Mycoplasmal Infections
Diagnosis and Treatment of Gulf War Illness/CFIDS Patients

CFIDS Chronicle 9(3): 66-69 (1996)
Garth L. Nicolson, Ph.D.
Nancy L. Nicolson, Ph.D.

Introduction--The problem

Returning U.S. and coalition military forces from Operation Desert Storm/Desert Shield have reported a variety of health problems, including a collection of signs and symptoms characterized by disabling fatigue, intermittent fever, muscle and joint pain, impairments in short-term memory, headaches, skin rashes, gastrointestinal and respiratory problems and a collection of additional symptoms that has defied a careful case definition.1 This disorder has been called Persian Gulf War Syndrome, Gulf War Illness (GWI) or Desert Storm Illness, and it has afflicted approximately 100,000 Desert Storm veterans and their immediate family members. Since the signs and symptoms of GWI were not well established as criteria for particular illnesses and they did not readily fit into common military or Veterans Administration diagnosis categories, this has resulted in unknown diagnoses, or they have been diagnosed with psychological problems, such as Post Traumatic Stress Disorder.1 Military personnel that we interviewed were particularly disdainful of this explanation for GWI. Although the concept of a distinct syndrome peculiar to the Persian Gulf Theater of Operations has been advanced, it has not been proven,2 and we prefer to use the term Gulf War Illness instead of Gulf War Syndrome.

Recently Major General Ronald Blanck, commanding officer of Walter Reed Army Medical Center in Washington DC, stated at a recent CFIDS Association meeting that the symptomology of GWI is analogous to Chronic Fatigue-Immune Dysfunction Syndrome (CFIDS).3 At about this time we were in the process of analyzing our data on approximately 650 GWI patients,4,5 and we fund that the signs and symptoms of these GWI patients fit quite closely with the literature signs and symptoms of CFIDS6,7 (Figure 1).5 The classical working case definition of CFIDS is that of Holmes et al.8, who proposed that CFIDS is primarily characterized by persistent or relapsing, debilitating fatigue or easy fatigability in a person who has no previous history of similar symptoms, that does not resolve with rest and is severe enough to reduce or impair average daily activity below 50% of the patient's premorbid activity level. In addition to the absence of clinical conditions that could easily explain the symptoms, such as malignancies or autoimmune diseases, patients present with mild fever, sore throat, joint and muscle pain, generalized muscle weakness, headaches, painful lymph nodes, sleep difficulties, and neuropsychologic complaints, such as memory loss, light sensitivity, confusion, transient visual problems, irritability and depression.8 These CFIDS signs and symptoms closely parallel those found in GWI (Figure 1).4,5

A few of the patients that have some of the multiple chronic symptoms shown in Figure 1 may eventually have their diagnoses linked to chemical exposures in the Persian Gulf, such as oil spills and fires, smoke from military operations, chemicals on clothing, pesticides, chemoprophylactic agents, chemical weapons and others. In some cases, such exposure may have resulted in Multiple Chemical Sensitivities (MCS). MCS shares some but certainly not all of the symptoms in Figure 1. In many of the soldiers with GWI the spread of the illness to immediate family members was not consistent with a diagnosis of MCS. The U.S. Senate Committee on Banking, Housing and Urban Affairs found that 77% of the spouses and 65% of the children of GWI patients have developed the same or similar signs and symptoms. Thus we feel that the most appropriate syndrome that characterizes GWI is CFIDS, and this type of GWI/CFIDS is apparently being transmitted to close family members.5

Hypotheses on the origin of Gulf War Illness

Several hypotheses have been advanced to explain the pathophysiologic origins of CFIDS, but the model of Cheney10 is particularly useful in discussing the complex, multiorgan signs and symptoms of CFIDS. In this model, the syndrome is initiated by immune activation and the stimulated release of interferons and cytokines that cause neurotoxicity and other systemic effects. We have proposed that GWI/CFIDS may be initiated by host responses to chronic infectious agents resulting in interferon and cytokine production.5 There were a number of potential sources of chronic infectious agents in the Persian Gulf Theater of Operations, including the vaccines that were used to immunize soldiers, endogenous infectious agents in the Persian Gulf, blow-back of Chemical/Biological Warfare (CBW) agents from bombing of CBW factories and supply depots and offensive Iraqi CBW weapons mounted on SCUD missiles and other projectiles. Of these, we consider the most likely sources of potential chronic infectious agents to be the vaccines and Iraqi offensive CBW weapons, some of which were originally purchased from U.S. companies and transferred to Iraq.9 We have concluded that in addition to the signs and symptoms, the causes of GWI/CFIDS are also complex, and as a disease it is probably caused by several types of agents or conditions.4

We have concentrated on chronic infectious agents as one possible cause for GWI/CFIDS. Irrespective of the source(s) of possible chronic infectious agents, it was necessary to develop diagnostic procedures to identify if these agents might be present in at least some of the Operation Desert Storm veterans and their family members who have GWI/CFIDS. From our own experience with GWI/CFIDS (our step-daughter returned with GWI/CFIDS 6 months after service in Operation Desert Storm in a U.S. Army Airborne Division; eventually our entire family presented with CFIDS signs and symptoms), we suggested that most of the GWI/CFIDS signs and symptoms could be explained by chronic pathogenic mycoplasma infections.11 Mycoplasma infections usually produce relatively benign diseases limited to particular tissue sites or organs, such as urinary tract or respiratory infections; however, the types of mycoplasmas that we have detected in Desert Storm veterans and their family members that may be causing the CFIDS and other symptoms are very pathogenic, colonize a variety of organs and tissues, and are difficult to treat.12

Mycoplasmal infections in GWI/CFIDS patients

Our personal experience with GWI/CFIDS suggested that this disorder might respond to particular antibiotics that are known to be effective against mycoplasmal infections, such as doxycycline.11 In fact, we found that of the 73 Desert Storm veterans who had most of the GWI/CFIDS symptoms listed in Figure 1, 55 had good responses with doxycycline, and after multiple 6-week courses (up to 6) of antibiotics eventually recovered.11 We then set out to test the hypothesis that chronic mycoplasmal infections were the underlying event that may have triggered the GWI/CFIDS syndrome by first analyzing for mycoplasmal infections. The types of mycoplasmas that we eventually found are not easily detected but can be identified in blood leukocytes (white blood cells) by a technique that we developed called Gene Tracking.13 This technique uses a very sensitive and specific DNA hybridization procedure to positively identify unique DNA sequences that are indicative of specific species of mycoplasmas and other organisms. In our preliminary study on 30 veterans with GWI/CFIDS and their families, we have found evidence of mycoplasmal infections in about one-half (14/30) of the GWI/CFIDS patients' blood leukocytes.12 Not every Desert Storm veteran had the same type of mycoplasma DNA sequences in their blood, but we found that the majority of the mycoplasmas identified in the nuclear fractions prepared from blood leukocytes were identified as Mycoplasma fermentans (incognitus strain).12 Even pathogenic mycoplasmas, such as M. fermentans (incognitus strain) or M. penetrans, should be treatable with multiple courses of antibiotics,11 such as doxycycline (200-300 milligrams/day).14 We found four antibiotics that were useful for treatment of GWI/CFIDS patients and have suggested that these be used in multiple 6 week courses: doxycycline (200-300 milligrams/day), azithromycin (Zithromax, 500 milligrams/day), minocycline (200-300 milligrams/day) and ciprofloxacin (Cipro, 1,000-1,500 milligrams/day). One cycle of antibiotic therapy was not sufficient to completely suppress the mycoplasmal infections. Most GWI/CFIDS patients required several (2-6) cycles of antibiotic therapy to completely recover, and even then some of these patients continued to relapse occasionally when they were physically stressed, although their symptoms were almost always less severe than their initial relapses after their first few cycles of antibiotic therapy.

Some GWI/CFIDS case reports

We consider it quite likely that a large fraction of the Desert Storm veterans suffering from GWI/CFIDS may have been infected with pathogenic mycoplasmas and other possible pathogens (invasive bacteria), and such infections can produce the signs and symptoms in Figure 1, sometimes long after exposure. This would also explain the apparent contagious nature of GWI/CFIDS seen in many veterans, and the appearance of similar GWI/CFIDS symptoms in their immediate family members.

One of our fist patients was a Special Forces officer (U.S. Navy SEAL) now in the Delta Force at Fort Bragg, NC. He was in charge of Special Forces units that were involved in sensitive covert missions during Operation Desert Storm. He presented several months after the Gulf War with a flu-like illness that progressed to chronic fatigue, fever, stomach cramps, joint pain, skin rashes, memory loss, dehydration, headaches, heart pain and other symptoms. His vision became so diminished that physicians at Womack Army Hospital at Fort Bragg were considering surgery. After several courses of doxycycline, he completely recovered and has recently been promoted to the Executive Officer of our DELTA FORCE.

Another subject was an U.S. Army officer who served in the 101st Airborne Division (Air Assault). He was deployed on the deep insertions into Iraq. His unit did not come under enemy fire, and he considered his service relatively uneventful, until months after he returned to the U.S. What started out as a relative benign series of flu-like illnesses became progressively worse with intermittent fever, coughing, nausea, gastrointestinal problems, skin rashes, joint pain, memory loss, vision problems and severe headaches. Then his wife began to have chronic fatigue and gynecological problems, aching joints, headaches, and her stomach began to swell, causing severe pain. His 7 year-old daughter also became ill with similar flu-like symptoms that did not go away and progressively became worse, resulting in chronic fatigue, skin lesions, vomiting, headaches, aching joints, and inability to gain weight. Several other families of Gulf War veterans at his base had similar health problems. These families were being told that their symptoms were the result of psychological problems, but their signs and symptoms were more consistent with GWI/CFIDS. This officer and his family tested positive for M. fermentans (incognitus strain) and were placed on several 6 week cycles of doxycycline (their child was placed on 50 milligrams/day doxycycline). They and others on their base have recovered and for the most part no longer have GWI/CFIDS, although some of their symptoms reappear occasionally.

Another patient was a U.S. Air Force intelligence officer attached to the 5th Special Forces Group based at King Fahd Airport west of Dhahran and at King Khalid Military City in Saudi Arabia. He was involved in the Special Forces operations in Iraq, but was not involved in combat. He was exposed repeatedly to attacks by SCUD B missiles. After his return to the U.S., he noticed that he had a constant sore throat, night sweats, and intermittent fevers that progressed to include shortness of breath, dizziness, joint pain, short term memory loss, vision problems, diarrhea and other bowel problems, skin rashes and severe to moderate fatigue. He eventually left the military and could not obtain treatment from VA hospitals for his GWI/CFIDS. He tested positive for M. fermentans (incognitus strain), received several courses of doxycycline, and he has completely recovered. Upon retesting his blood for the presence of M. fermentans (incognitus strain) after he recovered, this infection was no longer present.

One patient was a 48 year-old U.S. Marine Corps officer was attached to the Central Command Staff in Saudi Arabia at Operation Desert Storm Command Headquarters. His only noteworthy experience was that he examined SCUD B (SS-1) missile impact sites. Within 10 months after his return to the U.S. he presented with chronic fatigue, skin rashes, diarrhea, headaches, aching joints, muscle pain, fevers, sleep problems, nausea, vision problems, memory loss and dental problems. His wife also became ill with GWI/CFIDS and had similar symptoms. Using Gene Tracking both tested Positive for M. fermentans (incognitus strain) and were placed on doxycycline. After 2-3 cycles of therapy, he completely recovered and his wife is recovering, but still relapses occasionally with GWI/CFIDS signs and symptoms.

Conclusions

We have found that a sizable fraction of Desert Storm veterans and their immediate family members who have GWI/CFIDS also have chronic mycoplasmal infections.12 Almost all of these patients responded to antibiotics: doxycycline, azithromycin, minocycline or ciprofloxacin. Eventually these GWI/CFIDS patients recovered, but they still relapse occasionally with some of the GWI/CFIDS signs and symptoms.12 Not all Desert Storm veterans with GWI/CFIDS responded to antibiotic therapy, suggesting that some patients probably display GWI/CFIDS signs and symptoms because of some other type of chronic infection or other cause, such as chemical insults.15 In addition, some veterans have MCS and cannot take certain antibiotics, such as doxycycline; however, they seem to tolerate other antibiotics (azithromycin, ciprofloxacin), especially if given intravenously. Our results and those of others who are examining other possible causes for GWI/CFIDS indicate that there are multiple causes for these CFIDS illnesses, but a sizable fraction of veterans with GWI/CFIDS have identifiable chronic mycoplasmal infections that can be successfully treated with the appropriate antibiotics. We have begun to examine some civilians with CFIDS, and we have some preliminary evidence indicating that a subset of CFIDS patients may have chronic infections, such as caused by mycoplasmas, and these cases can be successfully treated with antibiotics similar to the GWI/CFIDS patients.

References

1. NIH Technology Assessment Workshop Panel: The Persian Gulf Experience and Health. JAMA. 1994;272:391-396.

2. Boaz Milner I, Axelrod BN, Pasquantonia J, Silanpaa M: Is there a Gulf War Syndrome? JAMA 1994; 271:661.

3. Schmidt P, Blanck RM: Gulf War Syndrome and CFS. CFIDS Chronicle 1995;8:25-27.

4. Nicolson GL, Hyman E, KorÈnyi-Both A, Lopez DA, Nicolson NL, Rea W, Urnovitz H: Progress on Persian Gulf War Illnesses--reality and hypotheses. Int J Occup Med Tox 1995;4:365-370.

5. Nicolson GL, Nicolson NL: Chronic fatigue illnesses and Operation Desert Storm. J Occup Environ Med 1996;38:14-17.

6. Shafran S: The chronic fatigue syndrome. Amer J Med 1991;90:730-739.

7. Bell DS: Chronic fatigue syndrome update. Postgrad Med 1994;96:73-81.

8. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, et al.: Chronic Fatigue Syndrome: A working case definition. Ann Int Med 1988;108:387-389.

9. U.S. Senate Committee on Banking, Housing and Urban Affairs: U.S. chemical and biological warefare-related dual use exports to Iraq and their possible impact on the health consequences of the Persian Gulf War. U.S. Senate Report to the 103rd Congress, May 25, 1994.

10. Cheney PR: Proposed pathophysiologic model of CFIDS. CFIDS Chronicle 1994;7:1-3.

11. Nicolson GL, Nicolson NL: Doxycycline treatment and Desert Storm JAMA. 1995; 273:618-619.

12. Nicolson GL, Nicolson NL: Diagnosis and treatment of mycoplasmal infections in Persian Gulf War Illness-CFIDS patients. Int J Occup Med Immunol Tox 1996;5: 69-78.

13. Nicolson NL, Nicolson GL: The isolation, purification and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes. Meth Mol Genet 1994;5:281-298.

14. Lo S-C, Buchholz CL, Wear DJ, Hohm RC, Marty AM: Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain). Mod Pathol 1991;6:750-754.

15. Vojdani A, Ghoneum M, Brautbar N: Immune alteration associated with exposure to toxic chemicals. Toxicol Ind Health 1992;8:239-254.

Figure Legend

Figure 1. Comparison of the most commonly found signs and symptoms in approximately 650 Desert Storm veterans suffering from GWI/CFIDS with CFIDS (from Nicolson and Nicolson12).