Unraveling the Tuskegee Study of Untreated Syphilis

COMMENTARY Unraveling the Tuskegee Study of Untreated Syphilis

ODAY WE repeatedly and public health in relation to and/ that contributed to the genesis of the hear about the or concurrent with the TSUS. This in- TSUS will be briefly described. Tuskegee Study of cludesactivitiesbythegovernmentand In the early 1930s, the Rosen- Untreated Syphilis nongovernment entities. If Americans wald Memorial Fund, a Chicago- (TSUS) in the media. do not understand the historical con- based philanthropic foundation, TThe TSUS was the 1932 through text and the successes and failures of undertook what had not been per- 1972 US Public Health Service past public health policy and medical formed before in America—a study (USPHS) study involving approxi- practices,wemayrepeatsimilarerrors. of the prevalence of syphilis among mately 400 African American men A historically correct, empiri- African Americans. The study was with syphilis who were found un- cally based analysis of the TSUS is performed with the cooperation of treated in rural Alabama and were ob- presented in this article. This is im- the USPHS. The purpose of the study served to autopsy. As a control, there portant given the impact that pre- was to determine the practicability was also a comparable group of 200 vious interpretations (ie, racism, and effectiveness of measures for African American men without syphi- genocide, and conspiracy) of the mass control of syphilis. Macon lis who were observed to autopsy.1 TSUS have had on present-day re- County, Alabama, was one of 6 ru- The TSUS is a topic the domain search, medical practice, and race re- ral counties chosen for study; the of which includes not only medicine lations. Four areas that begin to pro- other counties were Albermarle and research but also the social and vide clarity and specificity in County, Virginia; Pitt County, North political sciences. In the popular press understanding the TSUS are the foci Carolina; Bolivar County, Missis- and medical literature, it is linked to of this article: (1) the public health sippi; Tipton County, Tennessee; and discussions about maternal-infant context, (2) the age of the 400 male Glynn County, Georgia. Macon transmission of human immunodefi- syphilitic participants, (3) the pub- County was included because of its ciency virus (HIV) trials in develop- lication of articles about the TSUS proximity to the Tuskegee Institute ing countries,2 the cold-virus trials,3 by the American Medical Associa- and its hospital, the John A. Andrew andallegedCIAdistributionofcocaine tion (AMA), and (4) the public re- Hospital, and the Tuskegee Veter- in Los Angeles, Calif.4,5 The myths in- lations context as interpreted by me- ans Administration Hospital—both clude many scenarios, ie, that the 400 dia and historiographers. These African American–run institutions. men in the study were infected with discussions will emphasize the his- The county and state health depart- syphilis by the government, that no torical perspective with respect to the ments were also cooperative.9 African Americans knew about the standards of medical practice and The Rosenwald Study was the study until the study was exposed in public health at the beginning and first successful attempt to control ve- 1972, and that none of the men re- during the first 20 years of the study. nereal disease in rural areas. The ceived penicillin.5,6 Sir William Osler techniques developed from this his- hascalledsyphilis,initslatestage,“the A PUBLIC HEALTH PROBLEM toric project were adopted by the great imitator” because it could simu- USPHS as a model for venereal dis- late or complicate practically every Former Surgeon General Thomas ease control nationwide. Although condition known to internal medi- Parran (1936-1948) provided the the treatment given was not exten- cine.7 And so has the TSUS, at this late following definition of a public sive enough to cure all patients, the stage, become “the great imitator.” It health problem: USPHS physicians were able to ren- has been used to exemplify and vali- der most of the cases noninfec- date government mistrust and con- whenever a disease is so widespread in tious.10,11 Because of the different so- a population, so serious in its effects, so spiracies, primarily those against Af- costly in its treatment, that the individual cioeconomic conditions in the 6 rican Americans. unaided cannot cope with it himself.8 counties, the USPHS also, with re- Absent from current discussions gard to syphilis, learned that fac- are the historical policies, programs, With this definition in mind, tors such as social and economic and procedures surrounding syphilis the immediate prior research events conditions had a more important im-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 pact on disease prevalence than whose objectives were seemingly to evaluate and required consider- race.12 Dr Taliaferro Clark, consult- positive.5,17-20 In the Rosenwald able time (ie, 10-20 years) to deter- ant to the Rosenwald Memorial Study, treatment consisted of 8 or 9 mine the outcome. Specifically, the Fund and one of the USPHS offic- doses of an arsenical, which was less question arose whether clinical and ers who initiated the TSUS, stated than the adequate treatment of 20 serological evaluations were as accu- that “syphilis is not peculiarly a ra- doses and far short of the defini- rate as autopsy examinations in de- cial disease, but is also influenced in tively curative treatment of 70 termining the presence or absence of large measure by environment and doses.21 disease.16 In fact, Dr Felix Under- social standards.”13,14 Dr Charles Johnson, a rural so- wood, a Mississippi public health of- Macon County, the poorest of ciologist from Fisk University, Nash- ficial, after listening to the presenta- the 6 counties, had the highest syphi- ville, Tenn, wrote a classic book tion of an article on the Rosenwald lis prevalence rate—approximately about the people of Macon County Study, contemplated whether syphi- 40%. Clark surmised that the high who the Rosenwald Memorial Fund lis was a major public health prob- prevalence rate was a result of the surveyed. In his book Shadow of the lem in African Americans. He ques- low rate of previous antisyphilitic Plantation, Johnson commented that tioned whether syphilis caused treatment (33 treated out of 1200 se- the physicians noted the large num- damage that resulted in loss of time ropositives [3%]), ie, treatment while ber of positive Wassermann test re- from work and decreased work effi- the patient was infectious.15 Evi- sults (ie, seropositive for syphilis) cacy as well as neurological and car- dence from Albermarle and Pitt among elderly men and women. On diovascular disease. It appeared to counties, which had the lowest examination of these people, the Underwood that since there was such prevalence rates (10% and 13%, re- physicians expected to find more a low percentage of African Ameri- spectively), supported this view. Al- than a positive blood test result (eg, cans receiving treatment, “either though the treatment that was re- evidence of syphilitic destruction). syphilis is not causing the negro of ceived by the residents in Albermarle They further noted that the peak the South much discomfort, or the and Pitt counties seemed inad- positive Wassermann test result rate medical practitioners of the respec- equate, Maxcy and Brumfield,16 was in the group aged 25 to 29 years tive states are not diagnosing 95 per medical faculty members at the Uni- for men and 20 to 24 years for wom- cent of the syphilis” in these states.22 versity of Virginia, believed it may en.9 Subsequent to these peaks, there However, the USPHS officers be- have been sufficient to render early was a decrease in the percentage of lieved that the TSUS “should for- cases noninfectious, thereby halt- positive serological results with ad- ever dispel the rather general belief ing the spread of syphilis. The dif- vancing age that was more abrupt that syphilis is a disease of small con- ferences between residents in Alber- and marked than anticipated. Data sequence to the Negro.”23 marle and Pitt counties and Macon from the other 5 rural counties sup- The results of the Rosenwald County were a function of access to ported this pattern of the “disease” Study and the debate over the re- social, economic, and educational becoming asymptomatic and dem- sults and about whether syphilis opportunities.16 Parran’s definition onstrating serologically negative test caused damage in African Ameri- of a public health problem fit syphi- results later in the life of an un- cans may have contributed to the sci- lis in the population of poor black treated patient—characteristics pre- entific thought that led to the TSUS. sharecroppers in Macon County in viously described in the Oslo Study, The specific precursors seemingly the early 1930s. Clearly, according a retrospective study of untreated were to observe patients with un- to Clark, “the extensive prevalence primary and secondary syphilis. The treated latent syphilis to autopsy and of syphilis” in Macon County con- physicians ruled out a treatment ef- verify the presence or absence of stituted “a public health problem of fect, death, and incapacitation by syphilitic destructive lesions. No prime importance.”13 neurologic or cardiovascular syphi- other prospective study of this type The findings from the Rosen- lis as causes for the decreasing per- had ever been performed. Based on wald Study and the decision to treat centage of positive serological re- the prior experimental data avail- patients to render them noninfec- sults with age.16 able from the Rosenwald Study, the tious were presented and recorded Public health officials were con- risk to the men did not appear to ex- at a constituent meeting of the 1932 cerned about whether clinical and se- ceed the importance of the informa- Annual Convention of the Na- rological evaluations could serve as tion that could be derived. tional Medical Association (NMA) a surrogate for the frequency of syphi- at Howard University, Washing- litic infection in latent syphilitic dis- AGE OF THE MALE ton, DC. This information was pro- ease. Primary, secondary, tertiary PARTICIPANTS vided to African American physi- (neurologic and cardiovascular), and cians by Clark of the USPHS about pregnancy-related syphilis have eas- In 1973, William J. Curran24 re- a month and a half prior to his ini- ily evaluable study end points, such viewed the report of the ad hoc ad- tiation of the TSUS. There were no as infectious lesions, skin lesions, vis- visory panel to the Department of objections to Clark’s presentation ceral lesions, and pregnancy out- Health, Education, and Welfare recorded in the minutes. Critics of come, respectively. Latent syphilis, (DHEW) that investigated the TSUS. the TSUS do not condemn the pro- however, with a positive blood test He reported that he had hoped a vision of noncurative treatment in result in the presence or absence of more thorough historical review of the Rosenwald Study—a study clinical findings, was more difficult the study would have been con-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 ducted by the panel. He also wrote rican American physician to write a to latency plus 9 or more years). that more information would have medical textbook, Syphilis and Its “About 800” of these patients were been helpful regarding the charac- Treatment, which was published in “intentionally untreated.” The un- teristics of the African American 1936. In his book, he devoted 40 treated patients served as controls for male participants—namely, their pages to describing primary and sec- comparison with those patients re- ages. Age appeared to have an in- ondary syphilis and 4 paragraphs to ceiving arsenic and heavy-metal fluence on treatment at the incep- latent or asymptomatic tertiary treatment. In general, entry criteria tion of the TSUS and for 20 years into syphilis.29 into the study included the follow- the study. For example, the USPHS In an article in the New En- ing: (1) no symptoms or physical reported that primarily younger men gland Journal of Medicine,30 Hinton signs of syphilis infection (ie, neu- (approximately 178) in the TSUS re- discussed the disposition of a pa- rosyphilis, cardiovascular syphilis, ceived some treatment (ie, 1-15 tient with only seropositive syphilis or benign tertiary syphilis); (2) pre- doses of an arsenical).25,26 Given that and the difficulties in determining the sumed duration of infection greater the 9-member panel voted (with its indication for treatment. He main- than 4 years; (3) serologic evidence chairman abstaining) that the TSUS tained that if he were the patient (ie, of syphilis; (4) negative cerebrospi- was unethical at inception in 1932, Ͼ50 years), as an informed man with nal fluid test results if the patient al- I will consider syphilis and age in seropositive syphilis and no clinical lowed cerebrospinal fluid to be historical context. findings who was presumably in- taken; and (5) negative findings on fected 25 years earlier, he would not fluoroscopic examination of the SYPHILITIC PATIENTS OLDER want treatment. He believed that 15 chest for aortitis. No further details THAN 50 YEARS to 20 years after the primary infec- of the study procedures were pro- tion it was unlikely for an untreated vided in the article. In 1935, Dr Charles Gordon Haig, individual to have serious (ie, car- Regional studies of syphilis had President of the American Medical diovascular or neurologic) injury names. The study of untreated syphi- Association (AMA), introduced a from syphilis.29 In the discussion that lis (ie, primary and secondary cases) 9-reel film series of educational lec- followed, other syphilologists agreed at the University of Oslo was en- tures by nationally reputable syphi- with Hinton relative to the treat- titled the “Oslo Study of Untreated lologists. Dr Paul O’Leary of the Uni- ment disposition of the noninfec- Syphilis,” and the study of un- versity of Minnesota discussed latent tious, seropositive man—an indi- treated syphilis (ie, patients with la- syphilis and its treatment.27 O’Leary vidual similar to approximately 30% tent syphilis who were 25 years or described a 62-year-old white man of “the male Negroes” in the study of older) at the Tuskegee Institute was who had syphilis for 40 years. The “untreated syphilis.”26 entitled the “Tuskegee Study of Un- farmer received “pills” when the sec- At about that same time, phy- treated Syphilis.”32,33 The study of un- ondary signs were recognized; he re- sicians at the Stanford University treated syphilis (ie, patients with late- ceived no other therapy; he had no School of Medicine31 felt that (1) la- latent syphilis who were 50 years or symptoms; and his blood test re- tent syphilis was overtreated; (2) evi- older) at Stanford University could sult was strongly positive for syphi- dence of the efficacy of antisyphi- perhaps be entitled the “Stanford lis. O’Leary’s recommendation was litic therapy for late-latent syphilis Study of Untreated Syphilis.” that no treatment was indicated. His was lacking; (3) patients with late- rationale was as follows: (1) the latent syphilis suffered no discom- SYPHILITIC PATIENTS farmer had controlled his disease for fort or disability from their infec- YOUNGER THAN 50 YEARS 40 years, (2) the man was noninfec- tions; and (4) if these patients tious, and (3) nothing could be suffered, it was from anxiety and so- Two intertwined controversies re- gained with treatment. Thus, ac- cial disruption caused by the stigma garding treatment and survival con- cording to O’Leary, the syphilis and attached to syphilis. As a result of fronted the management of syphi- the positive blood test result for these beliefs, it was the policy of the litic patients younger than 50 years. syphilis could be ignored. The only Stanford Clinic to withhold treat- In 1943, the Alabama legislature action necessary for the farmer was ment intentionally from patients passed a unique law that mandated a reexamination once a year. with late-latent syphilis (presumed blood tests for syphilis for all its ci- Many of the contemporary re- duration of infection Ͼ4 years) who vilians between the ages of 14 and views of the TSUS do not cite the were older than 50 years. 50 years. Family members younger work of Dr William A. Hinton of Dr Charles Barnett and col- than 14 or older than 50 years un- Harvard Medical School.5,17,18,20 Hin- leagues 31 at Stanford studied 1900 derwent blood testing only if an- ton was well known by the NMA, the whites (300 of these were “Orien- other family member in the same National Association for the Ad- tal, Filipino, and American In- household tested positive. Early in vancement of Colored People dian”) and 666 Negroes; 1472 were the program treatment included 8-, (NAACP), and the syphilology com- men and 1094 were women. Of the 16-, or 30-week heavy-metal therapy munity for his work in syphilis.28 Of 2566 patients, 628 patients were ob- for early syphilis and a 40-week al- note was his development of a sen- served for 5 years (ie, minimum of ternating course of heavy-metal sitive syphilis serological test named 4 years to latency plus 5 years), and therapy for late-latent syphilis.34 after him—the Hinton test. He was 316 patients were observed for 9 or Two years later, in the Birming- also credited with being the first Af- more years (ie, minimum of 4 years ham and Jefferson County arm of the

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 program, 271 000 people were sur- required, mandating rigorous pa- pectancy.42 The data were derived veyed. Whites and blacks had par- tient screening. Initially, the inclu- from the University of Virginia Hos- ticipation in the survey (ie, 163 000 sion criteria permitted the enroll- pital clinical records. The hospital and 108 000, respectively) repre- ment of syphilitic patients with drew patients from 11 counties and senting 89% of their respective popu- untreated dark-field–positive pri- the city of Charlottesville. From lations. Three percent of whites and mary and secondary disease, latent 1920 to 1941, the period studied, 30% of blacks had positive test re- disease, neurosyphilis, and congen- 2908 people with acquired syphilis sults for syphilis. Ninety-three per- ital syphilis. There were treatment were admitted to the hospital cent of those infected who received centers in Birmingham, Ala; San (whites, 540 men, 405 women; therapy for early syphilis at the Francisco–Oakland, Calif; St Louis, blacks, 979 men, 984 women). Based USPHS-run rapid treatment center Mo; Washington, DC; Chicago, Ill; on the number of syphilitic pa- in Birmingham were African Ameri- New Orleans, La; New York, NY; tients admitted to the hospital, crude can35; a total of 3231 people with Charlotte, NC; Durham, NC; Nor- prevalence rates of syphilis in the early syphilis were treated at the folk, Va; and South Charleston, area can be estimated at 7% for black rapid treatment center. WVa.37,38 men, 1.6% for white men, 7% for However, the treatment of In 1948, enrollment in the black women, and 1.3% for white syphilis and its indication had study was limited to patients with women. In that service area, the changed. Public health officials untreated dark-field–positive sec- Rosenwald Study reported similar thought that early syphilis was in- ondary syphilis. The Blue Star Study prevalence rates for blacks.16 Both fectious and a danger to the public accrued 1769 patients (543 whites clinic and private patients were in- health; they also thought that late- and 1226 blacks). Among the syphi- cluded in the record review. The au- latent syphilis was noninfectious and litic patients enrolled, there were 26 thors claimed that this group of pa- only a danger to the infected. Jeffer- with late-latent disease (4 whites and tients received more treatment than son County Health Officer Deni- 22 blacks) and 968 with secondary a comparative group elsewhere. son and State Venereal Disease Con- disease (255 whites and 713 blacks). However, life expectancy of syphili- trol Director Smith35 claimed that Although the authors implied that tic patients was reduced with treat- people in the community inferred information on the efficacy of treatment in comparison with nonsyphi- that penicillin treatment was indi- ment for patients with late-latent litic patients. cated for all cases of syphilis. In the syphilis would be provided, no data If the data of Smith and Bruyere Birmingham and Jefferson County on the outcome for these patients ap- are examined in the same way that program, penicillin was indicated peared in the publications. Penicil- Heller and Bruyere analyzed their only for the early cases (ie, dura- lin was recommended to treat early data (ie, calculation of differences tion of infection Ͻ4 years). Treat- syphilis; however, no recommenda- and percentage life expectancy re- ment was 1.2 ϫ 106 U of penicillin tion for late-latent syphilis was ductions for 5-year age groups be- sodium administered intramuscu- made.37-39 tween 25 and 50 years), additional larly in 72 divided doses (1 dose ev- Regarding the relationship of findings become apparent. White ery 3 hours for 9 days); treatment age to survival, Heller and Bru- syphilitic patients who received with arsenic (5 doses) and bismuth yere40 described mortality data af- treatment had their life expectancy (3 doses) was also included. An es- ter the first 12 years of the TSUS. In reduced more than blacks. Specifi- timated 25 000 to 30 000 patients comparison with the nonsyphilitic cally, white women who received with late-latent syphilis uncovered group, life expectancy of the un- treatment had their life expectancy by screening who presumably de- treated syphilitic group between the reduced more than black women manded penicillin were turned away ages of 25 and 50 years was re- (18% vs 3%); white men who re- by public clinics and private physi- duced by 20%. After age 50 years, the ceived treatment had their life ex- cians.35,36 differences between the untreated pectancy reduced marginally more Restricting penicillin to pa- and control groups decreased with than black men (18% vs 12%). Black tients with early syphilis was not lim- age. They also noted a distinct peak female controls had approximately ited to Alabama. This may have been in the mortality rate curve for their a 2-year disadvantage in life expec- national research policy. In 1945, the untreated black syphilitic patients at tancy compared with white female USPHS and 11 treatment centers approximately age 50 years. Usil- controls. This was reversed in the across the nation began a study ton and Miner41 described a similar syphilis groups that received treat- among syphilitic patients called the peak in black men and attributed it ment (ie, black women who re- Blue Star Study. The objectives of the to deaths from cardiovascular syphi- ceived treatment experienced a Blue Star Study were to determine lis at this age.41 In contrast to the men 2-year advantage in life expectancy the efficacy of various penicillin in the TSUS, these men had been un- compared with white women who treatment schedules with or with- der treatment for at least 6 months. received treatment). Also, in the out other agents in curing primary, There was no similar peak for white Smith and Bruyere data set, white secondary, and latent syphilis and to men. men and women had a distinct peak prevent infectious relapse or sero- Interestingly, the article that in their mortality rate curves be- logical relapse and the late develop- followed the Heller and Bruyere ar- tween ages 45 and 50 years; mortal- ment of crippling complications. In- ticle examined, retrospectively, the ity curves of the black patients did tensive posttreatment follow-up was effect of treated syphilis on life ex- not have the distinct peak. It is un-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 clear why the statistician of this ar- in life expectancy in the white male cess failed to recognize and act ap- ticle excluded this method of analy- age group of 25 to 29 years. He found propriately toward a study that has sis, considering that both statisticians that this reduction in life expec- come to symbolize racism in medi- were in the Venereal Disease Divi- tancy in the syphilitic white men cine. sion of the USPHS and even shared who received treatment was “iden- the same surname.40,42 tical” to the finding in the un- THE FIRST TSUS ARTICLE Is the reduction in life expec- treated black men in the TSUS.44 tancy a result of lack of treatment Rosahn’s basic science work The first article on the TSUS was read (Heller and Bruyere40) or treatment demonstrated that mice infected before the Section on Dermatology (Smith and Bruyere42)? There were with syphilis had reduced survival and Syphilology at an AMA session at least 2 prevailing views to ex- compared with uninfected mice. in Kansas City, Mo.14 It was in the plain these data, depending on the When infected with syphilis, the first article that the USPHS officers focus on the men’s race. First, the mice did not show any lesions from acknowledged the cooperation and journal editors who published both the syphilis. Based on these data and assistance of Tuskegee Institute’s articles commented and provided a other, similar data described in his hospital, the John A. Andrew Me- USPHS perspective (Dr John Heller, article, he had strong convictions morial Hospital, and the Tuskegee editor) on the 2 articles with seem- that Veterans Administration Hospital, ingly conflicting data (ie, no treat- both African American–run facili- ment reduced the survival rate and Evidence is not available by which it can ties. This article documented that the treatment reduced the survival rate be determined whether the reduced lon- morbidity in African American men with syphilis infection). The edi- gevity of untreated syphilitic patients was with untreated syphilis far ex- the result of absence of therapy, or tors focused on the black men who whether the reduced longevity of treated ceeded that in the nonsyphilitic con- received treatment in the Smith and patients was related to exposure to treat- trol group. Sixty-one percent of the Bruyere article, who had a reduc- ment itself.44 controls had no morbid findings, and tion of life expectancy of 8% to 15% 16% of the patients with untreated in the age groups of 25 to 50 years. According to Rosahn, patients in- syphilis had no morbid findings. In The editors stated that no informa- fected with syphilis had not only the the group younger than 40 years, tion was provided in the article on risk of syphilitic lesions but also the 77% of the controls had no morbid the amount of treatment given. risk of mortality from nonsyphilitic findings and 25% of the patients with Therefore, inferences could not be disease. The latter risk was a risk that untreated syphilis had no morbid made regarding the amount of treat- may not respond to antisyphilitic findings. In the group older than 40 ment required to counter the influ- treatment. Rosahn’s article received years, 49% of the controls had no ence of syphilis on life expectancy. first prize in the annual essay con- morbid findings and 8% of the pa- The editors wrote that the 2 ar- test of the American Dermatological tients with untreated syphilis had no ticles indicated that treatment pro- Association in 1952.44 morbid findings. The cardiovascu- longed life.43 lar system was most commonly The second perspective was THE AMERICAN MEDICAL found to have morbid findings. from Dr Paul Rosahn of Yale Uni- ASSOCIATION Twenty-four percent of the con- versity School of Medicine. Rosahn trols had cardiovascular findings (eg, had a major interest in the biologi- There were 14 known articles (2 ar- x-ray or clinical evidence of aorti- cal, clinical, and pathological as- ticles were published twice) about tis), and 47% of the patients with un- pects of syphilis. In his article on the the TSUS published under 9 differ- treated syphilis had cardiovascular adverse effect of syphilis on longev- ent journal titles.14,25,26,33,40,45-53 Three findings. In the group younger than ity in humans and mice, he demon- of the articles that document the ex- 40 years, 6% of the controls had car- strated a clear understanding of the istence and continuance of the TSUS diovascular findings and 25% of the implications of the first 3 TSUS ar- were published by journals of the patients with untreated syphilis had ticles that had been published. He AMA.14,33,52 The last 2 of these 3 ar- cardiovascular findings. In the group wrote that “the morbidity in the un- ticles were published after the AMA older than 40 years, 38% of the con- treated male syphilitic Negroes far House of Delegates adopted a docu- trols had cardiovascular findings and exceeded that in a comparable pre- ment entitled Principles of Ethics 63% of the patients with untreated sumably nonsyphilitic group,” “the Concerning Experimentation With Hu- syphilis had cardiovascular find- untreated Negro men of age 25 to 50 man Beings in 1946.54 These were the ings. years with syphilis had their life ex- first written principles of research The first article was the only pectancy reduced on an average of drafted in the United States and in- TSUS report to have a treated com- about 20%,” and “an untreated cluded provisions for consent of the parator arm. This third arm of 275 syphilitic population exhibits a human subject, scientific rationale, African American men with syphi- greater frequency of morbid states and scientifically competent in- lis was derived from the syphilis clin- than an uninfected population of vestigators; they were written in ics of 5 major universities (the Clini- similar characteristics and environ- response to the Nuremberg doc- cal Cooperative Group). The men ment.”44 When Rosahn reviewed the tors’ trial.54 had received treatment within 2 Smith and Bruyere data, he was most Apparently, the medical estab- years of their primary infection. Ad- impressed with the 20% reduction lishment and the peer-review pro- equate treatment in early syphilis

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 was stated to be important to pre- teraction.55 One of these interracial man,62 reported the results of the use vent infectious relapse and early interactions took place in 1938 when of penicillin in the treatment of late- complications of syphilis. Ad- Dr Raymond Vonderlehr of the latent syphilis. equate treatment was defined as 20 USPHS presented data from the first The latter article claimed that doses of arsenicals and heavy- AMA publication on the TSUS at the late-latent syphilis (ie, positive se- metal therapy within the first 2 years John A. Andrew Clinical Society.56 rologic result, asymptomatic, and of infection; inadequate treatment Over 100 African American physi- duration Ͼ4 years) was relegated to was less than 20 doses of arseni- cians may have attended his presen- the background with regard to treat- cals. Only 68 (25%) of the 275 Af- tation and possibly many more re- ment compared with early infec- rican American men received ad- ceived a copy of his article when the tious syphilis. The reasons for the equate treatment. However, ade- Annual Bulletin was distributed to the lack of interest in this stage of the quate treatment in the early phase entire membership. Vonderlehr was disease included varying opinions as of infection prevented all 68 pa- invited to speak again the follow- to the value of therapy in the treat- tients from returning within 15 years ing year at the Annual Convention ment of late-latent syphilis, the feel- of follow-up with evidence of de- of the NMA in New York57 and 2 ing of patients that a positive sero- structive lesions of syphilis. years later at the Public Health Meet- logical test result for syphilis placed The first article was published ing of the John A. Andrew Clinical a stigma on them, and the fact that twice—in JAMA14 and in Venereal Society.58 Apparently, he had an on- these patients had no symptoms or Disease Information.45 The text of the going relationship with African signs and were not incapacitated. 2 publications was identical. The American physicians and the lead- Niedelman claimed that people older only difference was that an abstract ership of their organizations. than 60 years with late-latent syphi- of the discussion that followed the This ongoing relationship was lis were often exempted from any oral presentation was also pub- generalized to the USPHS and its therapy. He thought that other natu- lished in JAMA. leadership. A letter from the presi- ral causes would end their lives be- The discussion included infor- dent of the NMA criticized the fore syphilitic progression. In 1957, mation about racial differences with USPHS for providing public health a panel of prominent syphilologists regard to central nervous system fellowships to aliens but denying the from the University of Pennsylva- syphilis, common administration of same opportunity to African Ameri- nia and the World Health Organi- inadequate therapy for syphilis in ac- can citizens. Dr Roscoe Giles re- zation writing for the Archives of In- tual community practice, compara- marked that African Americans ternal Medicine reviewed the data tive prevalence rates of syphilis, found the USPHS fair, that Surgeon from this 1956 article on penicillin symptom and clinical evaluation cor- General Cummings had extended in the treatment of late-latent syphi- relations of cardiovascular syphilis himself for African American causes, lis. The panel dismissed its rel- by sex, and the problem of history and that the current surgeon gen- evancy because the follow-up of the taking in the men of the TSUS.14 eral (Parran) was considered a friend patients was less than 3 years.63 Was the information from this by the NMA.59 It was during Cum- In the second AMA article, first article about the TSUS readily mings’ and Parran’s terms as sur- Olansky et al52 reported that among available to African American phy- geon general that the TSUS was ini- the male Negroes with untreated sicians? Historical data suggest that tiated and continued.60 late-latent syphilis only 38 of 299 this was the case and document an who had serological follow-up re- ongoing relationship between the THE SECOND TSUS ARTICLE ceived no treatment prior to the first USPHS and representatives of Afri- PUBLISHED BY THE AMA follow-up examination in the late can American organized medicine. 1930s. The other 261 subjects were In 1912, the John A. Andrew Clin- The second AMA article52 was pub- treated as follows: 137 subjects re- ics were founded at the John A. An- lished after 22 years had elapsed. ceived less than 3 doses of arseni- drew Hospital in Tuskegee. Six years That issue of AMA Archives of Der- cals or heavy metal (eg, mercury), later the John A. Andrew Clinical So- matology was dedicated to August 116 subjects received 3 to 11 doses ciety was founded. These continu- von Wassermann. The success of of arsenicals, and 8 subjects re- ing medical education activities were penicillin in the treatment of early ceived more than 12 doses of arseni- founded by and for African Ameri- syphilis had resulted in the “and cals. In the article by Schuman et al,26 cans. Their work filled a void in the Syphilology” being dropped from the the Sing Sing criteria for adequate growth and development of Afri- title of the journal. At the time of therapy for syphilis were de- can American medical profession- publication, the prevalence of infec- fined—no treatment: no treatment als in a segregated society. African tious syphilis had declined by about or less than 12 doses of arsenicals American physicians traveled to 90%.61 and/or bismuth injections; inad- Tuskegee to the John A. Andrew Two articles preceding “Un- equate treatment: 12 doses of ar- Clinics and the John A. Andrew treated syphilis in the male Negro” senicals and/or bismuth but less than Clinical Society every spring, where in the AMA Archives of Dermatol- adequate or less than 2.4 ϫ 106 Uof they provided service to the needy ogy reported on the use of penicil- penicillin; and adequate treatment: sick, professional training for Afri- lin in the treatment of syphilis: one 20 doses each of arsenicals and bis- can American physicians, interre- was an overview by J. F. Ma- muth or 30 injections within 2 years gional interaction, and interracial in- honey,61 and the other, by Niedel- or a rapid treatment schedule of

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 2.4 ϫ 106 U or more of penicillin. 1948-1949 examinations; only 2 new ceptualization seemed to fuel out- According to the Sing Sing criteria cases of late syphilis were detected rage of laypeople and the media. for treatment, only 8 of the 299 sub- at the 1963 examinations.33 Initially white and black phy- jects would have been considered to This article identified patients sicians approached the issues sur- be adequately treated. who had received penicillin and had rounding the TSUS with more rea- Based on the serologic rever- syphilitic abnormalities. Seven pa- son than outrage. Shortly after the sal data in this article, the USPHS of- tients received penicillin in the 1950s. media’s expose´, however, Dr Ru- ficers revised the definition of un- Three of these patients had tertiary dolph Kampmeier, editor-in-chief, treated to patients who received syphilitic abnormalities and ap- wrote an article in the Southern fewer than 3 arsenical doses. They peared to receive penicillin acciden- Medical Journal outlining the medi- considered 124 of the 299 subjects tally, incidentally, and unintention- cal and scientific grounds for his as “treated.” The best serological re- ally for the treatment of syphilis (ie, disagreement with the unethical versal occurred in the treated sub- a 2- to 4-year interval between the de- overtones placed on the TSUS.65 jects aged 25 to 39 years with a du- tection of an abnormality and the ini- He based his opinion on his review ration of infection of less than 15 tiation of penicillin). Eight other pa- of the TSUS published reports, the years. The worst serological rever- tients had tertiary abnormalities and 1972 recommendations of the sal occurred in the untreated sub- received no penicillin.33 National Commission on Venereal jects aged 25 to 39 years with a du- In an earlier article, Schuman Disease, and other publications ration of infection of less than 15 and collaborators26 claimed that concurrent with the TSUS. His years. Intermediate serological re- some of the men in the TSUS were points included doubt that treat- versal occurred in both the treated “inadvertently rounded up and sent ment was purposefully withheld and untreated subjects aged 40 to 54 to rapid treatment centers” and from subjects if desired, doubt that years with a duration of infection of treated with penicillin. The 32 men arsenic or penicillin was efficacious 15 to 29 years. Untreated subjects who were identified as having re- in the treatment of late-latent aged 55 to 69 years with a duration ceived inadequate penicillin therapy syphilis, and a belief that few indi- of infection of 30 to 44 years had a (ie, Ͻ2.4 ϫ 106 U) may have been gent rural Southern people would serological reversal comparable with those men. Twelve other men were have received full treatment. the aforementioned best group (ie, described as having received ad- Kampmeier’s background was in treated, younger subjects with a equate penicillin therapy for pneu- syphilology, a specialty whose spe- shorter duration of infection). monia and as a premarital precau- cific journals had ceased to exist 2 Interestingly, the same panel tion. Four of these men received decades earlier in the United that reviewed the article by Niedel- penicillin in the late 1940s. Be- States, and, in general, the impor- man62 reviewed the second AMA ar- tween the 2 reports,26,33 14 men in tance of syphilology as a field was ticle. Both reviews of these 2 ar- the TSUS had received adequate in sharp decline.66 He was also well ticles were in the section entitled penicillin therapy. respected in organized medicine. “Penicillin in Late Latent Syphilis.” The third AMA article, pub- In the Journal of the National Although the panel of experts of- lished in the Archives of Internal Medical Association, Dr Montague fered an opinion on the penicillin ar- Medicine, prompted a response from Cobb, editor-in-chief, wrote an article (ie, that the follow-up period one of its readers. Dr Irwin Schatz ticle outlining the development of was “much too brief”), they only re- of Detroit, Mich, wrote to the USPHS the study and the issues that needed ported the conclusions of the sec- authors about his objections. Schatz to be addressed.67 He based his opin- ond AMA article. No other opin- objected to the denial of effective ion on his review of the TSUS pub- ions were offered.63 therapy for a potentially fatal dis- lished reports, other publications ease. According to Schatz, even if the concurrent with the TSUS, and the THE THIRD TSUS ARTICLE benefits of the results outweighed the report of the ad hoc advisory panel PUBLISHED BY THE AMA risks, the investigators required re- to the DHEW. Cobb made several evaluation of their moral judg- points: (1) A valid question existed The third AMA article33 was pub- ment. This was the first complaint in 1932 whether syphilitic subjects lished after the TSUS had existed for of its kind received by the USPHS did better if left untreated. (2) Syphi- 30 years. It was read before the An- about the TSUS.60 litic subjects who were classified as nual Symposium on Recent Ad- After 40 years, numerous pub- “cured through treatment” in the vances in the Study of Venereal Dis- lications in the medical literature, 1930s had a mortality rate that was eases in Houston, Tex. The authors and presentations of the data at na- 10% to 20% higher than that of those commented that after the age of 55 tional and international medical who were untreated or inadequ- years, the process of aging had be- meetings,14,25,26,33,40,45-53 an Associ- ately treated. (3) The effect of peni- come evident and significant in both ated Press expose´ evoked public out- cillin on the public health control of the syphilitic subjects and con- cry and led to the cessation of the venereal diseases in the 1950s had trols. Eleven (12%) of the 90 syphi- TSUS.64 What may have been a sci- not been all salutary. (4) There was litic subjects had evidence of late entifically valid endeavor at incep- a national rise in the prevalence of syphilis at their 1963 examination was now cast as government- venereal disease while penicillin was tions. Most of these 11 subjects had sanctioned malpractice on poor and readily available in 1973. (5) The re- evidence of late syphilis at their uneducated guinea pigs. This recon- port of the ad hoc advisory panel to

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 the DHEW was not a comprehen- rican Americans and syphilis. (5) In graphs in that section of the book. sive objective report. (6) Evidence the 1950s, penicillin was the pre- In addition, the photograph in which did not appear to have been brought ferred treatment for syphilis. Dr Stanley Schuman appears was forward in proof that anyone was Brandt’s ethical conclusions in- mislabeled; the person in the goggles subjected to the avoidable risk of cluded the following: (1) The USPHS with him performing fluoroscopy death or physical harm. (7) There regarded the men in the TSUS as less was not Mr Bouie but Dr Jesse was no way to know if any benefi- than human and believed that the ex- Jerome Peters.50 In a group photo- cial findings were derived from the perimental circumstances occurred graph, the affiliation of Dr G. C. TSUS. Finally, according to Cobb, a naturally because the men would not Branche was incorrectly given as the study like the TSUS should not be be treated anyway. (2) The USPHS USPHS; Branche was the clinical di- done again. Cobb was well re- did not tell the men they were in an rector of the Tuskegee Veterans Ad- spected and his background was in experiment. (3) Since only the offer ministration Hospital. In another the history of medicine, African of treatment would maintain the in- example, Jones provided the educa- American organized medicine, and terest of the men in the study, the tional backgrounds (eg, medical civil rights. men participated under the guise of school attended and training) of the Here were 2 men of medicine, treatment. To accomplish this end, white physicians (eg, Drs Vonder- white and black, respectively, dis- the USPHS deceived the men into be- lehr, Clark, Wenger, Heller, and Par- cussing the scientific and medical is- lieving they were receiving treat- ran) who were involved with the sues surrounding the TSUS. Kamp- ment. (4) The USPHS prevented the TSUS. However, he did not provide meier represented a medical men from receiving treatment. (5) similar information about the black organization with a history of ra- Bringing the men to autopsy re- physicians who were involved (eg, cially restrictive membership.68 Cobb quired deceptions and induce- Drs Eugene Dibble, Peters, Branche, represented a medical organization ments. (6) The entire health of the and J. Ward). Moreover, 4 of the 5 dedicated to dissolving racially re- community was at risk by leaving a names and titles of the all-white 1969 strictive memberships.69 Although communicable disease untreated. (7) ad hoc committee members were their organizations had differ- The USPHS lied to the men. printed in the text of the book, ences, they appeared to express more Raising some of the same is- whereas 7 of the 9 names and titles reason than outrage about the TSUS. sues, Dr James Jones, professor of of the ad hoc advisory panel of the Then historiographers en- history at the University of Hous- DHEW, the most of whom were tered the debate. They reviewed not ton, wrote a lay-oriented book, Bad black, appeared only in a footnote only the published reports and other Blood.60 Bad Blood is considered the in the back of the book. concurrent publications but corre- major authoritative book on the Second, Jones presented dis- spondences and meeting minutes of TSUS. However, this was achieved senting views in a biased manner. the USPHS and other organiza- at the expense of physicians. Jones’ White professionals were cited tions. Dr Allan Brandt, as a gradu- book constitutes a major negative prominently in the text, while black ate student at Columbia Univer- commentary on the medical profes- professionals were cited in foot- sity, New York, NY, was one of the sion, the editors of its journals, the notes or in the back of the book. For first historians to conduct such an peer-review process, and the clini- example, there was a solo dissenter analysis.18 His review of informa- cians who read the journals. Accord- during the 1969 ad hoc meeting to tion that was presumably not easily ing to Jones, “For many blacks, the discuss continuance of the TSUS; in- available to the public, editors of Tuskegee Study became a symbol of formation about the dissension of Dr journals, or peer reviewers, re- their mistreatment by the medical es- Eugene Stollerman was in the text sulted in a number of historical and tablishment, a metaphor for deceit, of the book. There was a solo ab- ethical conclusions. conspiracy, malpractice, and ne- stainer for the first question charged Brandt’s historical conclu- glect, if not outright genocide.”70 to the ad hoc advisory panel of the sions included the following: (1) The Bad Blood, however, may not be DHEW (ie, whether the study was medical profession supported the reliable historiography because Jones justified in 1932 and whether it turn-of-the-century prediction that handled information on whites and should have been continued when the newly emancipated African blacks differently, suggesting bias. penicillin became generally avail- American populace would become For example, the author used full- able), but information about the ab- extinct in the 20th century as a re- face photographs of the white phy- stention of Dr Broadus Butler, chair- sult of crime, vice, and disease— sicians involved with the TSUS in a man of the panel, was in a footnote particularly venereal disease. (2) separate section of the book, while in the back of the book. Addition- Physicians discounted the socioeco- clear photographs of black physi- ally, commentary on Kampmeier’s nomic explanations for the condi- cians were noticeably absent. More- article65 dissenting on the charges tion of African Americans. (3) Bet- over, there were 2 photographs of a against the TSUS was in the text of ter medical care would not alter the black physician involved with the the book, while commentary on the evolutionary outcome of the extinc- TSUS shown with his face partially article by Dr Charles McDonald,1 tion of African Americans. (4) The covered; in the spinal tap photo- which described the contribution of USPHS officers who initiated and graph, his name was not preceded the TSUS to medical knowledge, was continued the TSUS accepted these by “Dr,” as it was for the names of in the “A Note on Sources” section mainstream assumptions about Af- the other physicians in the photo- in the back of the book.

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Third, Jones documented rac- acters, and careless use of sources.74 There were other reasons why ism in medicine in the early 1900s Similar biases and lack of balance African Americans appeared to re- solely from mainstream medical and were evident in Bad Blood. ceive an excessive degree of atten- historical sources. African Ameri- tion regarding their health. First, it can historical references and his- COMMENT was not popular to spend money on tory relating to activities of the NMA, the health of African Americans at NAACP, Tuskegee Civic Associa- The approach in the current article the time the TSUS began. African tion, and Urban League in and is to view the TSUS and activities Americans could not finance their around Tuskegee prior to and con- preceding and surrounding it with own health care. Many hospitals and current with the TSUS were absent the eyes of the medical experts who clinics refused to treat African from the book. These were organi- were taking care of syphilitic pa- American patients, and it was only zations dedicated to eradicating the tients and creating and executing with great difficulty that tax- unhealthy environment of African public health policy at the time the supported medical facilities were Americans as it was depicted in the study was undertaken. An alterna- made available for African Ameri- mainstream medical literature. tive view of what may have hap- cans, especially in the South. The at- In another example, Jones de- pened becomes apparent when we titude was: “Having no place to send scribed Ms Eunice Rivers, the Afri- focus on the public health prob- the Negro for medical care it is eas- can American public health nurse lem, the age of the 400 male syphi- ily assumed that there is small need and her role in the TSUS in detail. litic participants, the publications on to carry on an active and continu- Although Rivers coauthored 2 of the the TSUS by the AMA, and the pub- ous health educational cam- TSUS manuscripts,26,47 6 other wom- lic relations dilemma. Although paign.”76 The USPHS and the Rosen- en’s names (Geraldine A. Gleeson, more questions may be raised than wald Memorial Fund responded to Dorothy S. Rambo, Anne Roof Yobs, answered, this alternative perspec- this gross disparity in the alloca- Martha C. Bruyere, Lida Usilton, and tive warrants attention and consid- tion of health care dollars. As an ex- Eleanor V. Price) appeared on 10 of eration. It provides possible rea- ample of their intended action, in the TSUS articles under 7 different sons why there were no public 1929, Dr Oliver Wenger, one of the journal titles.25,26,33,46,48-53 Five of these complaints about the TSUS in the future USPHS investigators of the women were statisticians; Dr Yobs medical community for so long. It TSUS, informed Michael Davis of the was a physician and chief of medi- also begins to unravel issues and al- Rosenwald Memorial Fund that he cal research of the Venereal Dis- legations of exploitation, differen- would take the data from his recent ease Research Laboratory, Commu- tial treatment of blacks compared survey of syphilis in Mississippi to nicable Disease Center, PHS, DHEW. with whites, and denial of state-of- the Mississippi legislature. Accord- Finally, Jones presented oral the-art treatment in the TSUS. ing to Wenger, since the public history from white physicians who The magnitude of syphilis in health problems of the African were involved with the TSUS. The Macon County in the early 1930s fit American population had been ig- book did not present oral history Parran’s definition of a public health nored, this action was necessary.77 from any black physician. Jones’ Bad problem. The prevalence rate was The health of African Americans in Blood treated African Americans and extremely high. Treatment was Alabama was also ignored. Per- their issues in a biased and an un- costly, was of long duration, and re- haps, in parallel fashion, in the early balanced manner. Perhaps, like the quired expertise. Syphilis had seri- to mid-1940s, the morbidity data USPHS, Jones’s initial intent was be- ous implications for the commu- from the first AMA publication of the nevolent, but the end product was nity and complications for the TSUS were used to convince Ala- malevolent. Other comprehensive afflicted if not treated in its early, in- bama lawmakers to include Afri- articles in peer-reviewed journals by fectious stage. Conditions in Ma- can Americans in the mandatory Drs Cave, Brandt, and Reverby seem con County demonstrated that the blood testing program for syphilis for to demonstrate some of the same bi- problem would not resolve on its its citizens between the ages of 14 ases.17-19 own without help. Government and 50 years.20 Bad Blood seems to be viewed as agencies, philanthropic organiza- Second, the appearance of ex- the definitive analysis of the tions, and local leadership com- ploitation of African Americans in TSUS,5,71-73 and no negative review of bined to address the problem. Dr syphilis studies was an issue that was the author’s methods and conclu- Thomas Benedek corroborated the contemplated by the USPHS. In sions appears in scientific or medi- need to study syphilis in Macon 1930, Michael Davis of the Rosen- cal journals. However, a review of an County in a critique of the TSUS.75 wald Memorial Fund had concerns unrelated book by Jones, a biogra- He wrote that the clinical ramifica- about the reaction of blacks in the phy of Alfred Kinsey, presented no- tions of a disease could be studied North to the syphilis studies in the table criticisms similar to those cited most efficiently in the environ- South (ie, the celebrated Rosen- above. The reviewer criticized Jones’ ment in which it is most preva- wald 6-county studies). Clark of the work on the basis of personal bi- lent.75 Since data from a prior study USPHS wrote that it was the active ases, unsubstantiated assumptions, (the Rosenwald Study) indicated that cooperation of blacks in the South mean-spiritedness, pseudo-thorough- socioeconomic conditions had an that determined the use of blacks in ness, lack of critical in-depth analy- impact on syphilis, conditions in Ma- these studies. Clark believed it was sis, selective deletion of critical char- con County appeared optimal. an unfortunate handicap in the ef-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 fort for venereal disease control lologists may have recommended no TSUS who lived to be 90 years or among the white population that treatment. older, it appears that the nontreat- they (the USPHS) could not secure There are practical examples il- ment of patients with late-latent such cooperation. The choice of lustrating that the treatment of pa- syphilis was the policy for blacks and blacks for the studies, according to tients with latent syphilis younger whites in Alabama and elsewhere in Clark, was a matter of cooperation, than 50 years was not much differ- the mid- to late 1940s. Two survi- not discrimination.78 ent in the prepenicillin and early vors of the TSUS claim that when These privately written words penicillin eras. In the initial blood they were sent to the rapid treat- expressed attitudes that public health screen for syphilis for residents of ment center in Birmingham, they officials also stated publicly. A year Alabama in the mid-1940s, civil- were sent home without treat- later, at the Section on Public Health ians older than 50 years were ex- ment.60,80 What the survivors de- at the Southern Medical Associa- cluded by law. Men in the TSUS (ie, scribed (ie, not obtaining treat- tion Annual Meeting, Clark com- those younger than 50 years) who ment) may not have had anything to mented on the large number of black tested positive for syphilis by man- do with the TSUS. The outcome was patients who came forward in the datory blood testing may have been the same. Some of these men were not Macon County survey and the high sent to the rapid treatment center in treated with penicillin in Birming- proportion of syphilitic subjects who Birmingham. Like other blacks and ham. However, the reasons treat- received successful treatment. He whites with late-latent syphilis, they ment was not given in Birmingham further stated that these numbers may have been denied penicillin may have been historically different were large compared with the small treatment and sent home.35 As late than those given in the story as it was number of whites willing to come as 1948, although penicillin ap- later revised—revised to fit, presum- forward for treatment.13 Also, ac- peared to have great promise for the ably, a victim model. cording to the state health officers treatment of latent syphilis, penicil- The standard of care in local (Rosenwald investigators) in Ten- lin’s use was discouraged because of white communities was not always nessee, the history of primary syphi- a shortage of the antibiotic and be- practiced as described in text- litic lesions was more accurate for cause it was believed that a large books,18,71 and this may be illus- blacks than whites in the 1930s79— long-term study was needed to dem- trated by 3 examples. First, after the information that was shared at a onstrate its efficacy.31 Ironically, had presentation of the first AMA ar- Joint Session of the Health Officers the men in the TSUS been treated in ticle on the TSUS, a discussion en- and Epidemiology Sections of the an- Birmingham in the 1940s, the sued.14 Dr Harry M. Robinson from nual meeting of the American Pub- USPHS would still have considered Baltimore, Md, stated that many of lic Health Association. The timing them to have been inadequately his former students were not rec- of a primary syphilitic lesion was an treated. This is because they would ommending a full course of anti- important factor for determining the have received half the amount of syphilitic therapy to their patients approximate duration of infec- penicillin that was considered ad- (ie, state-of-the-art treatment: weekly tion—a criterion for inclusion in the equate for treatment in the 1950s.26 arsenotherapy or a heavy metal for TSUS. In another example, a na- 70 weeks56). Because of practice Age, duration of infection, and tional perspective illustrates how pa- competition in their communities, stage of disease were the determi- tients with late-latent syphilis were they were prescribing 7 to 10 injec- nants for the application of state-of- excluded from treatment pro- tions of arsenotherapy or bismuth the-art treatment for syphilis. Ap- grams. Although the Blue Star Study compounds as a complete treat- proximately 30% of the men who was initially set up to evaluate the ment for syphilis. participated in the TSUS were above efficacy of penicillin schedules in all Second, 3 years later, Dr Paul the age of 50 years and had late- stages of syphilis (including the late- Dudley White in Boston, Mass, pro- latent syphilis26; this is an estimate latent stage), patients with late- vided data that gave credence to Rob- because many of the men in the latent syphilis were excluded from inson’s claim. White and colleagues study were uncertain of their age. In the study about 3 years into the pro- studied patients for evidence of car- addition, about 52% of the men who gram. Patients with readily evalu- diovascular disease whose primary participated in the TSUS had syphi- able untreated dark-field–positive syphilis dated back 15 to 25 years.81 lis infections for 15 years or longer secondary syphilis were prime can- Seventy-one percent of the patients (41% for Ն20 years).52 Many major didates for this 1700-patient study (172 of 241) (all whites except 1 “ne- academic centers did not treat all pa- that was offered in treatment cen- gro”) had received 0 to 12 doses of tients with latent syphilis older than ters across the country. Had any of arsenotherapy within the first 5 years 50 years in the 1930s and 1940s be- the men in the TSUS younger than after infection. Seventy percent of cause a 15- to 20-year duration of 50 years with late-latent syphilis these patients (121 of 172) were again syphilis from the time of primary le- sought entry into the Blue Star Study inadequately treated with 0 to 12 sions was assumed. Based on this in- at treatment centers in Birming- doses of arsenotherapy within 5 to 15 formation, if any of the men who ham, New York City, Chicago, or years after infection. This latter pe- participated in the TSUS and were San Francisco–Oakland, they may riod was a second treatment oppor- older than 50 years had sought sec- have been denied access.37-39 tunity for these patients, but they, like ond opinions at the Mayo Clinic,27 Without challenging the cred- the “male Negroes in the study of un- Harvard,30 or Stanford,31 the syphi- ibility of some of the survivors of the treated syphilis,” received inad-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 equate treatment. There was no in- ment program in place, and in 1935 facto social and economic realities dication in the report that the patients these physicians willfully and inten- (eg, lack of access to health care and would receive additional antisyphi- tionally denied treatment to pa- poverty)26 were also major contrib- litic therapy. Perhaps additional treat- tients with late-latent syphilis older uting factors. Alternatively, at the ment was not offered because White than 50 years. Moreover, this newly time, a number of syphilologists may and colleagues, as they wrote in their uncovered information illustrates have attributed the approximate 30% article, believed that treatment 15 more than just the prevalent medi- rate of penicillin administration in years after infection would not pre- cal opinion at the Stanford Clinic the TSUS to “happenstance penicil- vent cardiovascular syphilis.81 during the period when the first half lin.” From 1947 to 1954, penicillin Third, syphilologists and pub- of the TSUS was conducted. It re- was widely used to treat many mi- lic health officials recognized that veals how patients similar to those nor nonsyphilitic illnesses. This only 15% to 25% of people with in- in the TSUS—whites and blacks— practice may have been responsible fectious syphilis completed a full were treated by a major medical infor the 90% reduction in infectious course of arsenic and heavy-metal stitution. syphilis between 1947 and 1954. therapy. A combination of social (eg, This may help to explain why, Subsequently, because of the fear of embarrassment), economic (eg, despite sufficient information in the anaphylactic reactions to penicil- cost), and medical (eg, remission of articles and information available lin, physicians withheld penicillin symptoms) reasons contributed to elsewhere, there was a failure to from general usage. In the subse- these widespread lapses of ther- recognize and act on a study whose quent 5-year period, the incidence apy.7,82,83 It appears that this behav- racist and unethical nature today of infectious syphilis tripled in the ior (the failure to complete cura- appears so obvious.18,19,71 A peer- United States.87,88 Although the tive therapy) was tolerated and reviewed article or editorial in a USPHS may have deprived the men accepted by public health officials. medical journal decrying the TSUS participating in the TSUS of peni- Although not curative by the stan- was not published before a newspa- cillin therapy, it was unsuccessful in dard of the time, the small amount per article exposed it.64 The scien- stopping the administration of “hap- of treatment received by these people tific and medical information con- penstance penicillin.” rendered them noninfectious. With tained in the TSUS-related articles Nevertheless, the critics of the regard to early syphilis, this accom- published by the AMA did not dis- TSUS have presumed that there was plished a basic public health goal: to turb the editors, peer reviewers, and clear scientific evidence for penicil- halt the spread of syphilis.56 The men readership, perhaps because many lin treatment of late-latent syphilis in the TSUS had endured the pri- of those involved participated in the while the TSUS was being con- mary and secondary stages of syphi- prevalent public health activities and ducted.18,60,73 There was not. In fact, lis without treatment and were non- medical practices of their commu- there was a prevailing belief that the infectious when they entered the nities at the time. late use of penicillin to treat syphi- study. Nonetheless, the charge that lis of long duration might be use- What was an experiment in medical officials lied to and de- less and/or harmful and that the op- Tuskegee (ie, nontreatment of syphi- ceived patients was not identifiable timal time for therapy was during litic patients who were older than 50 in the published reports but was un- early syphilis.81,89,90 The mecha- years and/or had late-latent syphi- covered years later in documents in nism of harm from treatment in the lis) may have been public health the National Archives.18,60 Unfortu- case of aortic disease (a potential policy and standard medical prac- nately, evidence of such alleged ethi- problem in the TSUS) was thought tice nationwide in the 1930s and cal misconduct was not readily avail- to occur through therapeutic reso- 1940s. In fact, there was a similar able to the editors of journals, peer lution of inflammation with sub- “untreated syphilis” study con- reviewers, and clinicians who read sequent scar formation and the de- ducted at Stanford University. It was journals.85,86 velopment of progressive aortic run by well-respected syphilolo- Finally, penicillin therapy was regurgitation. The paradoxical wors- gists and examined a sizable white available in the later stages of the ening of uncomplicated syphilitic population who had treatment pur- TSUS. By 1952, 28% of the syphi- aortitis in patients receiving high- posefully and intentionally with- litic patients examined in the TSUS dose penicillin compared with pa- held.31 Certainly, this could alter and had received penicillin therapy. tients who were not treated is an ex- possibly diminish the racist charge Ironically, only 33% of the controls ample of harm that may result from of the TSUS, since it is claimed in the received it.26 Why would the USPHS treatment in the late stages of syphi- literature that what happened in withhold penicillin therapy from lis.91 Since cardiovascular syphilis Tuskegee would never occur in a controls? Although the TSUS was a was a major potential risk in the white population.6,80 In Macon nonintervention trial, critics tend to TSUS, this problem was a real con- County in 1932, there was no treat- hold the USPHS responsible for peni- cern. ment program for patients with early cillin therapy being withheld from To address these and other is- and late-latent syphilis; the USPHS the men with syphilis who partici- sues, the DHEW convened a na- found these poor sharecroppers un- pated. Perhaps the decisions regard- tional commission of private medi- treated, some for as long as 20 ing treatment and nontreatment with cine and public health in 1971 to years.14,26,33,52,84 In contrast, at the penicillin were not based solely on review venereal disease and its treat- Stanford Clinic, there was a treat- medical and research factors, but de ment. The 17-member commission

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 had representation from the AMA intermingled with discussions about ment was indicated at inception and (Dr C. A. Hoffman, president- the virtues of penicillin. One as- denied, and a study that continued elect), American College of Physi- sumes that these expert authors from through the penicillin era. On the cians (Dr Rudolf Kampmeier), Johns Hopkins University, Univer- other hand, information from readily American Public Health Associa- sity of Pennsylvania, Harvard Uni- available, peer-reviewed literature tion (Dr John C. Hume), and NMA versity, University of North Caro- suggests that the high prevalence of (Dr John A. Kenney, Jr), as well as lina, and the World Health syphilis in Macon County consti- other experts from government, aca- Organization were not all racially bi- tuted a major public health prob- demic, and private organizations. ased. They had the expertise to de- lem; that a valid scientific, medical, The report of the commission stated tect the paradox of the efficacy of and public health rationale was the that the evidence supporting peni- penicillin in the treatment of latent basis for the initial design of the cillin treatment for primary and sec- syphilis and the continuation of the study; that at the study’s initiation ondary syphilis was clear and irre- TSUS. With all the information at and at least for the following 16 years futable. However, the report also their disposal, they had the oppor- at many major academic centers, it stated that it was unclear what role tunity, the medium, and the power was public health policy and stan- currently available penicillin prepa- to at least comment about the ambi- dard practice to permit nontreat- rations had in the treatment of late- guity of the efficacy of penicillin ment of patients with latent syphi- latent syphilis, that many patients therapy and the continuation of the lis older than 50 years; that although were allergic to penicillin, and that TSUS. there was a clear indication for treat- there were reports of spiral organ- ment of early, infectious syphilis (ie, isms resembling Treponema pall- CONCLUSIONS an issue of public health), the treat- idum in the cerebrospinal fluid and ment of late-latent syphilis—the aqueous humor of patients who had The medical profession should be condition of the men who partici- received adequate penicillin therapy more cognizant of the issues sur- pated in the TSUS—was a lower pri- for latent syphilis. The commission rounding the TSUS for several rea- ority; that the TSUS results were pre- recommended additional research to sons. sented at medical meetings and determine the role of penicillin in the First, current representations of published in mainstream peer- treatment of late-latent syphilis. the TSUS have contributed to nega- reviewed medical journals; that a few Ironically, this report was issued in tive perceptions in the African Ameri- patients in the TSUS were known to 1972—5 months before the TSUS can community, with the following have received penicillin; and that was exposed by the press.92 results: Many African Americans are black medical professionals were ex- Twenty years later, the status of reluctant to participate in clinical tri- perts on syphilis and seemingly valu- penicillin research for the treatment als. Few African Americans partici- able collaborators with white phy- of late-latent syphilis remained un- pate as organ donors. The health out- sicians in the TSUS. changed. Hook and Marra93 made the comes of African Americans are The presidential apology is now same claim about the persistence of worse because of their mistrust of the past. What is the value of an apol- viable treponemes in latently in- health care system.101-103 ogy from the government for its role fected people after receiving cura- Second, President William Jef- in the TSUS? What role can medical tive doses of penicillin to treat early ferson Clinton recently apologized professionals play now in health care disease. They further stated that for the TSUS on behalf of the gov- and health research, especially for the “there has been no large systematic ernment.104 The President’s apol- benefit of African Americans? With study of therapy of late-latent syphi- ogy included the following state- the information contained in this ar- lis with penicillin G benzathine.” Al- ments about the TSUS: The study ticle, medical professionals and re- though penicillin may have been rec- was clearly racist. The men were searchers have alternative informa- ommended to treat late-latent syphilis used without their knowledge and tion to discuss with their patients and because of its ease of administra- consent. The men were denied help. their patients’ families about some of tion, minimal toxic effects, and low The men were lied to and betrayed the issues surrounding the TSUS. As cost, the evidence supporting its ef- by the government. The physicians a result of these dialogues, perhaps ficacy was lacking. in Tuskegee were wrongfully asso- many African Americans will ac- Again, this may explain how the ciated with the study. His apology tively maintain their health, not de- TSUS continued beyond the discov- was intended to respond to the lack lay treatment, participate in clinical ery, investigation, and celebration of of trust African Americans have in research trials, and volunteer as or- penicillin (ie, the lack of evidence of the health care system. gan donors. If so, the future may hold its efficacy in the treatment of late- The apology, however, repre- promise for narrowing health out- latent syphilis). Scholarly journals, sented clear contradictions with the come disparities between blacks and such as the New England Journal of historical and scientific context of whites. Let us hope the apology does Medicine and the Archives of Internal the TSUS. On the one hand, the not backfire by generating despera- Medicine, published voluminous lit- TSUS supposedly was a racist medi- tion and fear. Unfortunately, there is erature reviews on syphilis in the cal experiment initiated and sus- evidence that when real or per- 1940s, 1950s, and 1960s, including tained by the federal government, a ceived racist events occur in America reviews of the TSUS publica- study whose unethical nature was or internationally, the TSUS is still tions.63,94-100 The TSUS literature was obvious, a study in which treat- thought of as an example of racism,

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