infections. The treatment of chemically exposed patients usually involves removal of offending chemicals from the patient's environment, depletion of chemicals from the patient's system and treatment of the signs and symptoms caused by chemical exposure(s).  Chemically exposed patients are often extremely sensitive to a variety of commonly encountered chemicals, including perfumes and air fresheners, petrochemical fumes, chlorine, cleaning solutions and solvents, among others.  They are also very sensitive to certain foods, and special diets are often necessary, and in some cases direct skin contact with certain substances can cause strong cutaneous reactions.  Therefore, an important part of treatment for chemical exposures requires limiting exposures to a variety of common chemicals and gradual removal of the toxic chemicals [25].

For Further Information

The Institute for Molecular Medicine is a nonprofit research organization.  It does not test or treat patients unless they are part of an approved, ongoing clinical trial at the Institute.  It does, however, provide free information for patients, physicians and other health care workers on chronic illnesses.  The website for further information is: www.immed.org.
 
Contact:

Prof. Garth L. Nicolson
The Institute for Molecular Medicine (website: www.immed.org)
16371 Gothard Street H, Huntington Beach, CA 92647
Tel: 949-715-5978 Fax: 714-596-3791
email: gnicolson@immed.org

References

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2. Nicolson GL, Nasralla M, Hier J, et al. Mycoplasmal infections in chronic illnesses: Fibromyalgia and Chronic Fatigue Syndromes, Gulf War Illness, HIV-AIDS and Rheumatoid Arthritis. Med. Sentinel 1999; 4:172-176. 

3. Nicolson GL, Nasralla M, Franco AR, De Meirlier K, et al. Mycoplasmal infections in chronic diseases.  J. Chronic Fatigue Syndr. 2000; 6(3/4):23-39.

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