Book Notes: From Fatigued to Fantastic

Chapter 5: Infections

In this section:

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Lack of Reliability of Current Testing For Chronic Infections

- Modified from a letter done by me and Dr Kent Holtorf (mostly Kent).

Infections

In a study published in the International Journal of Occupational Medicine, Immunology and Toxicology found that through specialized testing over half of Gulf War Syndrome/CFS patients had active mycoplasma infections that would not have been detected by standard serological IgG and IgM testing and that with a series of 6 week courses of doxycycline, 78% of the patients completely recovered. Additionally, all of recovered patients that were subsequently retested no longer had evidence of infection (187).

A study and review published in the Antimicrobics and Infectious Disease Newsletter discussed the high incidence of mycoplasma infections in CFS. They discuss the fact that the culturing procedures and serological testing are insensitive for detecting intracellular infections due to the fact that there is usually a lack of hormonal response with these infections resulting in “normal” antibody titers or an isolated elevation of IgG antibodies with a lack of IgM antibodies (188). Sophisticated PCR testing found multiple species of mycoplasma in the majority of CFS patients and recommends long term treatment with doxycycline. They found of the 87 GWI/CFS patients treated with antibiotics, most relapsed after the first 6 week trial and most felt worse, but after up to 6 cycles of 6 weeks of therapy approximately 80% of these patients recovered and were able to return to their normal functional capacity. This was not a placebo controlled trial, but they discuss the fact that it is unlikely a placebo effect that most patients felt worse during treatment. They conclude stating that in order to be successful in the treatment of CFS/GWI, a comprehensive treatment approach must be used that addresses the numerous pathophysicolgocal abnormalities, including long term antibiotics therapy. They state, “These infections cannot be successfully treated with the usual short courses of antibiotics due to their intracellular locations, slow proliferation rates, persistence and inherent insensitivity to most antibiotics (188).”

A study by Nasralla et al published in the European Journal of Clinical Microbiology & Infectious Disease entitled Multiple Mycoplasmal Infections Detected in Blood of Chronic Fatigue Syndrome and Fibromyalgia Syndrome Patients investigated the presence of different mycoplasmal species in blood samples from mycoplasma positive patients with chronic fatigue syndrome and/or Fibromyalgia. They found that the majority of patients had multiple species of mycoplasmal infections, with 59% of patients having active M. Pneumonia infections, 48% having active M fermentans infection, 31% having an active M. hominis and 20% having M pentrans (180).

A review published in the 2000 Journal of Chronic Fatigue Syndrome and the Doctors Educational Booklet from the CFIDS Association of America recommends long term antibiotics along with a compressive treatment program that addresses the multi-system dysfunction that has been demonstrated in this condition (190,191).

As stated above, it has been clearly demonstrated that a large number of chronic infections that are seen in the majority of patients with CFS and FM do not illicit the typical IgG and IgM antibody response that is typically used for diagnosis, and numerous studies have clearly demonstrated that there is active mycoplasma infection in the majority of patients with CFS and FM and concombinant treatment with antibiotic is indicated in these patients despite negative IgM antibodies (178-195).

A study by Dylewski et al in the New England Journal of Medicine demonstrates that in immune compromised patients, such as those with CFS/FMS, active infections correlate with elevations in IgG antibodies without elevations of IgM antibody and that a lack of elevation of IgM is not useful in these patients as a way to rule-out active infection. A high clinical suspicion must be maintained and implementation of anti-infective treatment should be based on elevated IgG levels (253).

In addition to mycoplasma, numerous studies have also demonstrated other bacterial and viral infections such as EBV, CMV, HHV-6, enterovirus among others in CFS and FM patients that cause or contribute to the symptoms and demonstrate that these infections are present and that an active infection correlates with an elevated IgG antibody, despite the lack of IgM antibodies (56,197,198,199,200,211,212,335,338,339,340). As with mycoplasmal infections, because these infections are generally not acute but rather intracellular reactivation of an old infection, an elevation of IgM antibodies is typically not seen with active infections of EBV, CMV, HHV-6, Borrelia and enterovirus (56,197,198,199,200,211,212,335,338,339,340). Due to the immune dysfunction seen in CFS, in addition to a lack of IgM antibody formation, there may also be a lack of IgG antibodies present despite the presence of an active infection in CFS patients (213,335,337). This has also been demonstrated to be the case with AIDS patients, as demonstrated in the study published in the New England Journal of Medicine entitled Absence of detectable IgM antibodies during cytomegalovirus disease in patients with AIDS (213). A study by Dylewski et al in the New England Journal of Medicine demonstrates that in immune compromised patients, such as this patient, active infections correlate with elevations in IgG antibodies without elevations of IgM antibody and that a lack of elevation of IgM is not useful in these patients as a way to rule-out active infection. A high clinical suspicion must be maintained and implementation of anti-infective treatment should be based on elevated IgG levels (253).

Immune suppression, as seen in CFS/FMS has been associated with all of members of the herpes virus family (EBV, CMV, HHV-6, etc) and Borrelia infections (201,202). Based on this patient’s laboratory data, including the abnormal NK Cell activity and RNAse-L activity (discussed in laboratory section), and the large volume of studies, there is almost assuredly a chronic infection contributing to many CFS patient’s symptoms, but a clear diagnosis of the specific etiology agent or agents in these patients is difficult and often not attainable by testing provided by standard clinical laboratories and treatment with antivirals has been demonstrated to be effective (203,204,205,206,207,208). None the less, it is clearly appropriate and within standard of practice given the labs and clinical findings in many CFS/FMS cases to give empirical anti-infectious treatments, and to make clinical diagnoses based on the labs and clinical setting. Again, I can understand many physicians’ lack of familiarity with the data and wish to rely only on testing, but when one ignores the patient and treats only the lab tests in these syndromes, a large body of data shows that this is hazardous to the patients’ likelihood of recovering from their disability.

A study published in Acta Pathologica, Microbiologica et Immunologica Scandinavica entitled Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of Chronic Fatigue Syndrome Patients: Association with Signs and Symptoms found 52% of CFS patients had active mycoplamsa infection, 30.5% had active HHV-6 infection, and 7.5% had Chlamydia pneumonia infections vs. only 6%, 9% and 1% of controls, respectively. They conclude, “The results indicate that a large subset of CFS patients show evidence of bacterial and/or viral infection(s), and these infections may contribute to the severity of signs and symptoms found in these patients (181).”

A study entitled A Chronic Illness Characterized by Fatigue, Neurological and Immunological Disorders, and Active Human Herpes virus Type 6 Infection published in the Annals of Internal Medicine found 70% of patients with CFS had active HHV-6 infection through the use of primary cell cultures and confirmation using assays of monoclonal antibodies specific for HHV-6 proteins and by PCR (Polymerase chain reaction). Again, an elevation of IgM antibodies is generally not seen (209).

As summarized below, when specialized testing is used to detect active vs. past infection of HHV-6, the overwhelming number of studies demonstrate a high incidence of active herpes virus infections. These reactivation infections often do not elicit an IgG and especially not an IgM response, so standard serologic testing is specific but not sensitive for such infections. As mentioned before, PCR testing in a research setting is much more reliable, sensitive and useful than in the clinical setting when the blood is usually not processed for 12-48 hours.

Wagner et al, found that 61% of CFS patients with elevated IgG antibodies and 81% with immune deficiency, as seen in this patient, had confirmed active HHV-6 infection vs only 19% of those patients who did not. This is regardless of whether or not IgM antibodies were elevated.

A study by Lerner, Chief of the Division of Infectious Diseases and a Professor of Internal Medicine at Wayne State University School of Medicine found that treating patients with 6 months of Valtrex resulted in significant improvement in symptoms (215). In a separate study, Lerner et al found that in CFS patients with elevated IgG antibody against CMV, treatment with the intravenous antiviral ganciclovir, which has a more broad spectrum coverage than Valtrex and anti-CMV activity, resulted in 72% of patients returning to their premorbid health states (total resolution of symptoms)(216). A randomized, placebo controlled study published in Clinical Infectious Diseases, demonstrated that in CFS patients with an elevated IgG antibodies against CMV, a combination of oral Valtrex and intravenous ganciclovir resulted in dramatic improvements with almost complete resolution of symptoms (217).

There is also evidence that CFS may be due to the above discussed infections with “stealth adaptation" (319,320,321,322,323,324,325,326,327,328,329). This is primarily due to the deletion of the genes coding for the major antigenic components normally targeted by the cellular immune system. “Stealth viral adaptation” results in replication that is less efficient than conventional viruses, but has a distinct advantage over conventional viruses in not having to confront the body's cellular immune defense mechanisms. They can, therefore, evade the immune system and create persistent ongoing infections in spite of an individual's intact immune system (319,320,321,322,323,324,325,326,327,328,329).

Testosterone Treatment

The same problems with testing for testosterone occur in this population as with other hormone tests, In addition, subclinical decreased cardiac function during exercise has been implicated as playing an important role in CSF and CHF is responsive to testosterone as is the muscle weakness present in these patients and thus testosterone replacement has been used in CFS and FM. For example, there is new research from a New Jersey team, authored by Doctors Arnold Peckerman, Benjamin Natelson et al., which found left-ventricular dysfunction following exertion and orthostatic stress in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Professor A. Martin Lerner argues that a prominent subset of the disease is a prolonged, chronic mononucleosis following infection with Epstein Barr virus (EBV), Human Cytomegalovirus (HCMV), or both, and/or possibly Human Herpes Virus 6 (HHV-6). Viral infection persists in the heart, causing left-ventricular dysfunction, producing exercise intolerance. Exercise, in turn, worsens the cardiac dysfunction. He has also postulated that the disease is an early dilated cardiomyopathy. More recently, physicist, physician, long-time ME/CFS researcher and clinician, and heart-transplant recipient Dr. Paul Cheney, M.D., Ph.D., has offered an alternative theory that a subset of ME/CFS patients suffer from a diastolic cardiomyopathy, a problem with ventricular filling. (361,362,363,364,365). Testosterone therapy has been shown to augment cardiac function in CHF (366). In addition, low RBC mass is very common in CFS (367) and optimizing testosterone levels increases RBC mass.

Laboratory tests

Some physicians feel that testing for infections in CFS/FMS is excessive and unnecessary. I agree that tests should not be done unless they have a reasonable likelihood of changing treatment decisions. However, the extensive testing is usually appropriate, useful and aids in therapeutic decision-making in CFS/FMS. Let’s discuss some of the tests that may seem excessive to someone not familiar to the complex pathophysioiolgy present in CFS and FM.

Natural Killer (NK) Cell Activity-Numerous studies have demonstrated that abnormally low NK cell activity is an objective measure of CFS and significant disability (276,277,278). In a study entitled Decreased Natural Killer Cell Activity Is Associated with Severity of Chronic Fatigue Immune Dysfunction syndrome, published in the Journal of Clinical Infectious Diseases, it was demonstrated that all normal individuals and all of those who suffer from only mild symptoms of CFS had normal NK cell activities while only those with severe disease had an abnormal NK cell activity (276). It can direct treatment as those with low NK cell activity will more often require treatment for chronic infections and neurologic abnormalities (278,279,280). It is also useful to monitor treatment response (279).

NK cell activity can differentiate those with an infectious etiology of CFS from non-infectious etiologies. Obtaining this test was extremely useful as it is used to direct treatment and provide information as to whether or not an infectious panel should be obtained. If this test was not obtained, it would require significantly more time and cost to obtain a correct diagnosis and consequently, the treatment would be less effective and cause needless risk.

Natural Killer cell activity is necessary to demonstrate the presence and level of immune deficiency in this patient. If this information was not obtained, I would not have the information needed to determine whether or not to treat an immune dysfunction. It would be inappropriate to expose the patient to treatment and the risks of treatment without first determining if an immune deficiency exists. If there is an immune deficiency and it is not treated, there is little hope of a positive outcome. Low NK Cell Activity makes the body unable to eradicate infections that would normally be fought off and allow reactivation of previously suppressed viruses.

The study entitled Immunologic Abnormalities in Chronic Fatigue Syndrome published in the Journal of Clinical Microbiology not only demonstrated that an abnormally low NK cell activity is a marker of CFS but that it also leads to reactivation of viruses (280). The authors conclude, “In summary, the results of the present study, in which a number of the attributes of immunologic function were determined in a single cohort of patients, as well as the combined results of a number of studies in the literature that was reviewed, suggest that CFS is a form of acquired immunodeficiency. This deficiency of cellular immune function was present in all the subjects that we studied. It has several manifestations, with NK cell dysfunction being the most consistent abnormality. The type of immune dysfunction observed would be anticipated to result in a propensity for chronic and recurrent EBV infection as well as other herpes virus infections (280).”

It is necessary to determine the presence and level of immune dysfunction in CFS/FMS. Stating this testing is not medically necessary is like stating that the measurement of immune dysfunction in an AIDS patient is not medically necessary. Natural killer cell activity is medically indicated for this patient (276-280).

RNAse-L-Activity-The RNAse-L-Activity is used to differentiate an active infection from other etiologies of CFIDS. Obtaining this test is medically useful to direct treatment and provide information as to whether or not there is an infectious etiology contributing to this patient’s condition. There are a number of studies that support the importance of this test (282,283,284,285,286,287,288).

This patient had a number of indicators that he was suffering from a chronic viral or intracellular bacterial infection, including a very low Natural Killer Cell (NKC) Activity and a very high RNAse-L-activity. These are discussed individually in the laboratory section.

Regarding suspected Mycoplasma, Lyme Disease, Chlamydia and Epstein-Barr Virus, studies indicating very high incidences of these infections with patients with CFS and FM are discussed as well as the fact that numerous studies confirm the fact that the typical method to diagnose an active infection (elevated IgG and IgM antibodies) is not typically useful in CFS patients, as they very frequently do not produce IgM antibodies despite having an active infection (178, 191, 192, 193, 194, 195, 187, 188, 253, 56, 197, 198, 199, 200, 211, 212, 335, 338, 339, 340).

Nijs et al published a study in the Journal Immunology and Medical Microbiology entitled High Prevalence of Mycoplasma infections among European Chronic Fatigue Syndrome Patients demonstrated that 68% of CFS patients had an active mycoplasma infection as diagnosed with polymerse chain reaction (PCR)(178). Being predominantly intracellular, there is typically not a significant serologic antibody response or just an isolated IgG response with this number of other intracellular infections so IgG and especially IgM antibodies are almost always in the normal range despite the presence of an active infection (178,191,192,193,194,195,253).

Numerous infections have been demonstrated in CFS, including Mycoplasma, Chlamydia Pneumonia, EBV, CMV, HHV6 and Borrelia (Lyme), but IGM antibodies are not helpful. As stated by Nijs, “Mycoplasma detection based on antibody test is characterized by a very high specificity [if IGG and IGM positive], but extremely low sensitivity [active infection almost always present without elevated IgG and IgM antibodies] renders it useless as a diagnostic tool (178).” A study by Dylewski et al in the New England Journal of Medicine demonstrates that in immune compromised patients, such as this patient, active infections correlate with elevations in IgG antibodies without elevations of IgM antibody and that a lack of elevation of IgM is not useful in these patients as a way to rule-out active infection. A high clinical suspicion must be maintained and implementation of anti-infective treatment should be based on elevated IgG levels (253).

A study entitled Diagnosis and Treatment of Chronic Mycoplasmal Infections in Fibromyalgia and Chronic Fatigue Syndrome: Relationship to Gulf War Illness published in Biomedical Therapy investigated the presence of active mycoplasmal infection by forensic PCR in patients with CFS and/or FM vs. controls. They found that 63% of CFS/FM patients had active mycoplasmal species infection compared to 9% of normals and more specifically the incidence of active Mycoplasma fermentans infection was 50% in CFS/FM patients vs. 0% of controls. They also treated and recommend treatment in these patients with long-term doxycycline.

The authors conclude, “We have proposed that chronic infections are an appropriate explanation for the morbidity seen in a rather large subset of CFS, FMS, GWI [Gulf War Illness] and some arthritis patients… Chronic infections, such as those caused by mycoplasmas, are likely to be an important underlying cause of morbidity in a rather large subset of CFS, FMS, GWI and arthritis patients.191-3, 26, 27 Before systemic mycoplasmal infections can be considered important in causing disease, certain criteria must be fulfilled:191-35 [a] 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 only a few percent compared to about one-half of Gulf War Illness patients.191-26, 27 [b] More of the mycoplasma must be recoverable from diseased patients than from those without disease. This has been found.191-26, 27 [c] An antibody response should be found at higher frequency in diseased patients than in those without disease. This has been seen, but usually not until the disease has progressed. According to Lo et al.191-15, 36, 37M. fermentans hide inside cells and do not elicit a strong immune response until near death. [d] A clinical response should be accompanied by elimination of the mycoplasma. This is exactly what has been found.191-26, 27 [e] Clinical responses should be differential, depending on the type of antibiotic. Only antibiotics that are effective against the pathogenic mycoplasmas result in recovery, and some antibiotics, such as penicillins, can worsen the condition.191-26, 27 [f] The mycoplasma must cause a similar disease in susceptible animals. The best description comes from Lo et al.,191-36…These animals display initially many chronic signs and symptoms. [g] The mycoplasma must cause a similar disease when administered to volunteers. This has not been done, because of ethical considerations. [h] A specific anti-mycoplasma antibody reagent or immunization protects against disease. This has not yet been done to our knowledge. Therefore, six out of eight of the above criteria have been fulfilled, at least in cases of M. fermentans…Multiple cycles of these antibiotics plus a nutritional support appear necessary for recovery (191).”

A study published in the International Journal Medicine Biology Environment tested the blood of 565 CFS and/or FM patients vs. 71 healthy controls. They found 53.1% of patients were positive for mycoplasmal infection vs. only 7 out of 71 controls and 24.6% of patients had an M. fermentans infection vs. 2.8% of normals (196).

A review published in Rheumatology International entitled Mycoplasma Blood Infection in Chronic Fatigue and Fibromyalgia Syndromes recommends long term doxycycline therapy stating that these patients...“appear to recover and reach their preillness state after long-term antibiotic therapy with doxycycline, and infection can not be detected after recovery (179 ordered study).” PCR testing has been extensively validated and shown to be very sensitive and specific for an active infection when done in research studies and the blood is immediately processed, but the delay in processing that occurs with clinical laboratories significantly reduces its sensitivity, making it not useful in clinical practice (21,191).

Footnotes and References:

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