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Toxins, test tubes, and tampons
EDITORIAL
Toxins, Test Tubes, and Tampons JAMES K. TODD, M.D. he evolution of our understanding of toxic shock syndrome (TSS) is a continuing reminder that, as much as we try to model human disease in vitro or in animal models, medical hypothesis ultimately can only be confirmed in the patient. On page 629 of this issue, Nahass and Gocke report on a single patient with TSS following nasal surgery-a condition that is noteworthy because it was not expected to develop in the patient. At the time of surgery, a synthetic nasal packing was used that in vitro had been shown not to promote production of toxic shock syndrome toxin- 1 (TSST- I), a toxin associated with TSS. If the theory was correct, the absence of toxin production in the test tube should predict that no disease would occur in the patient; but like the proverbial board examination question, such indirect attempts at predicting clinical risk may prove to be “true, but unrelated.” TSS was first described in children (three boys and four girls) and associated with Staphylococcus aureus infection in 1978 [I]. Two years later, it became a household word when it was linked to menstruation and tampon use. After a hurried epidemiologic study, TSS was specifically related to a particular brand of tampon, which was quickly removed from the market; and many assumed the problem was solved [2]. It all made intuitive sense; TSS seemed to be a new condition, it seemed to occur predominantly in menstruating females who were using a particular tampon, and now the offending product had been removed from the market. Case closed! But, in fact, menstrually associated cases of TSS continued to occur at the same rate in some states [3] and even increased in frequency in others [4]; and an increasing proportion of non-menstrual cases (including those associated with surgical wound infections) were recognized. In vitro theories have been no more conclusive than epidemiologic ones. In 198 1, two investigators indepen-
dently described a toxin-now called TSST- 1-that was an excellent marker for S. aureus strains isolated from menstrually associated TSS [5,6]. It was quickly assumed that this toxin must be the cause of TSS, but after several years of clinical surveillance, it became clear that TSS in some patients was associated with TSST-l-negative S. aureus strains. Laboratory investigators in the meantime turned out manuscript after manuscript about TSST-1 ‘s biologic properties, its effects in animals, and its production (or lack thereof) in the presence of tampons and other related materials. On the basis of this information, there is little doubt that TSST-1 plays a role (albeit not a mandatory one) in the pathogenesis of TSS. It is also clear that many variables influence its production in vitro, but results from different laboratories vary widely. Much less clear (as evidenced by this present case) is how (or whether) to extrapolate from such conflicting results to patient care decisions. It is now 10 years (and many theories) after TSS was originally described. In November 1987, an international symposium on toxic shock syndrome was held in Atlanta, Georgia. The conclusions of the symposium remind us to be cautious about applying simplistic solutions to complex clinical problems. TSS is still with us; it still occurs most commonly in menstruating women who are using tampons, even though many changes have been made in tampon composition based on epidemiologic and experimental data: a higher risk may occur for those using highabsorbency tampons but does not seem to be related to any particular factor of chemical composition [7]. TSS also occurs in patients using barrier contraceptive devices, postpartum women, and males as well as females with various staphylococcal infections (including after nasal surgery). TSST-1 appears to be only one of several staphylococcal products that may be involved in the
T
From the Children’s Hospital, and the University of Colorado School of Medicine, Denver, Colorado. Requests for reprints should be addressed to Dr. James K. Todd, Children’s Hospital, 1056 East 19th Avenue, Denver, Colorado 802 18- 1088. Manuscript submitted January 15, 1988, and accepted January 19, 1988.
March
1988
The American
Journal
of Medicine
Volume
84
579
EDITORIAL-TODD
pathogenesis of TSS. In vitro studies of conditions influencing TSST-1 production often produce conflicting results with only minor variations in technique-they should be interpreted with a strong dose of caution. It is possible that foreign materials (including nasal tampons, vaginal tampons, and barrier contraceptive devices) play only a passive role in maintaining local growth conditions that promote expression of disease in some patients as reported by Todd et al [8]. Until we know more about the precise pathogenesis of TSS, extrapolation from in vitro data to clinical application should be viewed with caution. Similarly, this admonition should be more broadly applied. In general, we too readily jump from an attractive theory to its clinical implementa-
tion, sometimes with unfortunate results. Many new drugs are widely and enthusiastically used before previously unnoticed adverse effects emerge. New diagnostic techniques-even very expensive ones-are widely implemented long before adequate information exists to establish their clinical usefulness. Certainly we should not be so cautious as to unnecessarily delay the implementation of promising new diagnostic or therapeutic modalities; but, at the same time, we should maintain a critical surveillance for the patient whose condition does not respond in the way the theory predicts. This one simple case of TSS in a patient with synthetic nasal packing teaches a great deal-the theory may be wrong, the patient certainly was not.
REFERENCES 1.
2.
3.
4.
5.
580
Todd JK, Fishaut M, Kapral F, Welch T: Toxic shock syndrome associated with phage-group-l staphylococci. Lancet 1978; II: 1116-1118. Schlech WF, Shands KN, Reingold AL, et al: Risk factors for development of toxic shock syndrome. JAMA 1982; 248: 835-839. Todd JK, Wiesenthal AM, Ressman M, Caston SA, Hopkins RS: Toxic shock syndrome. Am J Epidemiol 1985; 122: 857-867. Petitti DB, Reingold A, Chin J: The incidence of toxic shock syndrome in Northern California, 1972 through 1983. JAMA 1986; 255: 368-372. Bergdoll MS, Crass BA, Reiser RF, Robbins RN, Davis JP: A
March
1988
The American
Journal
of Medicine
Volume
6.
7.
8.
84
new staphylococcal enterotoxin, enterotoxin F, associated with toxic shock syndrome Staphylococcus aureus isolates. Lancet 1981; I: 1017-1021. Schlievert PM, Shands KN, Dan BB, Schmid GP, Nishimura RD: Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic shock syndrome. J Inject Dis 1981; 143: 509-516. Berkley SF, Hightower AW, Broome CV, Reingold AL: The relationship of tampon characteristics to menstrual toxic shock syndrome. JAMA 1987; 25: 917-920. Todd JK, Todd BH, France-Buff A, Smith CM, Lawellin DW: Influence of focal growth conditions on the pathogenesis of toxic shock syndrome. J Infect Dis 1987; 155: 673-681.
Toxins, Test Tubes, and Tampons JAMES K. TODD, M.D. he evolution of our understanding of toxic shock syndrome (TSS) is a continuing reminder that, as much as we try to model human disease in vitro or in animal models, medical hypothesis ultimately can only be confirmed in the patient. On page 629 of this issue, Nahass and Gocke report on a single patient with TSS following nasal surgery-a condition that is noteworthy because it was not expected to develop in the patient. At the time of surgery, a synthetic nasal packing was used that in vitro had been shown not to promote production of toxic shock syndrome toxin- 1 (TSST- I), a toxin associated with TSS. If the theory was correct, the absence of toxin production in the test tube should predict that no disease would occur in the patient; but like the proverbial board examination question, such indirect attempts at predicting clinical risk may prove to be “true, but unrelated.” TSS was first described in children (three boys and four girls) and associated with Staphylococcus aureus infection in 1978 [I]. Two years later, it became a household word when it was linked to menstruation and tampon use. After a hurried epidemiologic study, TSS was specifically related to a particular brand of tampon, which was quickly removed from the market; and many assumed the problem was solved [2]. It all made intuitive sense; TSS seemed to be a new condition, it seemed to occur predominantly in menstruating females who were using a particular tampon, and now the offending product had been removed from the market. Case closed! But, in fact, menstrually associated cases of TSS continued to occur at the same rate in some states [3] and even increased in frequency in others [4]; and an increasing proportion of non-menstrual cases (including those associated with surgical wound infections) were recognized. In vitro theories have been no more conclusive than epidemiologic ones. In 198 1, two investigators indepen-
dently described a toxin-now called TSST- 1-that was an excellent marker for S. aureus strains isolated from menstrually associated TSS [5,6]. It was quickly assumed that this toxin must be the cause of TSS, but after several years of clinical surveillance, it became clear that TSS in some patients was associated with TSST-l-negative S. aureus strains. Laboratory investigators in the meantime turned out manuscript after manuscript about TSST-1 ‘s biologic properties, its effects in animals, and its production (or lack thereof) in the presence of tampons and other related materials. On the basis of this information, there is little doubt that TSST-1 plays a role (albeit not a mandatory one) in the pathogenesis of TSS. It is also clear that many variables influence its production in vitro, but results from different laboratories vary widely. Much less clear (as evidenced by this present case) is how (or whether) to extrapolate from such conflicting results to patient care decisions. It is now 10 years (and many theories) after TSS was originally described. In November 1987, an international symposium on toxic shock syndrome was held in Atlanta, Georgia. The conclusions of the symposium remind us to be cautious about applying simplistic solutions to complex clinical problems. TSS is still with us; it still occurs most commonly in menstruating women who are using tampons, even though many changes have been made in tampon composition based on epidemiologic and experimental data: a higher risk may occur for those using highabsorbency tampons but does not seem to be related to any particular factor of chemical composition [7]. TSS also occurs in patients using barrier contraceptive devices, postpartum women, and males as well as females with various staphylococcal infections (including after nasal surgery). TSST-1 appears to be only one of several staphylococcal products that may be involved in the
T
From the Children’s Hospital, and the University of Colorado School of Medicine, Denver, Colorado. Requests for reprints should be addressed to Dr. James K. Todd, Children’s Hospital, 1056 East 19th Avenue, Denver, Colorado 802 18- 1088. Manuscript submitted January 15, 1988, and accepted January 19, 1988.
March
1988
The American
Journal
of Medicine
Volume
84
579
EDITORIAL-TODD
pathogenesis of TSS. In vitro studies of conditions influencing TSST-1 production often produce conflicting results with only minor variations in technique-they should be interpreted with a strong dose of caution. It is possible that foreign materials (including nasal tampons, vaginal tampons, and barrier contraceptive devices) play only a passive role in maintaining local growth conditions that promote expression of disease in some patients as reported by Todd et al [8]. Until we know more about the precise pathogenesis of TSS, extrapolation from in vitro data to clinical application should be viewed with caution. Similarly, this admonition should be more broadly applied. In general, we too readily jump from an attractive theory to its clinical implementa-
tion, sometimes with unfortunate results. Many new drugs are widely and enthusiastically used before previously unnoticed adverse effects emerge. New diagnostic techniques-even very expensive ones-are widely implemented long before adequate information exists to establish their clinical usefulness. Certainly we should not be so cautious as to unnecessarily delay the implementation of promising new diagnostic or therapeutic modalities; but, at the same time, we should maintain a critical surveillance for the patient whose condition does not respond in the way the theory predicts. This one simple case of TSS in a patient with synthetic nasal packing teaches a great deal-the theory may be wrong, the patient certainly was not.
REFERENCES 1.
2.
3.
4.
5.
580
Todd JK, Fishaut M, Kapral F, Welch T: Toxic shock syndrome associated with phage-group-l staphylococci. Lancet 1978; II: 1116-1118. Schlech WF, Shands KN, Reingold AL, et al: Risk factors for development of toxic shock syndrome. JAMA 1982; 248: 835-839. Todd JK, Wiesenthal AM, Ressman M, Caston SA, Hopkins RS: Toxic shock syndrome. Am J Epidemiol 1985; 122: 857-867. Petitti DB, Reingold A, Chin J: The incidence of toxic shock syndrome in Northern California, 1972 through 1983. JAMA 1986; 255: 368-372. Bergdoll MS, Crass BA, Reiser RF, Robbins RN, Davis JP: A
March
1988
The American
Journal
of Medicine
Volume
6.
7.
8.
84
new staphylococcal enterotoxin, enterotoxin F, associated with toxic shock syndrome Staphylococcus aureus isolates. Lancet 1981; I: 1017-1021. Schlievert PM, Shands KN, Dan BB, Schmid GP, Nishimura RD: Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic shock syndrome. J Inject Dis 1981; 143: 509-516. Berkley SF, Hightower AW, Broome CV, Reingold AL: The relationship of tampon characteristics to menstrual toxic shock syndrome. JAMA 1987; 25: 917-920. Todd JK, Todd BH, France-Buff A, Smith CM, Lawellin DW: Influence of focal growth conditions on the pathogenesis of toxic shock syndrome. J Infect Dis 1987; 155: 673-681.