The news media recently raised a great hue and cry following revelation of the study of a group of untreated syphilitics which was begun now 40 years ago and came to be known as the Tuskegee Study. Accounts and editorials in the printed news media stated outright or implied that treatment was purposefully withheld to evaluate the course of untreated disease. Only two will be quoted. Time1 stated, “people with syphilis were induced to go without treatment.… For the past 25 years, the service has had a proven remedy available and neglected to use it on its select test cases.” Even the AMA News2 was trapped into writing, “None of the men in the study received treatment for syphilis, even after the effectiveness of penicillin became known.” (The italics are the Editor’s.)
In complete disregard of their abysmal ignorance, members of the fourth estate bang out anything on their typewriters which will make headlines. Small wonder William Osler wrote more than half a century ago,
Believe nothing that you see in the newspapers—they have done more to create dissatisfaction than all other agencies. If you see anything in them that you know is true, begin to doubt it at once.
Dr. R. H. Kampmeier was a noted syphilis specialist and taught at the Vanderbilt University School of Medicine.
Originally published in the Southern Medical Journal 65 (1972): 1247–51. Reprinted by permission from the Southern Medical Journal.
An exposition of the quarter-truth publicized will not reach the eyes of newsmen. It is just as well for it would be over their heads; furthermore they live to write today and to forget tomorrow, irresponsible in the “dissatisfaction” they create. Only a handful of us are left, who had much experience in the management of syphilis at about the time of the inception of the Tuskegee Study and who thus might put this recent “tempest in a teapot” into proper historical perspective. Therefore, I have elected to review the setting of the study in 1932 and its continuation as a text for the education of the younger generation of physicians, the majority of whom have little knowledge of the venereal diseases.3 I have reviewed the papers upon the Tuskegee Study published over three decades to refresh my memory of their content. Certain facts need emphasis as background to understand the initiation of the Study and its continuance.
The only acceptable study of the natural course of untreated syphilis in medical history was begun by Professor Boeck, of Oslo, who withheld treatment from 1,978 patients between 1891 and 1910, since the inadequacy of mercury and even its hazard in the management of acute syphilis was obvious to all experienced observers of that day. Of course, these patients could only be diagnosed clinically because the infectious agent was not to be identified until 1905 and the Wassermann test to be described until 1906. Boeck’s pupil and successor, Bruusgaard,4 in 1929, reported a follow-up study of 473 of these patients, 309 living and 164 dead with necropsy in 40. In summary, he reported that: 9.5% of the patients had developed neurosyphilis, 12.8% cardiovascular syphilis, 12.2% late benign syphilis, 23.6% had had clinical relapse, and 22.6% had died of other causes. This then was the state of knowledge regarding the prognosis of untreated syphilis at the time the Tuskegee Study was begun in 1932. (Two elegant reviews of Boeck’s material appeared a quarter of a century later, in 1955, by Gjestland and by Clark and Danbolt.)
In 1910, Paul Ehrlich announced arsphenamine. His dream of a single sterilizing dose was quickly shattered by the appearance of infectious relapse and neuro-relapse. Several years later some of the complexities and hazards attending the use of arsphenamine were ameliorated to a degree by the development of neoarsphenamine which could be given by syringe. Nevertheless, the use of arsenotherapy was erratic, and generally without rhyme or reason,—an injection now and then, possibly for a symptom, some skin lesion, or when the patient had a ten dollar bill. The initial cost of the arsphenamines was fantastic.* Few doctors in the “teens” had need to become adept in venipuncture and intravenous treatment, other than in university clinics or public health clinics. The painful and often serious reactions to the arsphenamines, and later the painful effects of inept intramuscular injections of bismuth led to very irregular treatment and a high rate of clinical relapse in early syphilis.
Macon County, Alabama, the location of the Tuskegee Study, was a poor rural county. In the initial paper it was stated that “adequate treatment has not been freely available to most indigent citizens for a period longer than a decade,” and “In connection with the administration of adequate treatment, the tendency of all patients, whether white or colored, is to become dilatory in returning to the attending physician during the observation period.”5**
*When the German cargo submarine Deutschland popped up in Chesapeake Bay in 1916, much of its 1.5 million dollar payload was in arsphenamines. After our entry into the war, 1917, patent rights were forfeited and manufacturing was begun in the United States.
**Under the most sophisticated and intensive follow-up even in an urban community having a stable population, the completion of 60 weeks of treatment for infectious syphilis was discouraging in the days of chemotherapy. The Medical L Clinic of Vanderbilt University Hospital, with Miss Anne Sweeney as director of social service, had an unmatched record of efficiency. But even here only 56% of Negro patients and 76% of white patients completed an acceptable course of treatment for early syphilis.
As a sidelight, an experience is worth relating. In 1945, a colleague and I spent some days with a VD mobile unit in the State of Mississippi, visiting plantations and crossroads communities in the delta region of the State. I learned of the method of financing medical care among sharecroppers. Following a positive serologic test found upon the mobile unit’s visit to a plantation, its owner might write on a scrap of paper to be taken to the doctor, “Give one treatment to.…” The injection could then be given, be charged to the planter, who in turn charged it against the sharecropper’s account. I examined examples of such slips both in planters’ and in doctors’ offices. This was 13 years after the initiation of the Tuskegee Study!
The finding that continuous treatment of early syphilis (4 or more courses of an arsenical with interim mercury—at least 21 injections of an arsphenamine) reduced clinical or sero relapse to 21%, as against 89.2% in patients receiving 1 to 8 injections of arsenic, was described by Moore and Keidel,6 in 1926 (just 6 years before the Tuskegee Study). These findings were verified and established by the Cooperative Clinical Studies* of 1932, the year of the inception of the Study.
In June of 1943, a preliminary report suggested the curative effect of penicillin in acute syphilis. Promptly under the auspices of the war-time Office of Scientific Research and Development, a cooperative program was organized to include certain Army, Navy and USPHS installations and selected civilian clinics for the study of the effectiveness of penicillin in the treatment of acute syphilis. Though this laid the foundation for today’s treatment, a number of years were to pass during which several forms of penicillin and the results of their use could be evaluated and before treatment schedules could be recommended for general use. An authoritative report finally was made in 1948 by NIH to the AMA Council on Pharmacy and Chemistry (16 years after the inception of the Tuskegee Study). Early, because of limited supplies of penicillin, all of us involved in this study were not permitted to experiment in the treatment of late syphilis. However, by 1945, such permission was granted to the leaders in this study,—Drs. Wile, Moore and Stokes. Gradually, the efficacy of penicillin was established for some forms of late syphilis. The immediate results of penicillin treatment of late benign syphilis could be identified quickly. A collaborative study of the results of the treatment of paresis with penicillin and an obviously necessary 5 year follow-up was ready for publication in 1958 (a quarter of a century after the beginning of the Tuskegee Study). Reference to cardiovascular syphilis is postponed at this point.
Hence the historical background for the Tuskegee Study begun in 1932 may be summarized as follows: (a) One study of the unmodified natural history of syphilis was extant, based on clinical diagnosis. (b) Within a half dozen years Treponema pallidum was identified, a not highly sensitive serologic test was developed, and a treponemicidal drug was produced. (c) After almost a decade of dependence upon a costly foreign supply or arsenicals, neoarsphenamine became available for general use by doctors unskilled in intravenous therapy and without guidelines as to what constituted adequate treatment, hence with frequent untoward effects and with results commonly worse than no treatment in terms of relapse resulting from interference with the development of natural immunity. (d) Only in the year of the initiation of the Study did become apparent as to what might constitute adequate treatment of early syphilis, with no inkling of the effect of arsenotherapy in later years of the disease. (e) And, finally, at that time it would have been a rare circumstance that an indigent person in a rural southern county would have received adequately weekly metal therapy for 60 and more weeks.
A Review of the Tuskegee Study. This was conceived in 1932 following a serologic survey of 1,782 male Negroes over age 25 in Macon County in 1931–33. Among these were 472 with at least 2 positive tests and 275 who had had treatment during the first 2 years of the disease. In 1933, the initial examinations were recorded for 399 untreated Negro syphilitic men, 201 presumed nonsyphilitic men, and the 275 syphilitic men who had had variable amounts of antisyphilitic treatment.5 “The patients who had syphilis were all in the latent stage: any acute cases requiring treatment were carefully screened out for standard therapy.”7 The subjects thus had latent syphilis and were grouped as having become infected 3 years, 6 years, and 9 years previously—a highly significant fact (i.e., syphilis of 19, 22, and 25 years’ duration before the penicillin, which the news media1,2 think should have been used, became generally available). It is clear that the subjects were not deterred from obtaining treatment if they desired it or bothered to get what was available, the news media to the contrary. The report of the study at the 12 year point states that during these years a “considerable proportion of the syphilitics had received small amounts of treatment (usually 1 or 2 injections) although 12 had received as many as 10 injections.” (These now needed to be excluded from the study.8) The fifth paper in 1954 comments that most of the study group remained untreated although “after careful questioning, it was found that 34 of 133 patients with syphilis had received injections or oral medication which might possibly have been penicillin; 11 of the 34 received more than 3 injections.”9 It was commented that general medical care had not improved in 20 years, and although there are excellent medical facilities in the county, costs are prohibitive or patients are unaware of them.
*Because of the heterogeneity of programs of antisyphilitic treatment in the 15 to 20 years after the introduction of arsenotherapy, and a decade’s replacement of mercury by bismuth, medicine’s first cooperative study came into being. It was to consist of a series of publications over a half dozen years following the first in 1932. These studies consisted of pooled clinical and therapeutic data from some 5 university hospital clinics and the USPHS.
One paper is of especial interest because of the implications by news media of dishonesty and bribery in carrying out the study.7 One of its authors is the black public health nurse who provided the continuity over years of study as examining physicians came and went. Stories of the rural roads so poor that in rainy seasons the subjects spent hours getting the nurse’s car out of the mud, the reunion annually of the subjects as they met on the bus which picked them up at the crossroads, and the socializing, point up her rapport and empathy proven by the fact that she obtained 145 autopsies in 20 years and was refused only one. (The burial assistance mentioned by newspapers was through private philanthropy, the Milbank Memorial Fund.)
In preparation of this editorial I have reviewed all the papers of the study. I have alluded to those which are significant in view of the publicity given by the news media. The remaining papers detailing clinical studies and morbidity,10–12 life expectancy,13 and pathologic findings14 are not basic to this editorial review. The final paper, in 1964, the 30th year of observation, summarized much of what had appeared in the papers which had appeared periodically.15 Thus, the mortality during the first 12 years was 25% for the syphilitics and 14% for controls of about the same age. By the 20th year follow-up, 40% of the syphilitics and 27% of the controls had died. By the time of the 30th year evaluation, 59% of the syphilitics were dead, 21% alive and 20% lost to follow-up; for the control group, 45% were dead, 34% were living and 20% could not be traced. By now 96% of those examined had had treatment, as many as 33% having had “curative” therapy. Among the 90 living syphilitics 12% were said to have evidence of late syphilis—two-thirds of these of cardiovascular nature and known in most instances since 1948. (The results of pathologic studies were described better in 1955.14) Sixty-six percent continued to have a positive VDRL test, 91% an active TPI test and 97% were reactive to the FTA-ABS test.
This editorial was undertaken and completed after many hours of “library research” to clarify details surrounding the Tuskegee Study. The primary purpose is to expose the deleterious ramifications of an irresponsible press in its criticisms of the ethics and actions of the medical profession in its constant age-long efforts to improve the health of the human race. Secondly, it has the purpose of emphasizing Osler’s aphorism concerning the press and to put the profession always on guard in this respect and to urge disbelief of the press until proven facts appear. Thirdly, by putting the Tuskegee Study in historical perspective, hopefully the reader will have learned that syphilitic disease acquired in 1921, 1924, and 1929 would have benefited not at all from the antisyphilitic treatment as used in those days or in 1932, the time of setting the Study, in terms of the unlikelihood of continuous adequate therapy. Additionally, it should be clear that treatment was not withheld, and though no treatment was forced upon men of the Study, they had the freedom of taking what treatment they found convenient or could afford as did their brethren in the community. (That some availed themselves of this is documented, both as regards metal therapy and penicillin.)
That the untreated as well as treated syphilitics had both a greater rate of mortality and morbidity than the untreated matched controls was documented to be somewhat of the order found by Bruusgaard4 and others. This is not surprising. No one has ever implied that syphilis is a benign infection. Since the major cause of morbidity and mortality was related to cardiovascular disease, a final word must be directed to this problem.
Since it is obvious that a deformed aortic valve leaflet or a saccular aortic aneurysm can not be altered by medical treatment, the remaining questions are: (a) can aortic disease be prevented, and (b) if present, will treatment alter the course of cardiovascular disease—or in terms of the Tuskegee Study—would antisyphilitic treatment, if adequate in 1932, have prevented morbidity and mortality, ie, treatment after existence of latent disease 3, 6 or 9 years after infection or, even more, treatment with penicillin 19, 22 or 25 years after infection!
Basic to this question is whether uncomplicated syphilitic aortitis can be diagnosed—a question shrouded in controversy for four decades. In 1932, Moore and associates16 suggested seven criteria for the diagnosis of uncomplicated aortitis on the basis of findings in 105 cases shown at autopsy. Unfortunately, they left numerous gaps in the clinical and pathologic evaluations. However, the Cooperative Clinical Group accepted these criteria in 1936, and they were applied in the earlier papers of the Tuskegee Study. Kampmeier and colleagues17 reviewed this subject, documented disagreements by others of these criteria, and from their own necropsy studies concluded “that the clinical diagnosis of uncomplicated aortitis is, for practical purposes, impossible.” Since this diagnosis is open to question, the evaluation of antisyphilitic treatment as a prophylactic against cardiovascular syphilis can be determined only indirectly. The best data were provided by the Clinical Cooperative Group, which evaluated the outcome of treatment of 1,936 patients having latent syphilis treated adequately, and in only 31 patients could the diagnosis of cardiovascular syphilis be made at a later date. Moore and his associates18 published figures purportedly showing that treatment of patients having the complications of aortitis lived longer if given antisyphilitic treatment. (This and several other similar studies gave no consideration to the presence or absence of congestive failure as related to extension of life.) Kampmeier and Combs,19 in a study of 163 patients having syphilitic aortic insufficiency, concluded that their “study does not indicate that adequate antisyphilitic treatment influences favorably the prognosis of syphilitic aortic insufficiency.”
The implications for the Tuskegee Study are that if the men having latent syphilis of 3, 6 or 9 years’ duration had been forced to take adequate treatment (60 or more weekly doses of a metal), cardiovascular syphilis might have been avoided in most. In our free society, antisyphilitic treatment has never been forced. Since these men did not elect to obtain treatment available to them, the development of aortic disease lay at the subject’s door and not in the Study’s protocol. As for the failure to exhibit penicillin in the treatment of these patients the same statements apply—in fact it has been indicated above that 34 patients had received treatment with penicillin. Such treatment was, of course, of little significance, since syphilis generally takes its toll in mortality and/or morbidity by a quarter of a century after infection. Obviously much literature has accumulated in the area of syphilitic cardiovascular disease since the papers quoted in the thirties and early forties. However, attention to them would be inappropriate in a discussion of continuing evaluations of the Tuskegee Study which were based on concepts of diagnosis and treatment as practiced in the days of arsenotherapy.
Though the “curative” effect of 60 injections of a metal in continuous order, and later a few injections of penicillin in the treatment of early syphilis became firmly established, the effectiveness of treatment of late, and especially late latent syphilis has never been so well proven. The Tuskegee Study was undertaken to shed some light on this, but added little to Bruusgaard’s data. That these questions still remain is suggested by a recommendation of the National Commission on Venereal Disease,
That studies be undertaken to determine the effectiveness of current treatment of syphilis and gonorrhea, particularly of late latent and tertiary syphilis.20
Finally, in recapitulation, certain facts evolve. (a) At no time in the 40 year Tuskegee Study is there a hint that treatment desired by a subject was denied him; in fact all the periodic reviews reveal that more and more of the subjects had chosen to be treated under the same circumstances as others in their community, albeit inadequately, but as elected by the patient and/or his doctor. (The report* of 40 years stated all but one of the syphilitic group still living had had antisyphilitic treatment.) (b) The prognosis therefore in patients having late latent syphilis in the Study group was no better or no worse than that of many hundreds of thousands of other syphilitic US citizens of their generation bearing the diagnosis of late latent syphilis. (c) The most important manifestations of late syphilis, aortitis, as diagnosed in the uncomplicated state during the earlier years of the Study was on dubious, or at best upon controversial grounds. (d) The lethal complications of aortitis (coronary ostial stenosis, and especially aortic insufficiency or aneurysm) had never been proven indubitably to be altered by antisyphilitic treatment. (e) Granted adequate treatment of late latent syphilis might have delayed or avoided the complications of aortitis, but accepting the clinical experience that these complications develop by about a quarter of a century after infection, it becomes obvious that the institution of penicillin treatment at 19, 22, and 25 years after infection would raise questions. Firstly, why should these men be singled out over their fellows in the community for treatment not forced upon others, and secondly, would it alter the prognosis at all!* (f) The Study has shown that untreated syphilis is accompanied by morbidity, mortality and pathologic findings as described by others in the past.
*Read at the Annual Meeting of the American Venereal Disease Association, June 1971— unpublished.
This editorial should point up Osler’s accusations directed to an irresponsible press, and the irrelevancy of certain Congressmen’s emotional reaction to the Tuskegee Study.
R. H. K.
*In the days of the hazards of metal therapy, one well known syphilogist used to comment, “If the patient has had syphilis for 25 years without clinical disease, he is to be congratulated and not treated.” I followed this advice, with exceptions, of course.
1. A matter of mortality. Time (Aug. 7) 1972.
2. Tuskegee study wouldn’t happen today, PHS says. AMA News (Aug 18) 1972.
3. Greenburg JH (Editorial): Young physicians’ knowledge of venereal disease. JAMA 220: 1736–1737, 1972.
4. Bruusgaard E: Uber das Schicksal der nicht spezifisch behandelten Leutiker. Arch t Dermat u Syph 157:309.
5. Vonderlehr RA, Clark T, Wenger OC, Heller JR Jr: Untreated syphilis in the male Negro: a comparative study of treated and untreated cases. JAMA 107:856–859, 1936.
6. Moore JE, Keidel A: The treatment of early syphilis. I. A plan of treatment for routine use. Bull Johns Hopkins Hosp 39:1–55, 1926. (Quoted in Moore JE: The Modern Treatment of Syphilis. Springfield, Ill, Charles C. Thomas, Publisher 1933)
7. Rivers E, Schuman SH, Simpson L, et al: Twenty years of followup experience in a long range medical study. Pub Health Rep 68:391–395, 1953.
8. Deibert AV, Bruyere MC: Untreated syphilis in the male Negro: III Evidence of cardiovascular abnormalities and other forms of morbidity. J Ven Dis Inform 27:301–314, 1946.
9. Olansky S, Simpson L, Schuman SH: Environmental factors in the Tuskegee study of untreated syphilis. Pub Health Rep 69:691–698, 1954.
10. Heller JR, Bruyere PT: Untreated syphilis in the male Negro: II Mortality during 12 years of observation. J Ven Dis Inform 27:34–38, 1946.
11. Shuman SH, Olansky S, Rivers E, et al: Untreated syphilis in the male Negro: background and current status of patients in the Tuskegee study. J Chronic Dis 2:543–558, 1955.
12. Olansky S, Schuman SH, Peters JJ, et al: Untreated syphilis in the male Negro. X Twenty years of clinical observation of untreated and presumably nonsyphilitic groups. J Chronic Dis 4:177–185, 1956.
13. Shafer JK, Usilton L, Gleeson G: Untreated syphilis in the Negro male: a prospective study of the effect on life expectancy. Pub Health Rep 69:684–690, 1954.
14. Peters JJ, Peers JH, Olansky S, et al: Untreated syphilis in the male Negro: pathologic findings in syphilitic and nonsyphilitic patients. J Chronic Dis 1:127–148, 1955.
15. Rockwell DH, Yobs AR, Moore MB Jr: The Tuskegee study of untreated syphilis: the 30th year of observation. Arch Intern Med (Chicago) 114:792–798, 1964.
16. Moore JE, Danglade JH, Reissinger JC: Diagnosis of syphilitic aortitis uncomplicated by aortic regurgitation or aneurysm: comparison of clinical and necropsy observations in 105 patients. Arch Int Med 49:753–766, 1932.
17. Kampmeier RH, Glass RM, Fleming FE: Uncomplicated syphilitic aortitis—can it be diagnosed? Ven Dis inform 23:254–262, 1942.
18. Moore JE, Danglade JH, Reissinger JC: Treatment of cardiovascular syphilis. Results obtained in 53 patients with aortic aneurysm and in 112 with aortic regurgitation. Arch Int Med 49:879–924, 1932.
19. Kampmeier RH, Combs SR: The prognosis in syphilitic aortic insufficiency. An evaluation of factors other than antisyphilitic treatment. Am J Syph Gonor & Ven Dis 24:578–589, 1940.
20. Report of the National Commission on Venereal Disease, DHEW Publication No. (HSM) 72–8125. Washington, DC, US Government Printing Office, 1972.