Infections in CFIDS
By Joseph F. John, Jr., MD and Kenneth Friedman, PhD

Many people with chronic fatigue and immune dysfunction syndrome (CFIDS) suffer from fever, sore throat and lymph node swelling and tenderness. These symptoms often accompany diseases caused by microorganisms such as viruses and bacteria. It seems logical, therefore, that microbial infections could be linked to the development or perpetuation of CFIDS.

Yet the role of infections in CFIDS remains unclear and, in many cases, controversial. Good data suggest that one, or possibly many, microorganisms can trigger the onset of CFIDS or worsen its symptoms. But much work remains to identify these microbes and discover how they may function in CFIDS.

It is clear that at least 50 percent of people with CFIDS (PWCs) have an infectious episode prior to the development of CFIDS.¹ In some cases the inciting event is a mononucleosis-like illness, occasionally a standard Epstein-Barr virus (EBV)-associated mononucleosis. More often, it is a non-specific upper respiratory infection, a sinusitis or bronchitis or occasionally an influenza-like illness, the latter characterized by severe muscle pain, high fever and extreme malaise.

Some PWCs may actually describe vividly an event at a specific date and time of day when they became ill, relating that after that event they never felt healthy again. Paradoxically, the initial symptoms may blur over time for many patients with CFIDS, making them difficult to recapture in the medical history obtained years later.

Looking for a link
Many infectious agents seem capable of inciting CFIDS, but few good studies have linked the illness to specific agents. One early study depicted an outbreak of disease probably associated with human herpes virus 6 (HHV-6) at Incline Village, Nevada. In this outbreak there was evidence of depletion of B-cell lymphocytes, a specific type of immune cell that makes antibodies, and development of symptoms consistent with CFIDS.^1,2

Older observations from Europe suggested that an illness called myalgic encephalomyelitis had occurred in clusters that suggested an infectious/contagious basis for the outbreak.³ Although it is tempting to attribute CFIDS to an unresolved infection secondary to viral infection like mononucleosis or influenza, it is difficult to attribute the constellation of symptoms and signs that currently define CFIDS as due to a single infectious agent.

There is some evidence, however, that CFIDS may be associated with unresolved or persistent infectious agents. For example, most patients with CFIDS have persistently and, at times, markedly elevated antibodies to portions of the EBV, suggesting that their latent infection with EBV has in some way been re-activated. This indicates that they have been exposed to EBV at least once and possibly on an ongoing basis. The same can be said, albeit less assuredly, for HHV-6. Belgian and French co-workers also have reported recently that certain types of bacteria known as Mycoplasma are associated with precipitating or perpetuating the illness.¹ One species of special interest is Mycoplasma fermentans.

Other evidence for an infectious basis for CFIDS hinges on the recent observations that one of the major antiviral pathways in the immune systems of PWCs is dysfunctional. Over the last decade it has become clear that PWCs generate abnormal concentrations of an intracellular enzyme called RNase L.^1,4,5 Activated RNase L serves as one final arm in a more general antiviral pathway, triggered initially outside the cell by a group of compounds called interferons. Interferons are produced in response to foreign double-stranded DNA (usually a virus), and, in turn, stimulate the activation of a substance called 2-5 adenylate inside the cell. This substance activates RNase L, an enzyme capable of degrading single-stranded viral RNA or perhaps other messenger RNA and halting the virus from producing further damage.^4,5

In a sense, this system works as a nonspecific defense mechanism before specific humoral (antibody) and other specific cellular responses take over. Patients with CFIDS tend to fragment the functional, large molecular weight RNase L (80 Kda) and produce instead a dysfunctional, low molecular weight RNase L (37 Kda). So the symptoms suggestive of recurrent viral infections in PWCs may be due to such an alteration in this antiviral pathway.

Weighing the evidence
Very few infectious diseases cause the number and diversity of symptoms seen in patients with CFIDS. The disease that most resembles CFIDS is acute and subacute EBV infection. But patients with mononucleosis tend to be younger and do not suffer from the other primary symptoms of CFIDS such as cognitive dysfunction, sleeping disorders and allodynia.

Nevertheless, EBV was initially thought to be the cause of CFIDS. When blood was tested for antibodies against two EBV replicating enzymes, abnormal titers of antibodies were found twice as often in PWCs than in controls (34.1% vs. 17.1%). While this may indicate a more frequent occurrence of EBV in patients with CFIDS (or perhaps that EBV may precipitate CFIDS in a subset of PWCs), EBV is not the universal cause or precipitant of CFIDS.⁶

Buchwald et al tested 548 chronically fatigued patients, including patients with CFIDS, for prevalence of antibodies to 13 viruses. No consistent differences were found in PWCs compared to control subjects. An earlier study by Mawle et al at the U.S. Centers for Disease Control and Prevention (CDC) could not find elevated antibody titers to any herpes virus, including EBV.⁷ Recently, workers at CDC examined 26 patients and
52 controls for the presence of HHV-6 and HHV-7 and found no differences between patients and controls.⁸

The recent report of an “outbreak” of CFIDS in Japan⁹ which may be affecting as much as one-third of the Japanese workforce may rekindle efforts to identify an infectious agent as the cause of CFIDS. A preliminary report suggests that this is a post-hepatitis B vaccination outbreak and may be due to a contaminating organism.

The failure to find a single virus in all patients with CFIDS has led to the assertion by some that CFIDS is not caused by a viral agent. However, the failure to identify a causative viral agent does not preclude the possibility that CFIDS is caused by a yet-to-be-identified virus or co-infection with two or more viral agents or an unknown infective agent.

An intriguing, unifying hypothesis put forward by Lerner et al is that CFIDS symptoms are caused by a viral infection of the heart.¹⁰ These investigators have described electrocardiographic changes that can be explained by changes in membranes of some heart cells.¹¹ They believe that such changes may be caused by the presence of a virus and claim success with long-term therapy with antiviral medication.

Other non-CFIDS literature documents the ability of viral infection to alter the way that a cell moves substances across its membrane through specific “channels.” Human immunodeficiency virus type 1 (HIV-1) has been shown to inhibit a potassium channel in some brain and human spinal cord cells,¹² while herpes simplex virus has been shown to inhibit sodium channel activity in some nerve cells of adult guinea pigs.¹³ Virus-induced alteration of cell membrane function, therefore, is a possible, but unproven, mechanism of CFIDS pathophysiology.

There is other indirect immunologic evidence for persistent viral infection. Patients with CFIDS often have lower numbers of immune system cells called lymphocytes, in particular CD4+ and CD8+ lymphocytes. This type of depletion should not be confused with the CD4+ depletion seen with HIV infection. In HIV disease the CD4+ to CD8+ ratio is usually reversed.
 
Other diagnoses
Bacteria, viruses and parasites have been linked to fatiguing syndromes including brucella, bartonella and cyclospora.¹⁴ Not widely known, it has been reported that the cat scratch disease due to Bartonella henselae may be present as chronically fatiguing illness.¹¹ In considering bartonella infection as a cause of fatigue, a good history of cat exposure including being licked by or sleeping with the cat and cat scratch disease serology, coupled with newer techniques to amplify bartonella DNA in blood, should help eliminate that diagnosis.

Some patients complain of recurrent oral or vaginal candidiasis. Some may insist that they are chronically infected with yeast, a holdover from the pseudoepidemic promul-gated by some health care providers claiming that many patients with undefined disease had deep-seated, unresolved mycotic infection due to Candida albicans , thus the term “the yeast connection.”¹⁵ Nevertheless, in some patients C. albicans can be cultured at times from the oral cavities and genital tracts. Some patients in fact report improvement of fatigue when oral azoles are used to treat the mucosal infections.

In patients with Lyme disease, exhausting fatigue, deep bone and body pain and cognitive dysfunction are unusual. Nevertheless, in areas of the country where Lyme disease caused by Borrelia borgdorferi is endemic, patients with CFIDS and physicians will fixate on Lyme disease as a cause. To confound the clinical picture, Lyme disease does have a chronic form, and blood serology showing increased antibodies to Borrelia borgdorferi that was positive early in the disease may persist for years. Ehrlichiosis caused by agents related to the rickettsia is an emerging disease endemic in the same geographic regions as Lyme disease. The capacity for E. canis to produce a chronic disease like CFIDS has not been investigated.

As mentioned, workers in Belgium have reported in abstract form an association of circulating peripheral blood cell-associated Mycoplasma fermentans with CFIDS. This bacterium awaits more definitive studies to define its role in CFIDS.

In this age of emerging infectious agents, including those of bioterrorism, other new microbial agents will surely arise as causes of chronic fatigue.

Diagnostic tests
To initiate the workup of PWCs after a thorough history and physical examination, primary care physicians can obtain blood tests for EBV, HHV-6, cytomegalovirus (CMV), toxoplasmosis and HIV. The next level of testing could include other serologies, tests for HHV-6 viremia, RNase L determinations, Mycoplasma, ricksettial or chlamydia DNA amplification by PCR. These advanced tests may be difficult to obtain because of lack of insurance coverage. PWCs often have to secure and pay for this testing themselves by finding the most appropriate laboratory to perform the testing and arranging third-party payment — a very frustrating process indeed.

Regional specialty labs may be helpful to patients arranging specialized diagnostic testing. An infectious diseases physician specializing in CFIDS can assist the primary care physician in choosing tests that may support the diagnosis of CFIDS or other infectious diseases. The chart above outlines the diagnostic tests involving some infectious agents that may be considered for the patients with CFIDS.

Therapy
There are no studies that support the routine use of anti-infective medications in the therapy of CFIDS.¹⁶ Nevertheless, since CFIDS is devastating to individuals and their families, and since there is evidence that CFIDS may be associated with persistent infectious agents, it is reasonable to expect careful trials of antivirals, antibacterials and, in certain instances, antifungal agents.

PWCs with early CFIDS and high titers of antibody to DNA viruses may benefit from a one-to-two month trial of antivirals, usually starting with an agent like valcyclovir at doses of 500 mg two or three times a day. If there is no response at two months, therapy should be stopped.

Ampligen is a 50-base-pair compound consisting of double-stranded RNA that several studies have shown improve the Karnofsky score, a measure of well-being.¹⁷ Ampligen is a proprietary compound manufactured by Hemispherx Biopharma. Preliminary evidence has also been presented to show that Ampligen can decrease the level of low molecular weight RNase L. A current clinical trial now underway with Ampligen compared to placebo will determine if the product will be approved by the federal Food and Drug Administration.

Some PWCs will give a history of a profound response to an incidental antibacterial they had taken in the past. While there are no studies to substantiate empiric use of agents like the macrolides or quinolones, when patients are debilitated it seems reasonable to attempt one- or two-month trials in selected patients who have had such beneficial responses historically. New studies are underway to determine the efficacy of antimicrobials in those patients with evidence of active Mycoplasma infection. Since cytokine regulation may play a role in CFIDS, agents to modulate cytokine pathways like isoprinosine, infliximab or thalidomide will serve as yet another potentially exciting area for clinical trials.^18-20

Dr. Joseph John Jr. is chief of medical specialty services at the Ralph H. Johnson Department of Veterans Affairs Medical Center and Professor of Medicine, Immunology and Microbiology at the Medical University of South Carolina in Charleston. Besides, CFIDS, Dr. John’s diverse research interests include bacterial resistance, staphylococcal infections and infections in hospital settings.

Kenneth J. Friedman, PhD, is associate professor of pharmacology and physiology at the University of Medicine & Dentistry of New Jersey, New Jersey Medical School, in Newark.

References

1. DeMerleir K et al. “A 37 kDa 25 A binding protein as a potential biochemical marker for chronic fatigue syndrome.” Am J Med. 2000; 108:99-105.
2. Buchwald D et al. “Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities.” Arch Intern Med . 1994; 154:2049-53.
3. Lloyd AR et al. “Chronic fatigue syndrome: current concepts of pathogenesis and treatment.” Curr Clin Top Infect Dis . 1999; 19:135-59.
4. Suhadolnik RK et al. “Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome.” Clin Infect Dis . 1994; 18 supp 1:S96-104.
5. Suhadolnik RK et al. “Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res . 1997; 17:377-85.
6. Natelson BH et al. “High titers of anti-Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness.”  J Med Virol . 1994; 42:42-6.
7. Mawle AC et al. “Seroepidemiology of chronic fatigue syndrome: a case-control study.” Clin Infect Dis . 1995; 21:1386-9.
8. Reeves WC et al. “Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case-control study.” Clin Infect Dis . 2000; 31:48-52.
9. French HW. “A Postmodern Plague Ravages Japan’s Workers.” New York Times , East Coast Edition. Feb. 21, 2000, pA4.
10. Lerner AM et al. “A Unified Theory of the Cause of Chronic Fatigue Syndrome.” Infect Dis Clin Prac . 1997; 6:239-43.
11. Lerner AM et al. “Cardiac involvement in patients with chronic fatigue syndrome as documented with Holter and biopsy data in Birmingham, Mich., 1991-93.” Infect Dis Clin Prac . 1997; 6:327-33.
12. Kort JJ et al. “The nef protein of the human immunodeficiency virus type 1 inhibits a large-conductance potassium channel in human glial cells.” Neurosci Lett . 1998; 251:1-4.
13. Fukuda J et al. “Loss of membrane excitability after herpes simplex virus infection in tissue-cultured nerve cells from adult mammal.” Brain Res . 1981; 211:235-41.
14. Soave R. “Cyclospora: an overview.” Clin Infect Dis. 1996; 23:429-35.
15. Renfro L et al. “Yeast infection among 100 patients with chronic fatigue.” Am J Med . 1989; 86:165-8.
16. Whiting P et al. “Interventions for the treatment and management of chronic fatigue syndrome.” JAMA . 2001; 286:1360-68.
17. Strayer DR et al. “A controlled clinical trial with a specifically configured RNA drug...in chronic fatigue syndrome.” Clin Infect Dis . 1994; 18 supp 1:S88-95.
18. Hersey P et al. “Effect of isoprinosine on natural killer cell activity of blood mononuclear cells.” Int J Immunopharmacol . 1984; 6:315-20.
19. Simon LN et al. “Isoprinosine: an overview.” Cancer Treat Rep . 1978; 62:163-9.
20. Yee MF et al. “Treatment of complicated sarcoidosis with infliximab and anti-tumor necrosis factor alpha therapy.” Ann Intern Med . 2001; 135:27-31.

This article was adapted and reprinted with permission from A Consensus Manual for the Primary Care and Management of Chronic Fatigue Syndrome, published in 2001 by The Academy of Medicine of New Jersey, the University of Medicine and Dentistry of New Jersey and The New Jersey Dept. of Health and Senior Services. For more information on the manual, please see Research News in this edition.