Benefits and Harms of Doxycycline Treatment for Gulf War Veterans'
Illnesses
A Randomized, Double-Blind, Placebo-Controlled Trial

Annals of Internal Medicine, 20 July 2004, Volume 141, Issue 2,
Pages 85-94

Authors: Sam T. Donta, MD; Charles C. Engel, Jr., MD, MPH; Joseph F.
Collins, ScD; Joel B. Baseman, PhD; Lisa L. Dever, MD; Thomas Taylor, MD;
Kathy D. Boardman, RPh; Lewis E. Kazis, ScD; Suzanne E. Martin; Rebecca
A. Horney, BS; Annette L. Wiseman; Douglas S. Kernodle, MD; Raymond P.
Smith, MD; Aldona L. Baltch, MD; Christine Handanos, MD; Brian Catto, MD;
Luis Montalvo, MD; Michael Everson, PhD; Warren Blackburn, MD; Manisha
Thakore, MD; Sheldon T. Brown, MD; Larry Lutwick, MD; Dorothy Norwood,
MD; Jack Bernstein, MD; Catherine Bacheller, MD; Bruce Ribner, MD; L. W.
Preston Church, MD; Kenneth H. Wilson, MD; Prabhakar Guduru, MD; Robert
Cooper, MD; Joseph Lentino, MD; Richard J. Hamill, MD; Arnold B. Gorin,
MD; Victor Gordan, MD; David Wagner, MD; Cliff Robinson, MD; Pierre
DeJace, MD; Ronald Greenfield, MD; Lisa Beck, MD; Marvin Bittner, MD; H.
Ralph Schumacher, MD; Fredric Silverblatt, MD; James Schmitt, MD; Edward
Wong, MD; Margaret A.K. Ryan, MD, MPH; Javier Figueroa, MD; Christopher
Nice, MD; and John R. Feussner, MD, MPH, the VA Cooperative #475 Group



Background: It has been hypothesized that certain Mycoplasma species may
cause Gulf War veterans' illnesses (GWVIs), chronic diseases
characterized by pain, fatigue, and cognitive symptoms, and that affected
patients may benefit from doxycycline treatment.

Objective: To determine whether a 12-month course of doxycycline improves
functional status in Gulf War veterans with GWVIs.

Design: A randomized, double-blind, placebo-controlled clinical trial
with 12 months of treatment and 6 additional months of follow-up.

Setting: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of
Defense medical centers.

Participants: 491 deployed Gulf War veterans with GWVIs and detectable
Mycoplasma DNA in the blood.

Intervention: Doxycycline, 200 mg, or matching placebo daily for 12
months.

Measurements: The primary outcome was the proportion of participants who
improved more than 7 units on the Physical Component Summary score of the
Veterans Short Form-36 General Health Survey 12 months after
randomization. Secondary outcomes were measures of pain, fatigue, and
cognitive function and change in positivity for Mycoplasma species at 6,
12, and 18 months after randomization.

Results: No statistically significant differences were found between the
doxycycline and placebo groups for the primary outcome measure (43 of 238
participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8
percentage point [95% CI, –6.5 to 8.0 percentage points]; P > 0.2) or for
secondary outcome measures at 1 year. In addition, possible differences
in outcomes at 3 and 6 months were not apparent at 9 or 18 months.
Participants in the doxycycline group had a higher incidence of nausea
and photosensitivity.

Limitations: Adherence to treatment after 6 months was poor.

Conclusion: Long-term treatment with doxycycline did not improve outcomes
of GWVIs at 1 year.


Editors' Notes

Context

Some experts hypothesize that Mycoplasma species cause Gulf War veterans'
illnesses (GWVIs).

Contribution

In this double-blind trial, 491 deployed Gulf War veterans with GWVIs and
detectable Mycoplasma DNA in their blood were randomly assigned to
receive either doxycycline, 200 mg, or matching placebo daily for 1 year.
There were no long-term differences between the 2 groups in physical or
mental function or in pain or fatigue symptoms. Patients given
doxycycline had nausea and photo-sensitivity more often than did patients
given placebo.


Implications

Long-term doxycycline treatment probably doesn't benefit veterans with
GWVIs and may harm them.

–The Editors



Author and Article Information


>From Veterans Affairs Medical Centers (Boston, Massachusetts; Milwaukee,
Wisconsin; Montgomery, Alabama; Perry Point, Maryland; East Orange, New
Jersey; White River Junction, Vermont; Albuquerque, New Mexico; Bedford,
Massachusetts; Nashville, Tennessee; Albany, New York; Augusta, Georgia;
Birmingham, Alabama; Bronx, New York; Brooklyn, New York; Dayton, Ohio;
Charleston, South Carolina; Durham, North Carolina; Fargo, North Dakota;
Hines, Illinois; Houston, Texas; Manchester, New Hampshire; New Orleans,
Louisiana; Oklahoma City, Oklahoma; Omaha, Nebraska; Philadelphia,
Pennsylvania; Providence, Rhode Island; Richmond, Virginia; and San Juan,
Puerto Rico); Uniformed Services University of the Health Sciences,
Bethesda, Maryland; University of Texas Health Science Center, San
Antonio, Texas; Naval Health Research Center, San Diego, California; and
Department of Veterans Affairs National Central Office, Washington, DC.

Disclaimer: The views expressed by authors associated with military
institutions are their own and not the official position of any
university, medical center, or department of the U.S. government.

Note: SF-36 is a registered trademark of the Medical Outcomes Trust.

Grant Support: By the Cooperative Studies Program of the U.S. Department
of Veterans Affairs Office of Research and Development and the U.S.
Department of Defense. Pfizer Inc. donated the study drug and placebo.

Potential Financial Conflicts of Interest: Employment: R.P. Smith (U.S.
Department of Veterans Affairs), A.L. Baltch (U.S. Department of Veterans
Affairs), S.T. Brown (U.S. Department of Veterans Affairs);
Consultancies: C.C. Engel Jr. (U.S. Department of Defense), M. Bittner
(Pfizer); Honoraria: J. Lentino (Pfizer), R. Greenfield (Pfizer,
Bristol-Myers Squibb, GlaxoSmithKline, Abbott, Merck, Wyeth), M. Bittner
(Pfizer); Grants received: R.P. Smith (U.S. Department of Veterans
Affairs), M. Bittner (Pfizer).

Requests for Single Reprints: Joseph F. Collins, ScD, Veterans Affairs
Maryland Healthcare System, Cooperative Studies Program Coordinating
Center (151 E), PO Box 1010, Perry Point, MD 21902.

Current Author Addresses: Dr. Donta: Boston Veterans Affairs Medical
Center, 151 South Huntington Avenue, Boston, MA 02130.

Dr. Engel: Department of Psychiatry, Uniformed Services University, 4301
Jones Bridge Road, Bethesda, MD 20815.

Dr. Collins, Ms. Horney, and Ms. Wiseman: Veterans Affairs Maryland
Health Care System, Cooperative Studies Program Coordinating Center
(151E), PO Box 1010, Perry Point, MD 21902.

Dr. Baseman: Department of Microbiology, University of Texas Health
Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78284.

Dr. Dever: Veterans Affairs New Jersey Health Care System, 385 Tremont
Avenue, East Orange, NJ 07018.

Dr. Taylor: White River Junction Veterans Affairs Hospital, 215 North
Main Street, White River Junction, VT 05008.

Ms. Boardman: Cooperative Studies Program, 2401 Centre Avenue SE,
Albuquerque, NM 87106.

Dr. Kazis: Boston University School of Public Health, 715 Albany Street,
T3-W, Boston, MA 02118.

Ms. Martin: Cell Signaling Technology, Inc., 166 B Cummings Center,
Beverly, MA 01915.

Dr. Kernodle: Nashville Veterans Affairs Medical Center, 1310 24th Avenue
South, Nashville, TN 37212-2637.

Drs. Smith and Baltch: Stratton Veterans Affairs Medical Center, 113
Holland Avenue, Albany, NY 12208.

Dr. Handanos: Veterans Affairs Medical Center, 1501 San Pedro SE,
Albuquerque, NM 87108.

Drs. Catto and Montalvo: Veterans Affairs Medical Center Augusta, 1
Freedom Way (235), Augusta, GA 30904.

Dr. Everson: Capstone Clinical, 1222 14th Avenue South, Suite 208,
Birmingham, AL 35205.

Dr. Blackburn: Birmingham Veterans Affairs Medical Center, 700 19th
Street, Birmingham, AL 35233.

Dr. Thakore: VA Medical Center (151), 150 Huntington Avenue, Boston, MA
02130.

Dr. Brown: Bronx Veterans Affairs Medical Center, 130 West Kingsbridge
Road, Bronx, NY 10468.

Drs. Lutwick and Norwood: Veterans Affairs New York Harbor Health Care
System, 800 Poly Place, Brooklyn, NY 11209.

Dr. Bernstein: Veterans Affairs Medical Center, 4100 West Third Avenue,
Dayton, OH 45429.

Dr. Bacheller: Wright State University/Veterans Affairs, 4000 West Third
Street, Dayton, OH 45429.

Dr. Ribner: Emory University, 1364 Clifton Road NE, Atlanta, GA 30322.

Dr. Church: Veterans Affairs Medical Center, 109 Bee Street, Charleston,
SC 29403.

Dr. Wilson: Veterans Affairs Medical Center, 508 Fulton Street, Durham,
NC 27705.

Drs. Guduru and Cooper: Veterans Affairs Medical Center, 2101 North Elm
Street, Fargo, ND 58102.

Dr. Lentino: Hines Veterans Affairs Hospital, Fifth Avenue at Roosevelt
Road, Hines, IL 60141.

Dr. Hamill: Veterans Affairs Medical Center (111G), 2002 Holcombe
Boulevard, Houston, TX 77030.

Dr. Gorin: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030.


Dr. Gordan: Veterans Affairs Medical Center, 718 Smyth Road, Manchester,
NH 03104.

Dr. Wagner: Zablocki Veterans Affairs Medical Center, 5000 West National
Avenue, Milwaukee, WI 53295.

Dr. Robertson: Central Alabama Veterans Health Care System, 215 Perry
Hill Road, Montgomery, AL 36109.

Dr. DeJace: Veterans Affairs Medical Center, 1601 Perdido Street, New
Orleans, LA 70112.

Drs. Greenfield and Beck: Oklahoma City Veterans Affairs Medical Center,
921 NE 13th Street, Oklahoma City, OK 73104.

Dr. Bittner: Veterans Affairs Medical Center, 4101 Woolworth Avenue
(111D), Omaha, NE 68105.

Dr. Schumacher: Veterans Affairs Medical Center (151K), University and
Woodland Avenues, Philadelphia, PA 19104.

Dr. Silverblatt: Providence Veterans Affairs Medical Center, 830
Chalkstone Avenue, Providence, RI 02908.

Drs. Schmitt and Wong: McGuire Veterans Affairs Medical Center, 1201
Broad Rock Boulevard, Richmond, VA 23249.

Dr. Ryan: Branch Medical Clinic, Naval Training Center, 2659 Stockton
Road, Room A203, San Diego, CA 92106.

Dr. Figueroa: Veterans Affairs Medical Center, 10 Casia Street, San Juan,
Puerto Rico 00921.

Dr. Nice: Veterans Affairs Hospital, North Main Street, White River
Junction, VT 05001.

Dr. Feussner: Medical University of South Carolina, 96 Jonathan Lucas
Street, Charleston, SC 29425.

Author Contributions: Conception and design: S.T. Donta, C.C. Engel Jr.,
J.F. Collins, J.B. Baseman, L.E. Kazis, R.A. Horney, A.L. Wiseman, V.
Gordan, P. DeJace, M. Bittner, H.R. Schumacher, J.R. Feussner.

Analysis and interpretation of the data: S.T. Donta, C.C. Engel Jr., J.F.
Collins, J.B. Baseman, L.L. Dever, T. Taylor, L.E. Kazis, S.E. Martin,
R.A. Horney, A.L. Wiseman, K.H. Wilson, D. Wagner, P. DeJace, M. Bittner,
F. Silverblatt, M.A.K. Ryan, J.R. Feussner.

Drafting of the article: S.T. Donta, C.C. Engel Jr., J.F. Collins, J.B.
Baseman, T. Taylor, S.E. Martin, R.P. Smith, A.B. Gorin, P. DeJace, M.
Bittner, J.R. Feussner.

Critical revision of the article for important intellectual content: S.T.
Donta, C.C. Engel Jr., J.F. Collins, J.B. Baseman, L.L. Dever, T. Taylor,
K.D. Boardman, L.E. Kazis, S.E. Martin, D.S. Kernodle, S.T. Brown, D.
Wagner, M. Bittner, H.R. Schumacher, F. Silverblatt, M.A.K. Ryan, J.R.
Feussner.

Final approval of the article: S.T. Donta, C.C. Engel Jr., J.F. Collins,
L.L. Dever, T. Taylor, K.D. Boardman, R.P. Smith, A.L. Baltch, C.
Handanos, L. Montalvo, W. Blackburn, S.T. Brown, L. Lutwick, J.
Bernstein, C. Bacheller, K.H. Wilson, R. Cooper, R.J. Hamill, V. Gordan,
D. Wagner, P. DeJace, R. Greenfield, M. Bittner, H.R. Schumacher, F.
Silverblatt, J. Schmitt, E. Wong, M.A.K. Ryan, C. Nice, J.R. Feussner.

Provision of study materials or patients: S.T. Donta, C.C. Engel Jr.,
L.L. Dever, T. Taylor, K.D. Boardman, D.S. Kernodle, R.P. Smith, A.L.
Baltch, C. Handanos, B. Catto, L. Montalvo, M. Everson, W. Blackburn, M.
Thakore, B. Ribner, L.W.P. Church, K.H. Wilson, P. Guduru, R.J. Hamill,
A.B. Gorin, V. Gordan, D. Wagner, C. Robinson, P. DeJace, R. Greenfield,
L. Beck, M. Bittner, H.R. Schumacher, F. Silverblatt, J. Schmitt, E.
Wong, M.A.K. Ryan, J. Figueroa, C. Nice.

Statistical expertise: J.F. Collins.

Obtaining of funding: J.F. Collins, A.L. Wiseman.

Administrative, technical, or logistic support: J.F. Collins, S.E.
Martin, R.A. Horney, A.L. Wiseman, D. Norwood, A.B. Gorin, D. Wagner, L.
Beck, C. Nice, J.R. Feussner.

Collection and assembly of data: J.F. Collins, J.B. Baseman, T. Taylor,
R.A. Horney, A.L. Wiseman, D.S. Kernodle, A.L. Baltch, C. Handanos, B.
Catto, L. Montalvo, M. Everson, W. Blackburn, M. Thakore, S.T. Brown, L.
Lutwick, D. Norwood, J. Bernstein, C. Bacheller, B. Ribner, P. Guduru, R.
Cooper, J. Lentino, A.B. Gorin, D. Wagner, R. Greenfield, L. Beck, H.R.
Schumacher, J. Schmitt, E. Wong, M.A.K. Ryan, C. Nice.