International Journal of Occupational Medicine, Immunology and Toxicology 5: 83-86,  1996

FURTHER INFORMATION ABOUT PERSIAN GULF WAR HEALTH QUESTIONS--REPLY

Garth L. Nicolson  

Department of Tumor Biology,
The University of Texas M. D. Anderson Cancer Center, 
Houston, Texas 77030

1.	Address all correspondence to: Prof. Garth L. Nicolson, Office of the Director, The Institute for Molecular Medicine, 16371 Gothard St. H, Huntington Beach, California 92647
	
2.	Abbreviations: CDC, Center for Disease Control; CFIDS, chronic fatigue/immune dysfunction syndrome; GWI, Gulf War Illness; ODS, Operation Desert Storm.
	
3.	Key Words: Chronic fatigue syndrome, Desert Storm, environmental agents, infections, mycoplasma, doxycycline, antibiotics.
4.	

Service in Operation Desert Storm/Desert Shield resulted in a variety of chronic health conditions for over 50,000 U.S. participants (NIH Technology Assessment Workshop Panel, 1990), and we previously published that these conditions or illnesses (Gulf War Illness or Gulf War Syndrome) could be caused by a variety of environmental sources, including exposure to chemical and biological agents  (Nicolson et al., 1995).  As mentioned by General Blanck (1996), the Department of Defense, the Persian Gulf Veterans Coordinating Board and the Defense Science Board have issued categorical denials that such agents were released during Operation Desert Storm (ODS),  but we maintain that serious consideration must be given to all potential environmental sources.  There are enough documented reports and U.S. Congressional testimony to question the conclusion that there was no release of chemical or biological agents during ODS.  Rather than argue about whether or not chemical or biological agents or other conditions contributed to the chronic health conditions of ODS veterans, our article attempted to discuss several possible sources and solutions to GWI.  General Blanck (1996) was also concerned about our statement that over 1,300 ODS veterans have died from various cancers.  That over 1,300 ODS veterans died from cancers up to September 1994 is a matter of record in Department of Defense and Veterans Administration documents, copies of which have been provided to the Editor of this journal.

GWI patients have reported a variety of nonspecific signs and symptoms that do not readily fit into a common case diagnosis (Cotton, 1992; Boaz Milner et al., 1994; NIH Technology Assessment Workshop Panel, 1990), and this may have affected treatment of GWI (Nicolson et al., 1995).  Many GWI patients have symptoms that cycle and are characterized by long and variable incubation times, ranging from months to years after presumed exposure.  When we compared the 30 most common signs and symptoms of GWI to Chronic Fatigue Syndrome or Chronic Fatigue-Immune Dysfunction Syndrome (CFIDS), there was almost an identical match, suggesting that GWI is a CFIDS-like disorder and not a separate syndrome (Nicolson and Nicolson, 1996a).  In addition, we proposed that the appearance of similar signs and symptoms in immediate family members is consistent with a disease caused by biological agent(s). Thus it is likely that some GWI-CFIDS patients have a transmittable illness (Nicolson and Nicolson, 1996a).  

We have proposed that GWI-CFIDS could be caused, in part, by host responses to chronic infections (Nicolson and Nicolson, 1996a) or chemical insults (Vojani et al., 1992), resulting in cytokine production which produces many if not all of the signs and symptoms commonly found in GWI-CFIDS and CFIDS patients (Nicolson and Nicolson, 1995).  We previously suggested that most of the GWI-CFIDS signs and symptoms could be explained by chronic pathogenic infections, such as those caused by mycoplasmas and other microorganisms (Nicolson and Nicolson, 1995).  Most mycoplasma infections, however, produce diseases limited to particular tissue sites or organs, but can progress to involve other organs and tissues.  The positive responses of GWI-CFIDS patients to antibiotics, such as doxycycline that are effective against mycoplasmal infections, suggested that such infections could be causing GWI-CFIDS in a sizable percentage of symptomatic ODS veterans (Nicolson and Nicolson, 1995). 
 
Recently we began to use a technique called Gene Tracking (Nicolson and Nicolson, 1994) to determine if GWI-CFIDS patients had evidence of mycoplasmal infections in their blood (Nicolson and Nicolson, 1996b).  When mycoplasmal infections were detected, specific treatment suggestions were made to primary care physicians who then evaluated each case and reported their findings.  Since pathogenic invasive mycoplasmas, such as M. fermentans  (incognitus) or M. penetrans,  should be treatable with multiple courses of antibiotics, such as doxycycline (Lo et al., 1991; Nicolson and Nicolson, 1995) or other antibiotics (ciprofloxacin, azithromycin), specific treatment recommendations were made for each mycoplasma-positive GWI-CFIDS patient.  In this study 14/30 GWI-CFIDS patients were mycoplasma-positive, and 11/14 completely recovered after multiple cycles of antibiotics and 3/14 are still relapsing and continuing on cycles of antibiotic therapy.  None of 21 normal adults showed evidence of mycoplasmal infections in their blood (Nicolson and Nicolson, 1996b).

Our hypothesis is that a large subset of soldiers with GWI, a CFIDS-like condition, have mycoplasmal infections that can be diagnosed and successfully treated.  In our limited patient sample, we found that approximately one-half of the GWI patients and their immediate family members that have similar GWI-CFIDS signs and symptoms show evidence of mycoplasmal infections in their blood.  In the GWI-CFIDS patients that tested positive, antibiotic therapy was very successful in alleviating most if not all of the GWI-CFIDS symptoms, and eventually these patients completely recovered.  We previously published that in 73 ODS veterans who had GWI-CFIDS, 55 had good responses with doxycycline therapy, and after multiple courses of antibiotic eventually recovered (Nicolson and Nicolson, 1995).  Unfortunately, in this uncontrolled study (Nicolson and Nicolson, 1995) the diagnostic tests to demonstrate penetrating mycoplasmal infections in white blood cells were not yet available.  With the availability of sensitive mycoplasma tests, it should now be possible to confirm whether large numbers of GWI-CFIDS patients have mycoplasmal infections in their blood and recommend appropriate treatments (Nicolson and Nicolson, 1996b).  Antibiotics such as doxycycline have proven to be a safe and effective means of suppressing mycoplasmal infections (Lo et al., 1991; Nicolson and Nicolson, 1995; 1996a,b).  Of course, the potential side effects of antibiotics such as doxycycline mentioned by General Blanck (1996) (hypersensitivity reactions, discoloration of teeth in children and exclusion of pregnant women) should be always considered when suggesting a possible therapy, but this class of antibiotic has proven its usefulness and safety over the years.

As to General Blanck's (1996) criticisms concerning the proposed blinded testing of GWI-CFIDS patients and controls with the Center for Disease Control in Atlanta, I have the following comments.  General Blanck indicates that "Dr. Nicolson has been unable to test these specimens pending sufficient standardization of the Gene Tracking assay he uses."  This statement is incorrect.  The samples to be provided by the Center for Disease Control are insufficient in numbers of leukocytes for the Gene Tracking test.  Therefore, we initiated a new investigation on the use of Polymerase Chain Reaction to detect mycoplasmal infections in small numbers of blood leukocytes such as those to be provided by the CDC.  Although we have slowly begun this new line of investigation with the CDC without a source of funding, it is a major part of a pending U.S. Army grant application submitted in August 1995 on Gulf War Illness.  Since the grant awards in this program (discussed in Blanck, 1996) have not been made, we are in the unfavorable position of being criticized for not completing a study that was proposed in a grant application that is still under review with no assurance of funding.

Finally, we agree with General Blanck (1996) that "Persian Gulf War veterans deserve the finest medical care available," and "conclusions about the causes and treatment of any clinical condition, including illnesses among Persian Gulf War veterans, must be based on rigorous scientific studies and not anecdotal accounts or uncontrolled investigations."  It is hoped that the Department of Defense will make avaliable the funds necessary to conduct such studies.  Without federal support, it will not be possible for appropriate controlled clinical trials to be conducted and evaluated by non-government institutions.

References

BLANCK, R.R. (1996) "Further information about Persian Gulf War health questions." Int. J. Occup. Med. Tox. in press.
Boaz Milner, I., Axelrod, B.N., Pasquantonia, J. and Silanpaa, M. (1994)  "Is there a Gulf War Syndrome?"  JAMA  271:661.
Cotton, P. (1992). "Gulf War symptoms remain puzzling."   JAMA  268:2619.
Lo, S.-C., Buchholz, C.L., Wear, D.J., et al.   (1991)  "Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain)."  Mod. Pathol.  6:750-754.
Nicolson, G.L. and Nicolson, N.L.  (1995) "Doxycycline treatment and Desert Storm."  JAMA 273:618-619.
Nicolson, G.L. and Nicolson, N.L.  (1996a) "Chronic Fatigue Illness and Operation Desert Storm."  J. Occup. Environ. Med. 5:69-78. 
Nicolson, G.L. and Nicolson, N.L.  (1996b) "Diagnosis and treatment of mycoplasmal infections in Gulf War Illness-CFIDS patients."  Int. J. Occup. Med. Tox. in press.
Nicolson, G.L., Hyman, E., Korényi-Both, A., Lopez, D.A., Nicolson, N.L., Rea, W., Urnovitz, H.  (1995) "Progress on Persian Gulf War Illnesses-Reality and hypotheses."   Int. J. Occup. Med. Tox.  4:365-370.
Nicolson, N.L. and Nicolson, G.L.  (1994)  "The isolation, purification and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes."  Meth. Mol. Genet.  5:281-298.
NIH Technology Assessment Workshop Panel (1990). "The Persian Gulf Experience and Health."  JAMA 272:391-396.
VOJDANI, A., GHONEUM, M., and BRAUTBAR, N. (1992)  "Immune alteration associated with exposure to toxic chemicals."  Toxicol. Ind. Health  8:239-254.