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American Journal of Epidemiology Advance Access originally published online on September 15, 2008
American Journal of Epidemiology 2008 168(7):683-686; doi:10.1093/aje/kwn112
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Commentary: More than Just Luck—The Impact of Dr. George W. Comstock on Tuberculosis in the 20th Century

Nandini Selvam1,2 and Marian Passannante1,2,3

1 School of Public Health, University of Medicine and Dentistry of New Jersey, Newark, NJ
2 Global Tuberculosis Institute, New Jersey Medical School, Newark, NJ
3 Department of Preventive Medicine and Community Health, New Jersey Medical School, Newark, NJ

Correspondence to Dr. Nandini Selvam, P.O. Box 1000, UGID-60, Upper Gwynedd, PA 19454 (e-mail: nandiniselvam{at}gmail.com).

When one thinks of advances in the field of tuberculosis in the 20th century, the name George W. Comstock immediately comes to mind. Described by Dr. Moyses Szklo as the "best epidemiologist" (1), Dr. Comstock received numerous honors and has many distinctions to his credit. He also authored more than 300 publications and multiple book chapters (2, 3), gave countless lectures and seminars, and mentored numerous students.

Dr. Comstock's work spanned more than 65 years and covered diverse topics including smoking, cardiovascular disease, and the effects of tuberculosis in various populations (4–7). Dr. Comstock, with Dr. Lundin, is responsible for conducting the first effective case-cohort study that associated maternal smoking with fetal and neonatal death (6, 8). Dr. Comstock's most prolific contributions were to the field of tuberculosis. Among his most important tuberculosis-related accomplishments were studies of bacille Calmette-Guérin (BCG) vaccine efficacy, including a 60-year follow-up of the long-term efficacy of such vaccines (9). The BCG studies convincingly show limited efficacy of the vaccine in preventing tuberculosis disease (10–12). Because of findings from Dr. Comstock's studies in Georgia, BCG vaccination was never recommended for general use in the United States. A paper entitled "Tuberculosis Studies in Muscogee County, Georgia" is reprinted in this issue of the Journal (10).

Ever modest, Dr. Comstock considered his life no more than a series of lucky events (1, 13). Even his decision to attend Harvard Medical School, instead of following his father's footsteps as a metallurgist, was attributed to luck (author interview with G. W. Comstock, 2003). Evidence shows that more than just luck shaped the life and work of George Wills Comstock, MD, DrPH. His work-related interest in Washington County, Maryland, immersed him in over 40 years of residence there, giving him the unprecedented opportunity to integrate himself into the community. His commitment to the people, and his quest to improve the world around him, earned him the trust of the communities he worked in and the respect of his colleagues.

At the age of 22 years, he was misdiagnosed as having tuberculosis. Although his illness was later diagnosed as histoplasmosis, according to Dr. Comstock, the "TB seed of interest" had been planted (G. W. Comstock interview, 2003). He took a position with the US Public Health Service upon graduation from medical school, where he became involved in studying tuberculosis.

One of his first studies was conducted at an industrial plant in 1946, evaluating a cohort of employees for tuberculosis initially and again after an 18-month interval (14). In a follow-up survey, 0.13 percent of the employees developed tuberculosis, demonstrating that resurvey at an 18-month interval had little value in finding cases. More than 20 percent of active cases were missed during the initial survey, which was partially attributed to low interreader reliability and emphasized the importance of accurate radiograph readings (14).

In 1947, Dr. Comstock became involved in the first US Public Health Service community trial of BCG vaccines, in Muscogee County (12). A community of 100,000 people was studied to understand the association of community-level effects with the spread of tuberculosis. This unique study combined an operating tuberculosis service with an extensive investigation into fundamental problems of tuberculosis epidemiology (15). The tuberculosis "experience" was an effective combination of clinical and epidemiologic investigations; close examination and follow-up of tuberculosis cases and suspected cases; communitywide chest x-ray screening and survey; BCG vaccination and tuberculin skin tests of all schoolchildren; and, later on, a combined x-ray, tuberculin skin test, and BCG vaccination program for the entire population (10, 15).

During the Muscogee study, the difficulty of preventing active tuberculosis disease in older subjects was recognized, especially since many had latent tuberculosis infection. There were discussions as to whether isolating "cases" would be an effective method of preventing disease in this older group, especially because primary infection could not be differentiated from reinfection (15). Dr. Comstock's tuberculosis work in Georgia prior to the advent of antituberculosis drugs demonstrated "what tuberculosis disease really could do." He believed that this understanding increased his appreciation of the impact of prevention and effective treatment of tuberculosis (G. W. Comstock interview, 2003).

The Muscogee study also served as the foundation for controlled trials of BCG in Puerto Rico during the mid-1950s (12). After multiple long-term projects in the United States and Puerto Rico, outcomes indicated little to no protective effect among those administered BCG vaccines (compared with those not vaccinated) with respect to preventing tuberculosis disease. In areas where tuberculosis infection rates were low, no benefits to BCG vaccination were found even after a 20-year observation period (10).

Data from the Muscogee studies were used for multiple analyses, including a study that evaluated the risk of reactivation among individuals with untreated inactive pulmonary tuberculosis (16). This study defined inactive tuberculosis as the absence of significantly active tuberculosis for at least 2 years after the individual was reported as a tuberculosis case or suspect case.

During the mid-1950s, Dr. Comstock obtained a doctorate from The Johns Hopkins University in a mere 1-year period, and he began a lifetime of collaboration as a faculty member. During his doctoral studies, the "opportunity of a lifetime" took him to Alaska and to the most crucial study, which impacted tuberculosis policy (G. W. Comstock interview, 2003).

A number of studies were undertaken by the US Public Health Service to characterize the epidemiology of tuberculosis, including controlled trials of isoniazid prophylaxis to prevent tuberculosis. Dr. Comstock conducted the trials among Alaskan Natives in the Bethel administrative area and in southeastern Alaskan boarding schools for Natives.

During these trials it was obvious that [latent tuberculosis (TB) infection] treatment had reduced the incidence of TB by 60% overall and by better than 90% among those who regularly took their pills. However, we felt obligated for those who took placebo. We didn't have the money to find everybody and do it individually, so we offered everybody another year of INH [isoniazid]. This gave those who had taken zero medication and those who had taken twice the currently recommended dose. As a result of that, after 19 years, we could see a cutoff around 9 months and the PHS [US Public Health Service] study of contacts — a 10-year follow-up — reported at about the same time also came up with the same break point. I presented this at the CDC [Centers for Disease Control and Prevention] and they reluctantly agreed about the 9 months. Strangely enough, 6 months had crept in without any sort of evidence whatsoever. Among the International Union there had been a study for 3, 6, and 12 months. Looking at it overall, going from 6 to 12 months, just increased the efficacy from 65% to 75%. But, among people who took it well, it increased the efficacy from 70% to 95% and that was ignored (G. W. Comstock interview, 2003).

Dr. Comstock's recommendation? He thought that latent tuberculosis infection treatment with isoniazid should be no less than 9 months long.

The BCG vaccine trial, conducted among the Alaskan Native and American Indian population, was seminal in the conception and implementation of tuberculosis prevalence studies. An 11-year follow-up of the original study showed a 75 percent reduction in radiographically diagnosed tuberculosis, and a 20-year analysis showed an 82 percent reduction in tuberculosis mortality attributable to BCG vaccination in this population (17, 18). In 2004, Dr. Comstock coauthored a 60-year follow-up of the long-term efficacy of BCG vaccines in American Indians and Alaskan Natives among individuals who participated in a placebo-controlled BCG vaccine trial during 1935–1938. This study analyzed data from both the BCG vaccine group and the placebo group. The incidence of tuberculosis was higher in the placebo group than in the BCG group, with 52 percent (95 percent confidence interval: 27, 69) vaccine efficacy, and this study showed that vaccine efficacy persisted for 50–60 years (9).

Dr. Comstock's extensive experience influenced his thinking related to tuberculin skin tests and the importance of accurately reading a positive reaction. In his 1975 publication, "False Tuberculin Test Results," faulty tuberculin skin test results were attributed to faulty administration of the test, incorrect measurement and interpretation of the induration, and failure of the tested person to react as expected (19). In a personal (e-mail) communication in 2004, he expressed his continuing concern about this subject as follows:

Tuberculin testing is one of the most poorly performed tests in medicine. Administering the test is not terribly critical but reading is extremely careless leading to gross misclassification most of the time. The problem is terminal digit preference with the peaks in the distribution of reaction sizes coming at 5, 10, 15 [mm], etc. The decision by the American Thoracic Society to make those peaks the cut points for various definitions of positive leads to gross misclassification.

Terminal digit preference results whenever there is uncertainty about the limits that are being measured. This occurs because the person does not know what they are supposed to do, has poor eyesight, or can see the measurement as it is being measured. There are two ways of tackling this problem.

The CDC recommended procedure of using the ballpoint method gives at least two definite points for measurement, which minimizes digit preference but does not remove it if the persons can see the scale when they are measuring the reaction. The best way to avoid terminal preference is to use calipers on which the scale cannot be seen until the calipers are set at the diameter of induration. Parke-Davis distributed such calipers at one time but did not put the scale on both sides. They are perfectly satisfactory if the scale is scratched off on one side so it can not be seen until the calipers are set and turned over to show the scale. It is much easier to use if a piece of fine sandpaper is glued onto the sliding portion so that it can be moved back and forth with the thumb of the hand that is holding it.

Another useful device is a sewing gauge with one scale in mm. It needs one modification: the slider needs to be removed and reversed so the scale is not visible while the gauge is being set.

At present tuberculin test reading in every health department that I have seen shows such extreme digit preference that they must result in a lot of people with truly negative reactions being put on prophylaxis and truly positive persons being called negative.

The cure? Supervisors should learn to make distribution of reaction sizes by individual mm and if terminal digit preference is present, teach their tuberculin testers to read them as described above.

According to Dr. Lee B. Reichman, one of Dr. Comstock's greatest accomplishments regarding tuberculosis was preventing the United States from administering BCG vaccine to its citizens and complicating effective tuberculosis control with ineffective vaccines, while depending on an inaccurate indicator (tuberculin skin tests) (L. B. Reichman, University of Medicine and Dentistry of New Jersey, in-person communication, 2004). Dr. Comstock's view on the continued administration of BCG in other parts of the world was that he would do the same if he were in charge of tuberculosis control in a developing nation. Dr. Comstock felt that he "would vaccinate and pray real hard that the vaccine used would turn out to be efficacious." He sympathized with the plight of tuberculosis controllers in endemic areas, where precautionary treatments are a luxury not afforded to the multitudes (G. W. Comstock interview, 2003). Besides, some BCG strains have shown a protective effect among young children in endemic areas (20, 21).

In his Wade Hampton Frost lecture given more than 30 years ago (this paper is also reprinted in this issue of the Journal), Dr. Comstock stated that, by keeping the infection rate at or close to zero, tuberculosis can be eliminated (21). Since the incubation period is variable and can even last a lifetime, control measures should stay in place until all reactors die, a period of about three generations. If emphasis were placed on preventing the development of active disease in infected persons, thousands could be saved from suffering from tuberculosis, and perhaps death (G. W. Comstock interview, 2003). Although prevention can occur as a result of individualized motivation and education of both patients and health care professionals, a number of additional factors—including homelessness, human immunodeficiency virus coinfection, and immigration from countries where tuberculosis is prevalent—contribute to the persistence of disease (G. W. Comstock interview, 2003).

His timeless advice to prevent tuberculosis included proper administration, measurement, and interpretation of the tuberculin skin tests and the need to educate health care professionals about the importance of treatment of positive tuberculin skin test reactions and its attendant next steps (21). Dr. Comstock's approach to treatment extended well beyond just clinical practice. A 2001 article by Taylor and O'Brien (22) suggested the need for better diagnostic tests and improved treatment regimens to reduce tuberculosis among foreign-born individuals, which Dr. Comstock agreed with in his response to this article (23). However, he stressed that "having the proper tools will not be sufficient if the populations for whose benefit they are intended do not understand the need for them and if we do not understand how best to convey our message" (23). Furthermore, "if we are to make tuberculosis control as effective among the foreign-born as among the native-born, we must learn to tailor our programs to meet each local situation. In tuberculosis control, one size does not fit all" (23).

Dr. Comstock's fear was that if we once again fail to acknowledge tuberculosis, we will have another spike in tuberculosis rates, not unlike the increase seen during the mid-1980s, but this time with multidrug-resistant tuberculosis. With reduced tuberculosis rates, his concern was that programs and funding will fail to maintain a level of control intensive enough to eliminate tuberculosis. Referring to the Nixon presidential administration in the United States, when tuberculosis funding cuts were huge, he stated "[w]hat they forgot is that when you let up on an infectious disease, it comes back, and it comes back in spades" (G. W. Comstock interview, 2003).

Dr. Comstock's lifetime decisions and systematic observations provided much of the scientific foundation for extensive tuberculosis policy guidance. In spite of his humble attribution of success to a series of lucky events, it is clear that Dr. Comstock's intellect, passion, motivation, determination, and commitment to the communities he studied were attributes that constituted more than just luck. Perhaps it is the field of public health that ought to consider itself lucky to have been bestowed with the humanity and intellect of George Wills Comstock.


   ACKNOWLEDGMENTS
 
The authors are grateful to Dr. George W. Comstock for taking the time to provide this information and for reviewing the manuscript. They also appreciate the valuable comments and feedback provided by Dr. Lee B. Reichman, Executive Director, New Jersey Medical School (NJMS) Global Tuberculosis Institute, University of Medicine and Dentistry of New Jersey (UMDNJ); Dr. Kenneth G. Castro, Assistant Surgeon General, Director, Division of TB Elimination, CDC; and Eileen Napolitano, Deputy Director, NJMS Global Tuberculosis Institute, UMDNJ.

Conflict of interest: none declared.


   References
TOP
 References
 

  1. Comstock George W, ASPH. "Lucky All My Life." (Written script of a movie). Washington, DC: Association of Schools of Public Health, 2003. (http://www.asph.org/movies/comstock.pdf).
  2. Comstock GW, O'Brien RJ, Tuberculosis. Bacterial infections of humans: epidemiology and control. Evans AS, Brachman PS, eds. (1991) New York, NY: Plenum Medical Book Co. 745–71.
  3. Comstock GW. Epidemiology of tuberculosis. In: Tuberculosis—Reichman LB, Hershfield ES, eds. (2000) New York, NY: Marcel Dekker, Inc. 129–56.
  4. Comstock GW, Edwards PQ. The competing risks of tuberculosis and hepatitis for adult tuberculin reactors. Am Rev Respir Dis (1975) 111:573–7.[Web of Science][Medline]
  5. Bush TL, Comstock GW. Smoking and cardiovascular mortality in women. Am J Epidemiol (1983) 118:480–8.[Abstract/Free Full Text]
  6. Comstock GW, Lundin FE Jr. Parental smoking and perinatal mortality. Am J Obstet Gynecol (1967) 98:708–18.[Web of Science][Medline]
  7. Comstock GW, Brownlow WJ, Stone RW, et al. Cigarette smoking and changes in respiratory findings. Arch Environ Health (1970) 21:50–7.[Web of Science][Medline]
  8. Comstock GW, Shah FK, Meyer MB, et al. Low birth weight and neonatal mortality rate related to maternal smoking and socioeconomic status. Am J Obstet Gynecol (1971) 111:53–9.[Web of Science][Medline]
  9. Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study. JAMA (2004) 291:2086–91.[Abstract/Free Full Text]
  10. Comstock GW. Tuberculosis studies in Muscogee County, Georgia. I. Community-wide tuberculosis research. Public Health Rep (1949) 64:259–63.[Web of Science][Medline]
  11. Comstock GW, Woolpert SF, Livesay VT. Tuberculosis studies in Muscogee County, Georgia. Twenty-year evaluation of a community trial of BCG vaccination. Public Health Rep (1976) 91:276–80.[Web of Science][Medline]
  12. Palmer CE, Shaw LW, Comstock GW. Community trials of BCG vaccination. Am Rev Tuberc (1958) 77:877–907.[Web of Science][Medline]
  13. Sandler DP. A conversation with George W. Comstock. Epidemiology (2003) 14:623–7.[CrossRef][Web of Science][Medline]
  14. Kramer M, Comstock GW, Stocklen JB. An evaluation of a chest x-ray resurvey of an industrial plant. Public Health Rep (1946) 61:1990–2001.
  15. Comstock GW, Burke MH. Tuberculosis studies in Muscogee County, Georgia. III. Tuberculosis mortality following a community-wide x-ray survey. Public Health Rep (1951) 66:695–711.[Web of Science][Medline]
  16. Comstock GW. Untreated inactive pulmonary tuberculosis. Risk of reactivation. Public Health Rep (1962) 77:461–70.[Web of Science][Medline]
  17. Aronson JD, Aronson CF, Taylor HC. A twenty-year appraisal of BCG vaccination in the control of tuberculosis. AMA Arch Intern Med (1958) 101:881–93.[Abstract/Free Full Text]
  18. Stein SC, Aronson JD. The occurrence of pulmonary lesions in BCG-vaccinated and unvaccinated persons. Am Rev Tuberc (1953) 68:695–712.[Web of Science][Medline]
  19. Comstock GW. False tuberculin test results. Chest (1975) 68:465–9.[CrossRef][Web of Science][Medline]
  20. Kumar P, Kumar R, Srivastava KL, et al. Protective role of BCG vaccination against tuberculous meningitis in Indian children: a reappraisal. Natl Med J India (2005) 18:7–11.[Medline]
  21. Comstock GW. Frost revisited: the modern epidemiology of tuberculosis. The third Wade Hampton Frost Lecture. Am J Epidemiol (1975) 101:363–82.[Free Full Text]
  22. Taylor Z, O'Brien RJ. Tuberculosis elimination: are we willing to pay the price? Am J Respir Crit Care Med (2001) 163:1–2.[Free Full Text]
  23. Comstock GW. One size fits all? Am J Respir Crit Care Med (2002) 165:305.[Free Full Text]

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