4 Hall SM, Lynn R. Reye's syndrome. In: Guy M, Nicoll A, Lynn R, eds. British ... Malcolm Molyneux, Terrie Taylor. *Division of Biochemistry and Molecular.
CORRESPONDENCE
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Fardella CE, Mosso L, Gomez-Sanchez CE, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile and molecular biology. J Clin Endocrinol Metab 2000; 85: 1863–67. Lim PO, Dow E. Brennan G. Jung RT MacDonald TM. High prevalence of primary aldosteronism in the Tayside hypertension clinic population. J Hum Hypertens 2000; 14: 311–15. Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young WF. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 2000; 85: 2854–59. Nishikawa T, Omura M. Clinical characteristics of primary aldosteronism: its prevalence and comparative studies on various causes of primary aldosteronism in Yokohama Rosai Hospital. Biomed Pharmacother 2000; 54 (suppl 1): 83–85.
Reye’s syndrome Sir—Ian Clark and colleagues’ hypothesis and speculations (Feb 24, p 625)1 are based partly on an outdated concept of Reye’s syndrome. Reye’s syndrome is not a severe sepsislike disease, as they describe it, but a syndrome, characterised by the combination of liver pathology and non-inflammatory encephalopathy.2 The non-specificity of this case definition covers a wide range of differential diagnoses. Even Reye and colleagues in their original paper stressed the non-specific character of the pathological findings, and stated that the fatty changes in the liver can be a secondary manifestation of a variety of diseases. These days, Reye’s syndrome is thought of as a descriptive term covering a group of heterogeneous disorders caused by infectious, metabolic, toxic, or druginduced disease.3 Also S Hall and colleagues4 agree that a case of Reye’s syndrome can rarely, if ever, be described as confirmed. Hence, what do Clark and colleagues mean by an authentic case of Reye’s syndrome? And what is the value of their conclusion based on one patient with clinically defined Reye’s syndrome? The link between Reye’s syndrome and acetylsalicylate is far from being proven. The epidemiological studies suggesting this link have been done on a heterogeneous group of children, which strongly weakens their validity. Moreover, by analysis of these studies, evidence was given that not only the use of acetylsalicylate, but also that of antiemetics was significantly greater in Reye’s syndrome cases than in controls.3 As to the decline of Reye’s syndrome, workers in several studies showed that this syndrome was
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overdiagnosed and over-reported at a time of extreme publicity, and that the proportion of definite compared with presumptive diagnosis varies between 0% and 62%. The apparent decline is, therefore, clearly related to medical progress, namely to more accurate modern diagnosis and recognition of infections as well as metabolic and toxic disease.3 Our greatest worry concerns the fate of febrile African children with or without malaria. By not giving children salicylates, do Clark and colleagues mean withholding all antipyretics, or do they mean replacing salicylates by other antipyretics, possibly resulting in toxic fulminant hepatic failure?5 *Maria Casteels-Van Daele, Christel Van Geet, Carine Wouters, Ephrem Eggermont Department of Paediatrics, University Hospital Gasthuisberg, B-3000 Leuven, Belgium 1
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Clark I, Whitten R, Molyneux M, Taylor T. Salicylates, nitric oxide, malaria, and Reye’s syndrome. Lancet 2001; 357: 625–27. National lnstitutes of Health. Diagnosis and treatment of Reye’s syndrome. JAMA 1981; 246: 2441–44. Casteels-Van Daele M, Van Geet C, Wouters C, Eggermont E. Reye syndrome revisited: a descriptive term covering a group of heterogeneous disorders. Eur J Pediatr 2000; 159: 641–48. Hall SM, Lynn R. Reye’s syndrome. In: Guy M, Nicoll A, Lynn R, eds. British paediatric surveillance unit 11th annual report. London: Royal College of Paediatrics and Child Health, 1997: 24–26. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300–04.
Authors’ reply Sir—We agree that the term Reye’s syndrome should not be used as if describing a homogeneous or defined syndrome, and did not intend to give the impression that we view it as such. We came to this area through an interest in understanding the pathophysiology of malaria, a disease that, like sepsis, is beginning to be discussed in terms of excessive generation of the inducible form of nitric oxide synthase (iNOS). Given the striking clinical similarity noted between childhood falciparum malaria and salicylate toxic effects,1 we have introduced the notion that the capacity of acetyl salicylate to increase induction of iNOS by interferon gamma2 might help to explain this congruency. Moreover, we have suggested that when contrasted with the well recognised reduction in iNOS generation through the NF- B by salicylates,3 this enhancement2 might help to explain the paradox by which
this useful anti-inflammatory drug sometimes generates a proinflammatory, sepsis-like disease.4 This implies that children (see our previous child vs adult arguments in our Hypothesis) might be unusually sensitive to salicylate toxic effects when they are carrying particularly high levels of interferon-gamma, and that malaria might be included in the list of systemic infections that could, in theory, bring this about. Such severe reactions in infected children given aspirin are, of course, exceptional, and, as we note, might occur only in the presence of a particular sequence or quantitative pattern of interacting stimuli, or when an as yet unrecognised inborn metabolic defect is also present. Nevertheless these concepts offer a novel insight into the paradox of salicylate possessing both antiinflammatory and proinflammatory properties, and in our view carry implications that warrant further study, for the possibility of sensitivity to salicylate toxic effects in childhood malaria. Exacerbation by salicylate of experimental infections with another tropical protozoan parasite, Trypanosoma brucei, has now been reported.5 As Quart and colleagues note, this carries reservations for the use of salicylates in trypanosome infection, and it may set a precedent for the principle we are suggesting. *Ian Clark, Richard Whitten, Malcolm Molyneux, Terrie Taylor *Division of Biochemistry and Molecular Biology, School of Life Sciences, Australian National University, Canberra, Australian Capital Territory 0200, Australia; Black Hills Pathology, Olympia, WA, USA; Wellcome Trust Research Laboratories, College of Medicine, University of Malawi, Malawi; School of Tropical Medicine, University of Liverpool, UK; and Michigan State University, East Lansing MI, USA 1
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English M, Marsh V, Amukoye E, Lowe B, Murphy S, Marsh K. Chronic salicylate poisoning and severe malaria. Lancet 1996; 347: 1736–37. Chen LC, Kepka LD, Wright TM, Morris SM. Salicylate-enhanced activation of transcription factors induced by interferon-gamma. Biochem J 1999; 432: 503–07. de Miguel LS, de Frutos T, Gonzalez FF. Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor-alpha release by cultured smooth muscle cells. Eur J Clin Invest 1999; 29: 93–99. Chalasani N, Roman J, Jurado RL. Systemic inflammatory response syndrome caused by chronic salicylate intoxication, South Med J 1996; 89: 479–82, Quart N, Mhlanga JDK Whiteside MB, Kristensson K, Herkenharn M. Chronic sodium salicylate treatment exacerbates brain neurodegeneration in rats infected with Trypanosoma brucei. Neurosci 2000; 96: 181–94.
THE LANCET • Vol 358 • July 28, 2001
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