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March 11, 1983, Vol 249, No. 10 >
ARTICLE | March 11, 1983

Scientific Uncertainties in the Studies of Salicylate Use and Reye's Syndrome FREE

Stephen R. Daniels, MD, MPH; Raymond S. Greenberg, MD, MPH; Michel A. Ibrahim, MD, PhD
[+] Author Affiliations

Reprint requests to School of Public Health, Rosenau Hall, 201H, University of North Carolina, Chapel Hill, NC 27514 (Dr Ibrahim).


JAMA. 1983;249(10):1311-1316. doi:10.1001/jama.1983.03330340053031
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References

IN 1963, R. D. K. Reye and coworkers1 first reported a syndrome of acute encephalopathy associated with the fatty degeneration of the viscera. After almost two decades of research, the etiology of this condition, now designated as "Reye's syndrome," remains obscure. Several recent studies2-6 have implicated salicylates as a causal factor in Reye's syndrome. Based on these investigations, the Surgeon General of the United States issued an advisory against salicylate use for children with influenza or chickenpox.7 In addition, the American Public Health Association and the Public Citizen Health Research Group advocated that warning labels should be required on products containing salicylates.8

A closer examination of the salicylate-Reye's syndrome studies discloses several questions about the validity of these investigations. In reviewing these studies, the Committee on Infectious Diseases of the American Academy of Pediatrics enumerated a number of potential biases that may have occurred in these studies,

REFERENCES

1 +
Reye RDK, Morgan G, Baral J:  Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood . Lancet 1963;;2:749-752.
2 +
Starko KM, Ray GC, Dominguez, et al:  Reye's syndrome and salicylate use . Pediatrics 1980;;66:859-864.
3 +
 Reye syndrome—Ohio, Michigan . MMWR 1980;;29:532, 537-539.
4 +
 National surveillance for Reye syndrome, 1981: Update, Reye syndrome and salicylate usage . MMWR 1982;;31:53-61.
5 +
Waldman RJ, Hall WN, McGee H, et al:  Aspirin as a risk factor in Reye's syndrome . JAMA 1982;;247:3089-3094.
6 +
Halpin TJ, Holtzhauer FJ, Campbell RJ, et al:  Reye's syndrome and medication use . JAMA 1982;;248:687-691.
7 +
 Surgeon General's advisory on the use of salicylates and Reye syndrome . MMWR 1982;; 31:289-290.
8 +
 American Public Health Association: Nader groups sue HHS over Reye's syndrome . Am Public Health Assoc 1982;;5:8.
9 +
Fulginiti VA, Brunell PA, Cherry JD, et al:  Aspirin and Reye syndrome . Pediatrics 1982;; 69:822-825.
10 +
Wilson JT, Brown RD:  Reye syndrome and aspirin use: The role of prodromal illness severity in the assessment of relative risk . Pediatrics 1982;;69:822-825.
11 +
 Diagnosis and treatment of Reye's syndrome . JAMA 1981;;246:2441-2444.
12 +
Bulugahapitiya DTD, Hebron B, Beck PR:  Salicylate hepatitis with acidosis in an infant . Lancet 1979;;1:1295-1296.
13 +
Bernstein BH, Singsen BH, King KK, et al:  Aspirin-induced hepatotoxicity and its effect on juvenile rheumatoid arthritis . Am J Dis Child 1977;;131:659-663.
14 +
Schaller JG:  Chronic salicylate administration in juvenile rheumatoid arthritis: Aspirin 'hepatitis' and its clinical significance . Pediatrics 1978;;62:916-925.
15 +
Rich R, Johnson J:  Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis . Arthritis Rheum 1973;;16:1-9.
16 +
Mortimer EA, Lepow ML:  Varicella with hypoglycemia possibly due to salicylates . Am J Dis Child 1962;;103:583-590.
17 +
Cotton E, Fahlberg V:  Hypoglycemia with salicylate poisoning . Am J Dis Child 1964;; 108:171-173.
18 +
Glick TH, Likosky WH, Levitt LP, et al:  Reye's syndrome: An epidemiologic approach . Pediatrics 1970;;46:371-377.
19 +
Linnemann CC Jr, Shea L, Partin JC, et al:  Reye's syndrome: Epidemiologic and viral studies, 1963-1974 . Am J Epidemiol 1975;;101:517-526.
20 +
Cornfield J:  A method of estimating comparative rates from clinical data: Applications to cancer of the lung, breast and cervix . JNCI 1951;;11:1269-1275.
21 +
Kupper LL, Karon JM, Kleinbaum DG, et al:  Matching in epidemiologic studies: Validity and efficiency considerations . Biometrics 1981;; 37:271-291.
22 +
Hill AB:  The environment and disease: Association or causation? Proc R Soc Med 1965;;58:295-300.
23 +
Ury HK:  Efficiency of case-control studies with multiple controls per case: Continuous or dichotomous data . Biometrics 1975;;31:643-649.
24 +
Sokol RJ, Heubi JE, Ferrell MK, et al:  Reye's syndrome: Primary cause of vomiting and hepatic dysfunction following varicella or URI . Pediatr Res 1982;;16:178A.
25 +
Kleinbaum DG, Kupper LL, Morgenstern H: Quantitative Methods in Epidemiology . Belmont, Calif, Lifetime Learning Publications, 1982;.
26 +
Kleinbaum DG, Morgenstern H, Kupper LL:  Selection bias in epidemiologic research . Am J Epidemiol 1981;;113:452-463.
27 +
Schoenbaum SC, Bianco S, Mack T:  Epidemiology of congenital rubella syndrome . JAMA 1975;;233:151-155.
28 +
Copeland KT, Checkoway H, McMichael AJ, et al:  Bias due to misclassification in the estimation of relative risk . Am J Epidemiol 1977;;105:488-495.
29 +
Sartwell PE:  Retrospective studies: A review for the clinician . Ann Intern Med 1974;; 81:381-386.
30 +
Sackett DL:  Bias in analytic research . J Chronic Dis 1979;;32:51-63.
31 +
Day E, Maddern L, Wood C:  Auscultation of foetal heart rate: An assessment of its error and significance . Br Med J 1968;;4:422-424.
32 +
Chambless LE, Greenberg BG:  Statistical methods in the study of toxic shock syndrome . Ann Intern Med 1982;;96:912-917.
33 +
Sullivan-Bolyai JZ, Corey L:  Epidemiology of Reye syndrome . Epidemiol Rev 1981;;3:1-26.
34 +
Cornfield J, Haenszel W:  Some aspects of retrospective studies . J Chronic Dis 1960;;11:523-534.

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1 +
Reye RDK, Morgan G, Baral J:  Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood . Lancet 1963;;2:749-752.
2 +
Starko KM, Ray GC, Dominguez, et al:  Reye's syndrome and salicylate use . Pediatrics 1980;;66:859-864.
3 +
 Reye syndrome—Ohio, Michigan . MMWR 1980;;29:532, 537-539.
4 +
 National surveillance for Reye syndrome, 1981: Update, Reye syndrome and salicylate usage . MMWR 1982;;31:53-61.
5 +
Waldman RJ, Hall WN, McGee H, et al:  Aspirin as a risk factor in Reye's syndrome . JAMA 1982;;247:3089-3094.
6 +
Halpin TJ, Holtzhauer FJ, Campbell RJ, et al:  Reye's syndrome and medication use . JAMA 1982;;248:687-691.
7 +
 Surgeon General's advisory on the use of salicylates and Reye syndrome . MMWR 1982;; 31:289-290.
8 +
 American Public Health Association: Nader groups sue HHS over Reye's syndrome . Am Public Health Assoc 1982;;5:8.
9 +
Fulginiti VA, Brunell PA, Cherry JD, et al:  Aspirin and Reye syndrome . Pediatrics 1982;; 69:822-825.
10 +
Wilson JT, Brown RD:  Reye syndrome and aspirin use: The role of prodromal illness severity in the assessment of relative risk . Pediatrics 1982;;69:822-825.
11 +
 Diagnosis and treatment of Reye's syndrome . JAMA 1981;;246:2441-2444.
12 +
Bulugahapitiya DTD, Hebron B, Beck PR:  Salicylate hepatitis with acidosis in an infant . Lancet 1979;;1:1295-1296.
13 +
Bernstein BH, Singsen BH, King KK, et al:  Aspirin-induced hepatotoxicity and its effect on juvenile rheumatoid arthritis . Am J Dis Child 1977;;131:659-663.
14 +
Schaller JG:  Chronic salicylate administration in juvenile rheumatoid arthritis: Aspirin 'hepatitis' and its clinical significance . Pediatrics 1978;;62:916-925.
15 +
Rich R, Johnson J:  Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis . Arthritis Rheum 1973;;16:1-9.
16 +
Mortimer EA, Lepow ML:  Varicella with hypoglycemia possibly due to salicylates . Am J Dis Child 1962;;103:583-590.
17 +
Cotton E, Fahlberg V:  Hypoglycemia with salicylate poisoning . Am J Dis Child 1964;; 108:171-173.
18 +
Glick TH, Likosky WH, Levitt LP, et al:  Reye's syndrome: An epidemiologic approach . Pediatrics 1970;;46:371-377.
19 +
Linnemann CC Jr, Shea L, Partin JC, et al:  Reye's syndrome: Epidemiologic and viral studies, 1963-1974 . Am J Epidemiol 1975;;101:517-526.
20 +
Cornfield J:  A method of estimating comparative rates from clinical data: Applications to cancer of the lung, breast and cervix . JNCI 1951;;11:1269-1275.
21 +
Kupper LL, Karon JM, Kleinbaum DG, et al:  Matching in epidemiologic studies: Validity and efficiency considerations . Biometrics 1981;; 37:271-291.
22 +
Hill AB:  The environment and disease: Association or causation? Proc R Soc Med 1965;;58:295-300.
23 +
Ury HK:  Efficiency of case-control studies with multiple controls per case: Continuous or dichotomous data . Biometrics 1975;;31:643-649.
24 +
Sokol RJ, Heubi JE, Ferrell MK, et al:  Reye's syndrome: Primary cause of vomiting and hepatic dysfunction following varicella or URI . Pediatr Res 1982;;16:178A.
25 +
Kleinbaum DG, Kupper LL, Morgenstern H: Quantitative Methods in Epidemiology . Belmont, Calif, Lifetime Learning Publications, 1982;.
26 +
Kleinbaum DG, Morgenstern H, Kupper LL:  Selection bias in epidemiologic research . Am J Epidemiol 1981;;113:452-463.
27 +
Schoenbaum SC, Bianco S, Mack T:  Epidemiology of congenital rubella syndrome . JAMA 1975;;233:151-155.
28 +
Copeland KT, Checkoway H, McMichael AJ, et al:  Bias due to misclassification in the estimation of relative risk . Am J Epidemiol 1977;;105:488-495.
29 +
Sartwell PE:  Retrospective studies: A review for the clinician . Ann Intern Med 1974;; 81:381-386.
30 +
Sackett DL:  Bias in analytic research . J Chronic Dis 1979;;32:51-63.
31 +
Day E, Maddern L, Wood C:  Auscultation of foetal heart rate: An assessment of its error and significance . Br Med J 1968;;4:422-424.
32 +
Chambless LE, Greenberg BG:  Statistical methods in the study of toxic shock syndrome . Ann Intern Med 1982;;96:912-917.
33 +
Sullivan-Bolyai JZ, Corey L:  Epidemiology of Reye syndrome . Epidemiol Rev 1981;;3:1-26.
34 +
Cornfield J, Haenszel W:  Some aspects of retrospective studies . J Chronic Dis 1960;;11:523-534.

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